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Immune system gene polymorphisms associated with severe dengue in Latin America: a systematic review

ABSTRACT

One of the main challenges in the clinical management of dengue is the early identification of cases that could progress to severe forms of the disease. A biomarker that may enable this identification is the presence of genetic polymorphisms in genes associated with immune responses. The objective of this study was to perform a systematic review of the Latin American literature on these genes. An electronic literature search was carried out in PubMed, Scopus, Lilacs, and the Virtual Health Library, and reference lists of systematic reviews in the area. Case-control studies conducted in Latin American countries examining at least one form of genetic polymorphism related to immune responses against severe dengue were included. In total, 424 articles were identified and 26 were included in this systematic review. Of the 26 selected articles, 16 reported polymorphisms associated with the risk of developing severe dengue (Risk); Similarly, 16 articles reported polymorphisms associated with a decreased risk of severe dengue (Protective). The final analysis revealed that multiple polymorphisms in immune system genes were early markers of the progression of dengue in Latin Americans and found that polymorphisms of the TNF-alpha gene may have a critical role in dengue pathogenesis.

Dengue; Polymorphism; Immunity

BACKGROUND

The bite of Aedes mosquitoes, which can be found in more than 100 countries, transmits an RNA-type virus that causes acute dengue and belongs to the Flaviviridae family11. Huang CH, Tsai YT, Wang SF, Wang WH, Chen YH. Dengue vaccine: an update. Expert Rev Anti Infect Ther. 2021;19:1495-502.. It is estimated that about 3 billion people live in areas with increased dengue risk22. Simmons CP, Farrar JJ, Nguyen VC, Wills B. Dengue. N Engl J Med. 2012;366:1423-32.. While around 390 million new cases are reported yearly, roughly 75% are asymptomatic and not included in each nation’s official statistics33. Harapan H, Michie A, Sasmono RT, Imrie A. Dengue: a minireview. Viruses. 2020;12:829.. This means that about 96 million dengue infection cases occur annually, with symptoms requiring health care attention44. Shepard DS, Undurraga EA, Halasa YA, Stanaway JD. The global economic burden of dengue: a systematic analysis. Lancet Infect Dis. 2016;16:935-41.. In the Americas, 1,173,674 dengue cases were reported in 2021, of which 2,821 (0.24%) were severe dengue cases55. Cabrera M, Leake J, Naranjo-Torres J, Valero N, Cabrera JC, Rodríguez-Morales AJ. Dengue prediction in Latin America using machine learning and the one health perspective: a literature review. Trop Med Infect Dis. 2022;7:322..

The following factors have been found to increase the severity of the clinical manifestations of dengue: Antibody Dependent Enhancement (ADE)66. Halstead SB. Immune enhancement of viral infection. Prog Allergy. 1982;31:301-64.; the immune response mediated by the dengue virus (DENV) serotype that first infects a patient (DENV1, DENV2, DENV3, DENV4) and the order of subsequent infections77. Burke DS, Nisalak A, Johnson DE, Scott RM. A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg. 1988;38:172-80.

8. González D, Castro OE, Kourí G, Perez J, Martinez E, Vazquez S, et al. Classical dengue hemorrhagic fever resulting from two dengue infections spaced 20 years or more apart: Havana, dengue 3 epidemic, 2001-2002. Int J Infect Dis. 2005;9:280-5.

9. Peláez O, Guzmán MG, Kourí G, Pérez R, San Martin JL, Vázquez S, et al. Dengue 3 epidemic, Havana, 2001. Emerg Infect Dis. 2004;10:719-22.
-1010. Sangkawibha N, Rojanasuphot S, Ahandrik S, Viriyapongse S, Jatanasen S, Salitul V, et al. Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am J Epidemiol. 1984;120:653-69.; age at the moment of the disease1111. Filomatori CV, Lodeiro MF, Alvarez DE, Samsa MM, Pietrasanta L, Gamarnik AV. A 5’ RNA element promotes dengue virus RNA synthesis on a circular genome. Genes Dev. 2006;20:2238-49.

12. Pothapregada S, Kamalakannan B, Thulasingham M. Risk factors for shock in children with dengue fever. Indian J Crit Care Med. 2015;19:661-4.

13. Gupta V, Yadav TP, Pandey RM, Singh A, Gupta M, Kanaujiya P, et al. Risk factors of dengue shock syndrome in children. J Trop Pediatr. 2011;57:451-6.
-1414. Wakimoto MD, Camacho LA, Guaraldo L, Damasceno LS, Brasil P. Dengue in children: a systematic review of clinical and laboratory factors associated with severity. Expert Rev Anti Infect Ther. 2015;13:1441-56.; pre-existing co-morbidities (especially diabetes and renal disease); and the presence of warning signs. Additionally, the clinical signs of a secondary dengue infection are often minor when it occurs less than two years after the first1515. Alvarez M, Rodriguez-Roche R, Bernardo L, Vázquez S, Morier L, Gonzalez D, et al. Dengue hemorrhagic fever caused by sequential dengue 1-3 virus infections over a long time interval: Havana epidemic, 2001-2002. Am J Trop Med Hyg. 2006;75:1113-7.,1616. Guzman MG, Alvarez M, Halstead SB. Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection. Arch Virol. 2013;158:1445-59.; however, intervals between two infections greater than four years have been linked to more severe clinical manifestations1717. Gibbons RV, Kalanarooj S, Jarman RG, Nisalak A, Vaughn DW, Endy TP, et al. Analysis of repeat hospital admissions for dengue to estimate the frequency of third or fourth dengue infections resulting in admissions and dengue hemorrhagic fever, and serotype sequences. Am J Trop Med Hyg. 2007;77:910-3..

The presence of allelic variants in the coding sequences for the major histocompatibility complex type B (MIC-B) and for phosphoinositide phospholipase C epsilon 1 (PLCE1)1818. Khor CC, Chau TN, Pang J, Davila S, Long HT, Ong RT, et al. Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1. Nat Genet. 2011;43:1139-41., as well as African ancestry1919. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13:e1006220.,2020. Halstead SB, Streit TG, Lafontant JG, Putvatana R, Russell K, Sun W, et al. Haiti: absence of dengue hemorrhagic fever despite hyperendemic dengue virus transmission. Am J Trop Med Hyg. 2001;65:180-3., are findings that link the individual’s genetic profile with the severity of dengue in individuals. Other genes control the inflammatory response, such as CD209, which produces the DC-SIGN dendritic cell receptor, and the tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine involved in the regulation of immune responses, cell proliferation, differentiation, and apoptosis. These genes also seem to have an essential role in controlling individuals’ susceptibility to severe dengue. Additional examples of genes involved in the control of dengue are the FcRIIA, which codes for Fc-type receptors expressed in antigen-presenting cells and is directly involved in the mechanisms of antibody-dependent enhancement (ADE)2121. Wang TT, Sewatanon J, Memoli MJ, Wrammert J, Bournazos S, Bhaumik SK, et al. IgG antibodies to dengue enhanced for FcgammaRIIIA binding determine disease severity. Science. 2017;355:395-8., and genes that encode for toll-like receptors (TLRs), which are involved in the activation of innate immunity cells.

