Influence of host genetic polymorphisms involved in immune response and their role in the development of Chikungunya disease: a review

Gotay, W.J.P.; Rodrigues, R.O.; Yaochite, J.N.U.

doi:10.1590/1414-431X2023e12557

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Brazilian Journal of Medical and Biological Research

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Review • Braz. J. Med. Biol. Res. 56 • 2023 • https://doi.org/10.1590/1414-431X2023e12557 copy

Influence of host genetic polymorphisms involved in immune response and their role in the development of Chikungunya disease: a review

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Chikungunya virus (CHIKV) is transmitted by the bite of infected mosquitoes and can cause significant pathogenicity in humans. Moreover, its importance has increased in the Americas since 2013. The primary vectors for viral delivery are the mosquito species Aedes aegypti and Aedes albopictus. Several factors, including host genetic variations and immune response against CHIKV, influence the outcomes of Chikungunya disease. This work aimed to gather information about different single nucleotide polymorphisms (SNPs) in genes that influence the host immune response during an infection by CHIKV. The viral characteristics, disease epidemiology, clinical manifestations, and immune response against CHIKV are also addressed. The main immune molecules related to this arboviral disease elucidated in this review are TLR3/7/8, DC-SIGN, HLA-DRB1/HLA-DQB1, TNF, IL1RN, OAS2/3, and CRP. Advances in knowledge about the genetic basis of the immune response during CHIKV infection are essential for expanding the understanding of disease pathophysiology, providing new genetic markers for prognosis, and identifying molecular targets for the development of new drug treatments.

Single nucleotide polymorphisms (SNPs); Chikungunya virus (CHIKV); Chikungunya disease; Immune response

Gene	Allele/polymorphism	Chromosome	SNP Type	Association	Reference
TLR3	rs3775291 [A/G]	Chr 4	Transition Substitution	AA genotype promotes increased CHIKV infection susceptibility.	(¹³13. Bucardo F, Reyes Y, Morales M, Briceão R, González F, Lundkvist Å, et al. Association of genetic polymorphisms in DC-SIGN, toll-like receptor 3, and tumor necrosis factor α genes and the Lewis-negative phenotype with Chikungunya infection and disease in Nicaragua. J Infect Dis 2021; 223: 278-286, doi: 10.1093/infdis/jiaa364. https://doi.org/10.1093/infdis/jiaa364... )
	rs3775290 [T/C]		Transition Substitution	TT genotype increases the risk of arboviruses coinfection. Increases the risk of Chikungunya infection.	(⁶⁸68. Sengupta S, Mukherjee S, Bhattacharya N, Tripathi A. Differential genotypic signatures of Toll-like receptor polymorphisms among dengue-chikungunya mono-and co-infected Eastern Indian patients. Eur J Clin Microbiol Infect Dis 2021; 1-13, doi: 10.1007/s10096-020-04125-x. https://doi.org/10.1007/s10096-020-04125... )
TLR7	rs3853839 [C/G]	Chr.X	Transversion Substitution	GC genotype is associated with increased risk of CHIKV infection. Increases the risk of fever and rash.	(¹¹11. Dutta SK, Tripathi A. Association of toll-like receptor polymorphisms with susceptibility to Chikungunya virus infection. Virology 2017; 511: 207-213, doi: 10.1016/j.virol.2017.08.009. https://doi.org/10.1016/j.virol.2017.08.... ,⁶⁸68. Sengupta S, Mukherjee S, Bhattacharya N, Tripathi A. Differential genotypic signatures of Toll-like receptor polymorphisms among dengue-chikungunya mono-and co-infected Eastern Indian patients. Eur J Clin Microbiol Infect Dis 2021; 1-13, doi: 10.1007/s10096-020-04125-x. https://doi.org/10.1007/s10096-020-04125... )
	rs179010 [T/C]		Transversion Substitution	