No specific treatment for dengue has been established to date, and the development of prophylactic vaccines is still incipient in managing the disease2222. Foucambert P, Esbrand FD, Zafar S, Panthangi V, Kurupp AR, Raju A, et al. Efficacy of dengue vaccines in the prevention of severe dengue in children: a systematic review. Cureus. 2022;14:e28916.. In fact, incidences of dengue continue to increase, and the virus that causes it is still widely spread2323. Saydam FN, Erdem H, Ankarali H, El-Arab Ramadan ME, El-Sayed NM, Civljak R, et al. Vector-borne and zoonotic infections and their relationships with regional and socioeconomic statuses: an ID-IRI survey in 24 countries of Europe, Africa and Asia. Travel Med Infect Dis. 2021;44:102174.. In this scenario, it is essential to continue exploring mechanisms that allow the early identification of severe cases, to improve clinical approaches and directly reduce the mortality rates of the disease. Therefore, we conducted a systematic review of the current literature to identify the genetic variants linked to the emergence of severe dengue (dengue hemorrhagic fever and dengue shock) in Latin American populations.

MATERIALS AND METHODS

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines2424. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. (Supplementary Table S1). The protocol was not registered before this review.

Search strategy

An electronic literature search was conducted in PubMed, Scopus, Lilacs, and the Virtual Health Library (VHL - BVS in Spanish). VHL is a specific database for the Americas. A search of the reference lists of systematic reviews in the area was also conducted2525. Cahill ME, Conley S, DeWan AT, Montgomery RR. Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis. 2018;18:282.

26. Oliveira M, Saraiva DP, Cavadas B, Fernandes V, Pedro N, Casademont I, et al. Population genetics-informed meta-analysis in seven genes associated with risk to dengue fever disease. Infect Genet Evol. 2018;62:60-72.

27. Pabalan N, Chaisri S, Tabunhan S, Tarasuk M, Jarjanazi H, Steiner T. Associations of tumor necrosis factor- α-308 polymorphism with dengue infection: a systematic review anda meta-analysis. Acta Trop. 2017;173:17-22.
-2828. Santos AC, Moura EL, Ferreira JM, Santos BR, Alves VM, Farias KF, et al. Meta-analysis of the relationship between TNF-α (-308G/A) and IL-10 (-819C/T) gene polymorphisms and susceptibility to dengue. Immunol Invest. 2017;46:201-20., combining MeSH and DeCS descriptors on dengue, polymorphism and the countries of Latin America. Specific terms were used to search the four databases, emphasizing the search for titles and abstracts. The supplementary material contains the strategy applied to search each database (Supplementary Table S2). English and Spanish terms were combined:

  1. Dengue virus OR Dengue OR Severe Dengue

  2. Polymorphism, Genetic

  3. Argentina OR Argentinian OR Bolivia OR Bolivian OR Brazil OR Brazilian OR Chile OR Chilean OR Colombia OR Colombian OR Ecuador OR Ecuadorian OR Paraguay OR Paraguayan OR Uruguay OR Uruguayan OR Venezuela OR Venezuelan OR Dominican Republic OR Dominican OR Costa Rica OR Costa Rican OR Cuba OR Cuban OR El Salvador OR Salvadorian OR Guatemala OR Guatemalan OR Haiti OR Haitian OR Honduras OR Honduran OR Mexico OR Mexican OR Nicaragua OR Nicaraguan OR Panama OR Panamanian OR Peru OR Peruvian OR Latin America OR Central America OR Caribbean

  4. (#1) AND (#2) AND (#3)

Inclusion and exclusion criteria

Case-control studies conducted in a Latin American country that examined at least one genetic polymorphism related to immune responses to severe dengue were included. Our review only included studies that evaluated polymorphism with well-documented genetic tests: polymorphism detection with PCR-SSP (polymerase chain reaction-sequence specific of primers); RFLP (Restriction Fragment Length Polymorphism) for the restriction enzyme; qPCR (real-time PCR), and the Amplification-refractory mutation system (ARMS-PCR). Articles published up to November 3rd, 2022, were included in the review. Studies on non-human genetics (e.g., viral genetics, mosquito genetics), case reports, letters to the editor, and other non-observational studies were excluded. Studies that did not employ confirmatory tests for dengue were also excluded. Tests that adhered to the World Health Organization (WHO) guidelines2929. World Health Organization. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2 nd ed. Geneva: WHO; 1997. [cited 2023 Apr 25]. Available from: https://apps.who.int/iris/handle/10665/41988
https://apps.who.int/iris/handle/10665/4...
,3030. World Health Organization. Dengue guildelines for diagnosis, treatment, prevention and control: new edition. Geneva: WHO; 2009. [cited 2023 Apr 25]. Available from: https://apps.who.int/iris/handle/10665/44188
https://apps.who.int/iris/handle/10665/4...
, using methods such as viral isolation techniques, detection of antigens or antibodies, and nucleic acid detection, were considered appropriate. Lastly, studies using laboratory-confirmed IgM ELISA or IgG ELISA and reverse transcription polymerase chain reaction (RT–PCR) methods were also included.

Study selection

Two authors (JESF and LSGC) independently reviewed titles and abstracts and identified potentially relevant articles, resolving discrepancies through further review and mutual consensus. Both investigators fully read all potentially relevant articles and determined the final reports to be included in this review. The data sets were extracted and organized in bibliographic tables. The primary fields contained information on the authors, country, year of publication, sample size for each study group, study objective, molecular test to determine the genetic polymorphism, the polymorphism evaluated, the group and type of immunity and WHO classification of the dengue cases (guideline 1997 or 2009). Types of immunity were classified according to Immunity Groups, which were based on the contributions of Harapan et al.33. Harapan H, Michie A, Sasmono RT, Imrie A. Dengue: a minireview. Viruses. 2020;12:829., and Bhat et al.3131. Bhatt P, Sabeena SP, Varma M, Arunkumar G. Current understanding of the pathogenesis of dengue virus infection. Curr Microbiol. 2021;78:17-32.: Group A) Innate immunity; Group A1) Interferons and interleukins; Group A2) Mannose-binding lectin (MLB2); Group A3) Others (histidine, serotonin, complement and nitric oxide); and Group B) Genetic (HLA).

Quality assessment

The quality of each study was assessed using the Newcastle-Ottawa Quality Assessment Scale for Case-Control Studies (NOS)3232. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle Ottawa Scale (NOS) for assessing the quality of non-randomised studies in meta-analyses. [cited 2023 Apr 25]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
http://www.ohri.ca/programs/clinical_epi...
, which evaluates the selection, comparability, and exposure determination of each study, and independently assessed by two authors (JESF and LSGC). Based on the NOS score and quality classification, the risk of bias in the initially selected studies was evaluated and classified as high risk (NOS≤6), some concerns (NOS=7), and low risk (NOS≥8). The study quality evaluation was summarized in a figure specifying whether studies met the criteria (green: low risk of bias), did not meet the criteria (red: high risk of bias), or if results were unclear (yellow: unclear risk/some concerns/lack). Supplementary Table S3 shows the scoring criteria based on the Newcastle scale.

RESULTS

Search results and article selection

In total, 424 bibliographic references were found: 97 in PubMed, 108 in Scopus, 20 in Lilacs, and 190 in VHL. Nine articles were obtained during the review of reference lists in systematic reviews of the area. A total of 185 studies were discarded due to duplication. Then, the remaining 230 articles were thoroughly reviewed. As a result, 26 articles met all the inclusion criteria (Figure 1).

Figure 1
PRISMA flowchart of the strategy used to identify papers assessing polymorphism genetics and severe dengue

Study characteristics

In total, 12 (46.2%) of the selected studies were conducted in Brazil3333. Cezar RD, Castanha PM, Freire NM, Mola C, Carmo RF, Cordeiro MT, et al. Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus-infected children. Int J Immunogenet. 2020;47:351-8.

34. Santos AC, Moura EL, Silva DM, Moura AW, Ferreira JM, Lira Neto AB, et al. Association of polymorphisms in serotonin and nitric oxide genes with clinical outcome of dengue in Brazilian northeast population. Acta Trop. 2019;190:144-8.

35. Figueiredo GG, Cezar RD, Freire NM, Teixeira VG, Baptista P, Cordeiro M, et al. Mannose-binding lectin gene (MBL2) polymorphisms related to the mannose-binding lectin low levels are associated to dengue disease severity. Hum Immunol. 2016;77:571-5.

36. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004.

37. Pastor AF, Moura LR, Neto JW, Nascimento EJ, Calzavara-Silva CE, Gomes AL, et al. Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression. Hum Immunol. 2013;74:1225-30.

38. Santos AC, Moura EL, Ferreira JM, Moura AW, Ferreira AD, Bezerra RP, et al. Association of TNFA (-308G/A), IFNG (+874 A/T) and IL-10 (-819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population. Asian Pac J Trop Med. 2017;10:1065-71.

39. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.

40. Xavier-Carvalho C, Cezar RD, Freire NM, Vasconcelos CM, Solorzano VE, Toledo-Pinto TG, et al. Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects. Hum Immunol. 2017;78:649-56.

41. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.

42. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9.

43. Silva LK, Blanton RE, Parrado AR, Melo PS, Morato VG, Reis EA, et al. Dengue hemorrhagic fever is associated with polymorphisms in JAK1. Eur J Hum Genet. 2010;18:1221-7.
-4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83.., seven in a Mexican population4545. Falcón-Lezama JA, Ramos C, Zuñiga J, Juárez-Palma L, Rangel-Flores H, García-Trejo AR, et al. HLA class I and II polymorphisms in Mexican Mestizo patients with dengue fever. Acta Trop. 2009;112:193-7.

46. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22.

47. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55.

48. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230.

49. Sánchez-Leyva M, Sánchez-Zazueta JG, Osuna-Ramos JF, Rendón-Aguilar H, Félix-Espinoza R, Becerra-Loaiza DS, et al. Genetic polymorphisms of tumor necrosis factor alpha and susceptibility to dengue virus infection in a Mexican population. Viral Immunol. 2017;30:615-21.

50. García-Trejo AR, Falcón-Lezama JA, Juárez-Palma L, Granados J, Zuñiga-Ramos J, Rangel H, et al. Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever. Acta Trop. 2011;120:67-71.
-5151. LaFleur C, Granados J, Vargas-Alarcon G, Ruíz-Morales J, Villarreal-Garza C, Higuera L, et al. HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol. 2002;63:1039-44., five in Cuba1919. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13:e1006220., 5252. García G, Sierra B, Pérez AB, Aguirre E, Rosado I, Gonzalez N, et al. Asymptomatic dengue infection in a Cuban population confirms the protective role of the RR variant of the FcgammaRIIa polymorphism. Am J Trop Med Hyg. 2010;82:1153-6.

53. García G, del Puerto F, Pérez AB, Sierra B, Aguirre E, Kikuchi M, et al. Association of MICA and MICB alleles with symptomatic dengue infection. Hum Immunol. 2011;72:904-7.

54. Sierra B, Alegre R, Pérez AB, García G, Sturn-Ramirez K, Obasanjo O, et al. HLA-A, -B, -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. Hum Immunol. 2007;68:531-40.
-5555. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, Alvarez M, et al. Tumor necrosis factor-alpha, transforming growth factor-beta1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever. Hum Immunol. 2010;71:1135-40., and two with a Venezuelan population5656. Fernández-Mestre M, Navarrete C, Brown J, Brown C, Correa E, Layrisse Z. HLA alleles and dengue virus infection in Venezuelan patients: a preliminary study. Inmunologia. 2009;28:96-100.,5757. Fernández-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 2004;64:469-72.. All of them were case-control studies, but one nested in a cohort4141. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.. Most studies applied WHO criteria to classify dengue cases2929. World Health Organization. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2 nd ed. Geneva: WHO; 1997. [cited 2023 Apr 25]. Available from: https://apps.who.int/iris/handle/10665/41988
https://apps.who.int/iris/handle/10665/4...
,3030. World Health Organization. Dengue guildelines for diagnosis, treatment, prevention and control: new edition. Geneva: WHO; 2009. [cited 2023 Apr 25]. Available from: https://apps.who.int/iris/handle/10665/44188
https://apps.who.int/iris/handle/10665/4...
, with only two articles not reporting this data4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..,5757. Fernández-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 2004;64:469-72.. Fifteen articles used the 1997 WHO dengue classification criteria1919. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13:e1006220.,3333. Cezar RD, Castanha PM, Freire NM, Mola C, Carmo RF, Cordeiro MT, et al. Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus-infected children. Int J Immunogenet. 2020;47:351-8.

34. Santos AC, Moura EL, Silva DM, Moura AW, Ferreira JM, Lira Neto AB, et al. Association of polymorphisms in serotonin and nitric oxide genes with clinical outcome of dengue in Brazilian northeast population. Acta Trop. 2019;190:144-8.
-3535. Figueiredo GG, Cezar RD, Freire NM, Teixeira VG, Baptista P, Cordeiro M, et al. Mannose-binding lectin gene (MBL2) polymorphisms related to the mannose-binding lectin low levels are associated to dengue disease severity. Hum Immunol. 2016;77:571-5.,3838. Santos AC, Moura EL, Ferreira JM, Moura AW, Ferreira AD, Bezerra RP, et al. Association of TNFA (-308G/A), IFNG (+874 A/T) and IL-10 (-819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population. Asian Pac J Trop Med. 2017;10:1065-71.,4343. Silva LK, Blanton RE, Parrado AR, Melo PS, Morato VG, Reis EA, et al. Dengue hemorrhagic fever is associated with polymorphisms in JAK1. Eur J Hum Genet. 2010;18:1221-7.,4747. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55.

48. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230.

49. Sánchez-Leyva M, Sánchez-Zazueta JG, Osuna-Ramos JF, Rendón-Aguilar H, Félix-Espinoza R, Becerra-Loaiza DS, et al. Genetic polymorphisms of tumor necrosis factor alpha and susceptibility to dengue virus infection in a Mexican population. Viral Immunol. 2017;30:615-21.

50. García-Trejo AR, Falcón-Lezama JA, Juárez-Palma L, Granados J, Zuñiga-Ramos J, Rangel H, et al. Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever. Acta Trop. 2011;120:67-71.

51. LaFleur C, Granados J, Vargas-Alarcon G, Ruíz-Morales J, Villarreal-Garza C, Higuera L, et al. HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol. 2002;63:1039-44.

52. García G, Sierra B, Pérez AB, Aguirre E, Rosado I, Gonzalez N, et al. Asymptomatic dengue infection in a Cuban population confirms the protective role of the RR variant of the FcgammaRIIa polymorphism. Am J Trop Med Hyg. 2010;82:1153-6.
-5353. García G, del Puerto F, Pérez AB, Sierra B, Aguirre E, Kikuchi M, et al. Association of MICA and MICB alleles with symptomatic dengue infection. Hum Immunol. 2011;72:904-7.,5555. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, Alvarez M, et al. Tumor necrosis factor-alpha, transforming growth factor-beta1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever. Hum Immunol. 2010;71:1135-40.,5656. Fernández-Mestre M, Navarrete C, Brown J, Brown C, Correa E, Layrisse Z. HLA alleles and dengue virus infection in Venezuelan patients: a preliminary study. Inmunologia. 2009;28:96-100., while only six considered the 2009 guidelines3636. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004.,3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.

40. Xavier-Carvalho C, Cezar RD, Freire NM, Vasconcelos CM, Solorzano VE, Toledo-Pinto TG, et al. Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects. Hum Immunol. 2017;78:649-56.

41. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.
-4242. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9.,4646. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22.. The remaining three studies applied the WHO guidelines from 19945454. Sierra B, Alegre R, Pérez AB, García G, Sturn-Ramirez K, Obasanjo O, et al. HLA-A, -B, -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. Hum Immunol. 2007;68:531-40., 20043737. Pastor AF, Moura LR, Neto JW, Nascimento EJ, Calzavara-Silva CE, Gomes AL, et al. Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression. Hum Immunol. 2013;74:1225-30., and 20084545. Falcón-Lezama JA, Ramos C, Zuñiga J, Juárez-Palma L, Rangel-Flores H, García-Trejo AR, et al. HLA class I and II polymorphisms in Mexican Mestizo patients with dengue fever. Acta Trop. 2009;112:193-7. (Table 1).

Table 1
Characteristics of the included papers assessing polymorphism genetics and severe dengue.

The number of people diagnosed with severe dengue in different studies ranged from 164545. Falcón-Lezama JA, Ramos C, Zuñiga J, Juárez-Palma L, Rangel-Flores H, García-Trejo AR, et al. HLA class I and II polymorphisms in Mexican Mestizo patients with dengue fever. Acta Trop. 2009;112:193-7. to 1434141. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.. Also, studies frequently included the general population and asymptomatic cases in their analyses1919. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13:e1006220.,3636. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004.

37. Pastor AF, Moura LR, Neto JW, Nascimento EJ, Calzavara-Silva CE, Gomes AL, et al. Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression. Hum Immunol. 2013;74:1225-30.

38. Santos AC, Moura EL, Ferreira JM, Moura AW, Ferreira AD, Bezerra RP, et al. Association of TNFA (-308G/A), IFNG (+874 A/T) and IL-10 (-819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population. Asian Pac J Trop Med. 2017;10:1065-71.
-3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.,4141. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.

42. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9.

43. Silva LK, Blanton RE, Parrado AR, Melo PS, Morato VG, Reis EA, et al. Dengue hemorrhagic fever is associated with polymorphisms in JAK1. Eur J Hum Genet. 2010;18:1221-7.

44. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..

45. Falcón-Lezama JA, Ramos C, Zuñiga J, Juárez-Palma L, Rangel-Flores H, García-Trejo AR, et al. HLA class I and II polymorphisms in Mexican Mestizo patients with dengue fever. Acta Trop. 2009;112:193-7.

46. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22.

47. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55.

48. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230.

49. Sánchez-Leyva M, Sánchez-Zazueta JG, Osuna-Ramos JF, Rendón-Aguilar H, Félix-Espinoza R, Becerra-Loaiza DS, et al. Genetic polymorphisms of tumor necrosis factor alpha and susceptibility to dengue virus infection in a Mexican population. Viral Immunol. 2017;30:615-21.
-5050. García-Trejo AR, Falcón-Lezama JA, Juárez-Palma L, Granados J, Zuñiga-Ramos J, Rangel H, et al. Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever. Acta Trop. 2011;120:67-71.,5252. García G, Sierra B, Pérez AB, Aguirre E, Rosado I, Gonzalez N, et al. Asymptomatic dengue infection in a Cuban population confirms the protective role of the RR variant of the FcgammaRIIa polymorphism. Am J Trop Med Hyg. 2010;82:1153-6.

53. García G, del Puerto F, Pérez AB, Sierra B, Aguirre E, Kikuchi M, et al. Association of MICA and MICB alleles with symptomatic dengue infection. Hum Immunol. 2011;72:904-7.

54. Sierra B, Alegre R, Pérez AB, García G, Sturn-Ramirez K, Obasanjo O, et al. HLA-A, -B, -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. Hum Immunol. 2007;68:531-40.

55. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, Alvarez M, et al. Tumor necrosis factor-alpha, transforming growth factor-beta1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever. Hum Immunol. 2010;71:1135-40.
-5656. Fernández-Mestre M, Navarrete C, Brown J, Brown C, Correa E, Layrisse Z. HLA alleles and dengue virus infection in Venezuelan patients: a preliminary study. Inmunologia. 2009;28:96-100.. The article by LaFleur et al.5151. LaFleur C, Granados J, Vargas-Alarcon G, Ruíz-Morales J, Villarreal-Garza C, Higuera L, et al. HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol. 2002;63:1039-44. is the oldest study in our review: it was carried out in 2002, while the most updated studies were conducted in 20203333. Cezar RD, Castanha PM, Freire NM, Mola C, Carmo RF, Cordeiro MT, et al. Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus-infected children. Int J Immunogenet. 2020;47:351-8.,4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..,4848. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230. (Table 1).

Figure 2
Summary of the assessment of risks of bias in the included articles. The classification is based on the Newcastle-Ottawa Quality Assessment Scale for Case-Control Studies (NOS).

The articles included in this review analyzed polymorphisms based on different immunological classifications: ten articles assessed polymorphisms with type A1 immunity (interferons and interleukins)3333. Cezar RD, Castanha PM, Freire NM, Mola C, Carmo RF, Cordeiro MT, et al. Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus-infected children. Int J Immunogenet. 2020;47:351-8.,3838. Santos AC, Moura EL, Ferreira JM, Moura AW, Ferreira AD, Bezerra RP, et al. Association of TNFA (-308G/A), IFNG (+874 A/T) and IL-10 (-819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population. Asian Pac J Trop Med. 2017;10:1065-71.,3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.,4343. Silva LK, Blanton RE, Parrado AR, Melo PS, Morato VG, Reis EA, et al. Dengue hemorrhagic fever is associated with polymorphisms in JAK1. Eur J Hum Genet. 2010;18:1221-7.,4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..,4747. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55.,4949. Sánchez-Leyva M, Sánchez-Zazueta JG, Osuna-Ramos JF, Rendón-Aguilar H, Félix-Espinoza R, Becerra-Loaiza DS, et al. Genetic polymorphisms of tumor necrosis factor alpha and susceptibility to dengue virus infection in a Mexican population. Viral Immunol. 2017;30:615-21.,5050. García-Trejo AR, Falcón-Lezama JA, Juárez-Palma L, Granados J, Zuñiga-Ramos J, Rangel H, et al. Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever. Acta Trop. 2011;120:67-71.,5555. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, Alvarez M, et al. Tumor necrosis factor-alpha, transforming growth factor-beta1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever. Hum Immunol. 2010;71:1135-40.,5757. Fernández-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 2004;64:469-72.; A2 immunity (Mannose-binding lectin - MLB2) was evaluated by Figueiredo et al.3535. Figueiredo GG, Cezar RD, Freire NM, Teixeira VG, Baptista P, Cordeiro M, et al. Mannose-binding lectin gene (MBL2) polymorphisms related to the mannose-binding lectin low levels are associated to dengue disease severity. Hum Immunol. 2016;77:571-5., Ornelas et al.3636. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004., and LaFleur et al.5151. LaFleur C, Granados J, Vargas-Alarcon G, Ruíz-Morales J, Villarreal-Garza C, Higuera L, et al. HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol. 2002;63:1039-44.; and eight articles included analyses on immunity group B (HLA Genetics)1919. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13:e1006220.,4141. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.,4242. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9.,4545. Falcón-Lezama JA, Ramos C, Zuñiga J, Juárez-Palma L, Rangel-Flores H, García-Trejo AR, et al. HLA class I and II polymorphisms in Mexican Mestizo patients with dengue fever. Acta Trop. 2009;112:193-7.,5252. García G, Sierra B, Pérez AB, Aguirre E, Rosado I, Gonzalez N, et al. Asymptomatic dengue infection in a Cuban population confirms the protective role of the RR variant of the FcgammaRIIa polymorphism. Am J Trop Med Hyg. 2010;82:1153-6.

53. García G, del Puerto F, Pérez AB, Sierra B, Aguirre E, Kikuchi M, et al. Association of MICA and MICB alleles with symptomatic dengue infection. Hum Immunol. 2011;72:904-7.
-5454. Sierra B, Alegre R, Pérez AB, García G, Sturn-Ramirez K, Obasanjo O, et al. HLA-A, -B, -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. Hum Immunol. 2007;68:531-40.,5656. Fernández-Mestre M, Navarrete C, Brown J, Brown C, Correa E, Layrisse Z. HLA alleles and dengue virus infection in Venezuelan patients: a preliminary study. Inmunologia. 2009;28:96-100.. The remaining articles covered other immunities, including histidine, serotonin, complement, and nitric oxide3434. Santos AC, Moura EL, Silva DM, Moura AW, Ferreira JM, Lira Neto AB, et al. Association of polymorphisms in serotonin and nitric oxide genes with clinical outcome of dengue in Brazilian northeast population. Acta Trop. 2019;190:144-8.,3737. Pastor AF, Moura LR, Neto JW, Nascimento EJ, Calzavara-Silva CE, Gomes AL, et al. Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression. Hum Immunol. 2013;74:1225-30.,3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.,4646. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22.,4848. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230. (Table 1).

Eight of the studies in our systematic review specifically investigated the association between TNF-alpha gene polymorphisms and severe dengue in Latin America. These studies focused on various single nucleotide polymorphisms (SNPs) within the TNF-alpha gene, including -308G>A, -238G>A, -857C>T, and -1031T>C. The results of these studies varied: while some reported significant associations between specific TNF-alpha SNPs and severe dengue, others found no significant correlations between these two factors. This heterogeneity may have resulted from differences in study populations, sample sizes, and genotyping techniques.

Table 1 shows that the most used genotyping method was the real-time polymerase chain reaction (qRT-PCR), employed in 14 studies1919. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13:e1006220.,3333. Cezar RD, Castanha PM, Freire NM, Mola C, Carmo RF, Cordeiro MT, et al. Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus-infected children. Int J Immunogenet. 2020;47:351-8.

34. Santos AC, Moura EL, Silva DM, Moura AW, Ferreira JM, Lira Neto AB, et al. Association of polymorphisms in serotonin and nitric oxide genes with clinical outcome of dengue in Brazilian northeast population. Acta Trop. 2019;190:144-8.

35. Figueiredo GG, Cezar RD, Freire NM, Teixeira VG, Baptista P, Cordeiro M, et al. Mannose-binding lectin gene (MBL2) polymorphisms related to the mannose-binding lectin low levels are associated to dengue disease severity. Hum Immunol. 2016;77:571-5.
-3636. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004.,3838. Santos AC, Moura EL, Ferreira JM, Moura AW, Ferreira AD, Bezerra RP, et al. Association of TNFA (-308G/A), IFNG (+874 A/T) and IL-10 (-819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population. Asian Pac J Trop Med. 2017;10:1065-71.

39. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.

40. Xavier-Carvalho C, Cezar RD, Freire NM, Vasconcelos CM, Solorzano VE, Toledo-Pinto TG, et al. Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects. Hum Immunol. 2017;78:649-56.

41. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.
-4242. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9.,4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..,4646. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22.

47. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55.
-4848. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230.. Four studies used the polymerase chain reaction–sequence-specific oligonucleotide (PCR-SSO)4545. Falcón-Lezama JA, Ramos C, Zuñiga J, Juárez-Palma L, Rangel-Flores H, García-Trejo AR, et al. HLA class I and II polymorphisms in Mexican Mestizo patients with dengue fever. Acta Trop. 2009;112:193-7.,5151. LaFleur C, Granados J, Vargas-Alarcon G, Ruíz-Morales J, Villarreal-Garza C, Higuera L, et al. HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol. 2002;63:1039-44.,5252. García G, Sierra B, Pérez AB, Aguirre E, Rosado I, Gonzalez N, et al. Asymptomatic dengue infection in a Cuban population confirms the protective role of the RR variant of the FcgammaRIIa polymorphism. Am J Trop Med Hyg. 2010;82:1153-6.,5656. Fernández-Mestre M, Navarrete C, Brown J, Brown C, Correa E, Layrisse Z. HLA alleles and dengue virus infection in Venezuelan patients: a preliminary study. Inmunologia. 2009;28:96-100.. Other genotyping methods were the polymerase chain reaction with sequence specific primers (PCR-SSP)5454. Sierra B, Alegre R, Pérez AB, García G, Sturn-Ramirez K, Obasanjo O, et al. HLA-A, -B, -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. Hum Immunol. 2007;68:531-40.,5555. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, Alvarez M, et al. Tumor necrosis factor-alpha, transforming growth factor-beta1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever. Hum Immunol. 2010;71:1135-40.,5757. Fernández-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 2004;64:469-72. and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)4949. Sánchez-Leyva M, Sánchez-Zazueta JG, Osuna-Ramos JF, Rendón-Aguilar H, Félix-Espinoza R, Becerra-Loaiza DS, et al. Genetic polymorphisms of tumor necrosis factor alpha and susceptibility to dengue virus infection in a Mexican population. Viral Immunol. 2017;30:615-21.,5050. García-Trejo AR, Falcón-Lezama JA, Juárez-Palma L, Granados J, Zuñiga-Ramos J, Rangel H, et al. Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever. Acta Trop. 2011;120:67-71..

Quality of the studies

In total, 46.2% of the 26 articles (n=12) presented some concern or risk of bias in their selection of cases and controls. The selection of cases was mainly based on WHO criteria from 1997 or 2009, with clinical confirmation through RT-PCR tests. In their assessment of comparability between groups, 34.6% of studies had a high risk of bias. Lastly, 96.2% of the studies presented some concern or a high risk of bias in their exposure assessment—they did not present any information on losing participants. Supplementary Table S4 presents the eight quality review criteria for each study included in this review.

DISCUSSION

This systematic review demonstrated the existence of multiple polymorphisms in immune system genes that are related to the clinical outcomes of dengue virus infections. As Table 1 summarizes, 17 of the 26 articles reported finding polymorphisms that are associated with the risk of severe dengue (Risk) and 17 articles reported detecting polymorphisms that are associated with a decreased risk of severe dengue (Protective). Notably, most of these studies were conducted in Brazil (n=12).

Regarding the immune response in dengue virus infection, both innate and adaptive responses play an essential role in defending organisms infected with severe dengue, and that the regulation of these responses directly impacts the clinical outcome of the disease5858. Murphy BR, Whitehead SS. Immune response to dengue virus and prospects for a vaccine. Annu Rev Immunol. 2011;29:587-619.. One of the first mechanisms employed by the innate immune system is the production of interferon and proinflammatory cytokines to trigger the initial response against the virus through dendritic cells5959. Costa VV, Fagundes CT, Souza DG, Teixeira MM. Inflammatory and innate immune responses in dengue infection: protection versus disease induction. Am J Pathol. 2013;182:1950-61.. However, this mechanism may lead to cell permeability and fluid leakage.

Most genes reported in the analyzed studies are related to the innate immune response. Polymorphisms in Toll-like receptors responsible for recognizing viral proteins4848. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230.; genes associated with the production of interleukins capable of inhibiting the synthesis of proinflammatory cytokines and suppressing the ability of cells to present antigens3333. Cezar RD, Castanha PM, Freire NM, Mola C, Carmo RF, Cordeiro MT, et al. Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus-infected children. Int J Immunogenet. 2020;47:351-8.,3434. Santos AC, Moura EL, Silva DM, Moura AW, Ferreira JM, Lira Neto AB, et al. Association of polymorphisms in serotonin and nitric oxide genes with clinical outcome of dengue in Brazilian northeast population. Acta Trop. 2019;190:144-8.,3838. Santos AC, Moura EL, Ferreira JM, Moura AW, Ferreira AD, Bezerra RP, et al. Association of TNFA (-308G/A), IFNG (+874 A/T) and IL-10 (-819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population. Asian Pac J Trop Med. 2017;10:1065-71.,3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.,4343. Silva LK, Blanton RE, Parrado AR, Melo PS, Morato VG, Reis EA, et al. Dengue hemorrhagic fever is associated with polymorphisms in JAK1. Eur J Hum Genet. 2010;18:1221-7.,4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..,4949. Sánchez-Leyva M, Sánchez-Zazueta JG, Osuna-Ramos JF, Rendón-Aguilar H, Félix-Espinoza R, Becerra-Loaiza DS, et al. Genetic polymorphisms of tumor necrosis factor alpha and susceptibility to dengue virus infection in a Mexican population. Viral Immunol. 2017;30:615-21.,5050. García-Trejo AR, Falcón-Lezama JA, Juárez-Palma L, Granados J, Zuñiga-Ramos J, Rangel H, et al. Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever. Acta Trop. 2011;120:67-71.,5555. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, Alvarez M, et al. Tumor necrosis factor-alpha, transforming growth factor-beta1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever. Hum Immunol. 2010;71:1135-40.,5757. Fernández-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 2004;64:469-72.; and genes coding for surface proteins in multiple cells of the immune system, such as the type C lecithin receptor (DC-SIGN)3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.,4646. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22.,4747. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55., MBL23535. Figueiredo GG, Cezar RD, Freire NM, Teixeira VG, Baptista P, Cordeiro M, et al. Mannose-binding lectin gene (MBL2) polymorphisms related to the mannose-binding lectin low levels are associated to dengue disease severity. Hum Immunol. 2016;77:571-5.,3636. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004. (it should be noted that Ornelas et al.3636. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004. only observed such an association after haplotype analyses), and CLEC5A3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.,4040. Xavier-Carvalho C, Cezar RD, Freire NM, Vasconcelos CM, Solorzano VE, Toledo-Pinto TG, et al. Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects. Hum Immunol. 2017;78:649-56.,4646. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22.,4747. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55.. One study also reported a protective effect mediated by complement3737. Pastor AF, Moura LR, Neto JW, Nascimento EJ, Calzavara-Silva CE, Gomes AL, et al. Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression. Hum Immunol. 2013;74:1225-30..

The substantial number of studies focused on TNF-alpha gene polymorphisms in this review highlights the importance of this cytokine in severe dengue pathogeneses. The inconsistent findings among these studies call attention to the complexity of the role of TNF-alpha in individuals’ susceptibility to severe dengue and the need for further investigation. Larger, multi-center studies with standardized methodologies and thorough genetic analysis are needed to clarify the association between TNF-alpha gene polymorphisms and severe dengue risks. Future research should also explore the role of interactions between TNF-alpha polymorphisms and other immune system genes in the pathogenesis of dengue, to further elucidate the genetic factors influencing individuals’ susceptibility to severe dengue.

Concerning cellular immunity, the activation of CD4+ and CD8+ T lymphocytes is essential for eliminating infected cells. However, T cells may cause immunopathology during DENV infections, in a phenomenon called original antigenic sin, in which the activation of memory lymphocytes generates an elevated production of proinflammatory cytokines with the consequences described above6060. Halstead SB, Rojanasuphot S, Sangkawibha N. Original antigenic sin in dengue. Am J Trop Med Hyg. 1983;32:154-6.. Studies by Falcón et al.4545. Falcón-Lezama JA, Ramos C, Zuñiga J, Juárez-Palma L, Rangel-Flores H, García-Trejo AR, et al. HLA class I and II polymorphisms in Mexican Mestizo patients with dengue fever. Acta Trop. 2009;112:193-7., Fernández-Mestre et al.5656. Fernández-Mestre M, Navarrete C, Brown J, Brown C, Correa E, Layrisse Z. HLA alleles and dengue virus infection in Venezuelan patients: a preliminary study. Inmunologia. 2009;28:96-100., García et al.5353. García G, del Puerto F, Pérez AB, Sierra B, Aguirre E, Kikuchi M, et al. Association of MICA and MICB alleles with symptomatic dengue infection. Hum Immunol. 2011;72:904-7., and Sierra et al.5454. Sierra B, Alegre R, Pérez AB, García G, Sturn-Ramirez K, Obasanjo O, et al. HLA-A, -B, -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. Hum Immunol. 2007;68:531-40. documented the influence of polymorphisms in the major histocompatibility complex responsible for the regulation of the immune system through the process of antigen presentation. García et al.5252. García G, Sierra B, Pérez AB, Aguirre E, Rosado I, Gonzalez N, et al. Asymptomatic dengue infection in a Cuban population confirms the protective role of the RR variant of the FcgammaRIIa polymorphism. Am J Trop Med Hyg. 2010;82:1153-6. in 2010 and Noecker et al.4646. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22. in 2014 also investigated this immune system and identified polymorphisms in the FcγRIIa gene, which encodes cell surface proteins that mediate responses in B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, among others. Other studies in our review focused on verifying the relationship between genetic immunity and the single nucleotide polymorphism (SNP) of G2431A IDO1, OSBPL10, and HLA-DRB11919. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13:e1006220.,4141. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.,4242. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9.,5151. LaFleur C, Granados J, Vargas-Alarcon G, Ruíz-Morales J, Villarreal-Garza C, Higuera L, et al. HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol. 2002;63:1039-44..

A previous systematic review demonstrated that genetic variations within MICB (meta-OR=2.35, 95% CI: 1.68–3.29), MBL2 (meta-OR=1.54, 95% CI: 1.02–2.31), and IFN-γ (meta-OR=2.48, 95% CI: 1.30–4.71) are associated with dengue2525. Cahill ME, Conley S, DeWan AT, Montgomery RR. Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis. 2018;18:282.; however, it did not differentiate between severe dengue and classic dengue or asymptomatic dengue. Another review analyzed different associations between DC-SIGN Promoter-336G/A (rs4804803)2525. Cahill ME, Conley S, DeWan AT, Montgomery RR. Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis. 2018;18:282. and concluded that dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) promoter-336G/A (rs4804803) polymorphism is associated with severe dengue. A study included in our review reported that rs4804803 behaved as a risk factor in Mexican people4646. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22., while as protective in Brazilian people3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.,4242. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9..

We noted some similarities and differences between the studies we analyzed and other studies concerning innate immunity polymorphisms: some reports from Thailand indicated that rs4804803 (CD209) and rs3753394 (CFH) polymorphisms were not linked to dengue2525. Cahill ME, Conley S, DeWan AT, Montgomery RR. Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis. 2018;18:282.. Similarly, the current review found no significant association between this polymorphism and severe disease in Latin American countries3838. Santos AC, Moura EL, Ferreira JM, Moura AW, Ferreira AD, Bezerra RP, et al. Association of TNFA (-308G/A), IFNG (+874 A/T) and IL-10 (-819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population. Asian Pac J Trop Med. 2017;10:1065-71.,4747. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55.. However, another study conducted with the Thai population confirmed CD209 with an OR=5.84 (2.77–12.31) of DHF compared to DF2525. Cahill ME, Conley S, DeWan AT, Montgomery RR. Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis. 2018;18:282..

While analyzing this same component of innate immunity, a study conducted in India confirmed OR=0.39 (0.16-0.88) of severe disease associated with rs3775291 (TLR3)2525. Cahill ME, Conley S, DeWan AT, Montgomery RR. Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis. 2018;18:282.. In contrast, no association between these factors was found in the Latin American population4848. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230.. Lastly, contrary to what was found in Indonesia regarding the TLR4 gene (no significant association with disease)2525. Cahill ME, Conley S, DeWan AT, Montgomery RR. Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis. 2018;18:282., our study confirmed a protective effect of TLR4- rs2737190- G/G/G in cases of severe dengue fever4848. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230..

While analyzing the genetic immunity groups, our study found significant associations of the MICB gene with the risk of severe dengue5353. García G, del Puerto F, Pérez AB, Sierra B, Aguirre E, Kikuchi M, et al. Association of MICA and MICB alleles with symptomatic dengue infection. Hum Immunol. 2011;72:904-7.. Previous studies conducted with the Asian population observed a similar scenario, confirming that the same increase in risk affected DSS: 1.58 (1.02–2.40) odds of DSS compared to non-DSS2525. Cahill ME, Conley S, DeWan AT, Montgomery RR. Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis. 2018;18:282.. Differences between countries in Latin America and those in other continents may occur due to specific ethnicity factors resulting in cases in which Asians are protected by polymorphisms but Latin Americans are not, or on the contrary, for some polymorphisms the protective effect occurs in Latin Americans but not in Asians.

Dengue is currently a public health problem in most Latin American countries. Since 2009, the disease has expanded its distribution, causing periodic epidemics with a constant raise in cases. Identifying the polymorphisms that affect dengue can help researchers find early markers that make it easier to predict the clinical outcome of this disease and may even be helpful in designing vaccines. Genetic studies are essential for gathering information on circulating viruses and creating a better understanding of DENV transmission and epidemiology in a specific region.

Multiple limitations influence the comparison of studies in this review: an example is the low representativeness of the samples in most studies. In effect, only 11 studies reported the power calculations they used to estimate SNP differences between cases and controls or presented the limitation of small samples3333. Cezar RD, Castanha PM, Freire NM, Mola C, Carmo RF, Cordeiro MT, et al. Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus-infected children. Int J Immunogenet. 2020;47:351-8.,3434. Santos AC, Moura EL, Silva DM, Moura AW, Ferreira JM, Lira Neto AB, et al. Association of polymorphisms in serotonin and nitric oxide genes with clinical outcome of dengue in Brazilian northeast population. Acta Trop. 2019;190:144-8.,3636. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004.,3838. Santos AC, Moura EL, Ferreira JM, Moura AW, Ferreira AD, Bezerra RP, et al. Association of TNFA (-308G/A), IFNG (+874 A/T) and IL-10 (-819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population. Asian Pac J Trop Med. 2017;10:1065-71.,3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.,4141. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.,4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..

45. Falcón-Lezama JA, Ramos C, Zuñiga J, Juárez-Palma L, Rangel-Flores H, García-Trejo AR, et al. HLA class I and II polymorphisms in Mexican Mestizo patients with dengue fever. Acta Trop. 2009;112:193-7.

46. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22.

47. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55.
-4848. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230.. Thus, few studies conducted multiple testing or applied methods of correction for small samples, such as Bonferroni’s correction, Welch’s correction, or Yates’ correction1919. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13:e1006220.,3737. Pastor AF, Moura LR, Neto JW, Nascimento EJ, Calzavara-Silva CE, Gomes AL, et al. Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression. Hum Immunol. 2013;74:1225-30.,4141. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.

42. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9.
-4343. Silva LK, Blanton RE, Parrado AR, Melo PS, Morato VG, Reis EA, et al. Dengue hemorrhagic fever is associated with polymorphisms in JAK1. Eur J Hum Genet. 2010;18:1221-7.,5353. García G, del Puerto F, Pérez AB, Sierra B, Aguirre E, Kikuchi M, et al. Association of MICA and MICB alleles with symptomatic dengue infection. Hum Immunol. 2011;72:904-7.,5555. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, Alvarez M, et al. Tumor necrosis factor-alpha, transforming growth factor-beta1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever. Hum Immunol. 2010;71:1135-40.

56. Fernández-Mestre M, Navarrete C, Brown J, Brown C, Correa E, Layrisse Z. HLA alleles and dengue virus infection in Venezuelan patients: a preliminary study. Inmunologia. 2009;28:96-100.
-5757. Fernández-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 2004;64:469-72..

Other limitations of our review include the variability in the classification of severe disease used in the studies we evaluated, which ranged from the 1994 WHO guidelines5454. Sierra B, Alegre R, Pérez AB, García G, Sturn-Ramirez K, Obasanjo O, et al. HLA-A, -B, -C, and -DRB1 allele frequencies in Cuban individuals with antecedents of dengue 2 disease: advantages of the Cuban population for HLA studies of dengue virus infection. Hum Immunol. 2007;68:531-40. to the more updated 2009 classification3636. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004.,3939. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.

40. Xavier-Carvalho C, Cezar RD, Freire NM, Vasconcelos CM, Solorzano VE, Toledo-Pinto TG, et al. Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects. Hum Immunol. 2017;78:649-56.

41. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.
-4242. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9.,4646. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22., and the fact that certain studies not specified which standard they used4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..,5757. Fernández-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 2004;64:469-72.. Additionally, the differences in the methods used to classify polymorphisms resulted in uncertainty in our analysis. Although more than half of the studies used the real-time polymerase chain reaction (qRT-PCR)1919. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13:e1006220.,3333. Cezar RD, Castanha PM, Freire NM, Mola C, Carmo RF, Cordeiro MT, et al. Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus-infected children. Int J Immunogenet. 2020;47:351-8.

34. Santos AC, Moura EL, Silva DM, Moura AW, Ferreira JM, Lira Neto AB, et al. Association of polymorphisms in serotonin and nitric oxide genes with clinical outcome of dengue in Brazilian northeast population. Acta Trop. 2019;190:144-8.

35. Figueiredo GG, Cezar RD, Freire NM, Teixeira VG, Baptista P, Cordeiro M, et al. Mannose-binding lectin gene (MBL2) polymorphisms related to the mannose-binding lectin low levels are associated to dengue disease severity. Hum Immunol. 2016;77:571-5.
-3636. Ornelas AM, Xavier-de-Carvalho C, Alvarado-Arnez LE, Ribeiro-Alves M, Rossi AD, Tanuri A, et al. Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil. Mem Inst Oswaldo Cruz. 2019;114:e190004.,3838. Santos AC, Moura EL, Ferreira JM, Moura AW, Ferreira AD, Bezerra RP, et al. Association of TNFA (-308G/A), IFNG (+874 A/T) and IL-10 (-819 C/T) polymorphisms with protection and susceptibility to dengue in Brazilian population. Asian Pac J Trop Med. 2017;10:1065-71.

39. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, Santos RS, Cruz OG, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infect Genet Evol. 2013;20:197-205.

40. Xavier-Carvalho C, Cezar RD, Freire NM, Vasconcelos CM, Solorzano VE, Toledo-Pinto TG, et al. Association of rs1285933 single nucleotide polymorphism in CLEC5A gene with dengue severity and its functional effects. Hum Immunol. 2017;78:649-56.

41. Azevedo BP, Farias PC, Pastor AF, Davi CC, Neco HV, Lima RE, et al. AA IDO1 variant genotype (G2431A, rs3739319) is associated whit severe dengue risk development in a DEN-3 Brazilian Cohort. Viral Inmunol. 2019;32:296-301.
-4242. Oliveira LF, Lima CP, Azevedo RS, Mendonça DS, Rodrigues SG, Carvalho VL, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27:245-9.,4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..,4646. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15-22.

47. Vargas-Castillo AB, Ruiz-Tovar K, Vivanco-Cid H, Quiroz-Cruz S, Escobar-Gutiérrez A, Cerna-Cortes JF, et al. Association of single-nucleotide polymorphisms in immune-related genes with development of dengue hemorrhagic fever in a Mexican population. Viral Immunol. 2018;31:249-55.
-4848. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230., others also applied the PCR-SSO, PCR-SSP, or PCR-RFLP.

CONCLUSION

Lastly, it is crucial to consider the time span of the studies included in this review, where the most recent studies occurred in 20203333. Cezar RD, Castanha PM, Freire NM, Mola C, Carmo RF, Cordeiro MT, et al. Association between interferon lambda 3 rs12979860 polymorphism and clinical outcome in dengue virus-infected children. Int J Immunogenet. 2020;47:351-8.,4444. Santos NC, Gomes TN, Góis IA, Oliveira JS, Coelho LF, Ferreira GP, et al. Association of single nucleotide polymorphisms in TNF- a (-308G/A and -238G/A) to dengue: case-control and meta-analysis study. Cytokine. 2020;134:155-83..,4848. Posadas-Mondragón A, Aguilar-Faisal JL, Zuñiga G, Magaña JJ, Santiago-Cruz JA, Guillén-Salomón E, et al. Association of genetic polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the clinical forms of dengue in patients from Veracruz, Mexico. Viruses. 2020;12:1230., and some were conducted almost two decades ago. The different biases previously described for each of the studies resulted in a high subjective heterogeneity. On the other hand, the lack of studies in most Latin American countries, probably due to low research funding, has hampered a thorough investigation of the potential of markers in preventing severe dengue in this region.

Nevertheless, this review provides an overview of the genetic aspects associated with severe dengue in this region, which is an essential analysis, considering the diversity that could be expected in this regard and the fact that these types of studies are mainly published in Asian countries. Despite the aforementioned scenario, the efforts made to understand the clinical course of patients with dengue are fully justified. The evidence collected so far will hopefully serve as a basis for improving disease prediction methods, positively affecting the early identification of cases that require greater health care attention.

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  • FUNDING
    San Martín University founded this study under the reference PYI-2021-013. The funders had no role in the study design, data collection, analysis, publication decision, or manuscript preparation.

Publication Dates

  • Publication in this collection
    01 Dec 2023
  • Date of issue
    2023

History

  • Received
    17 Nov 2022
  • Accepted
    25 Apr 2023
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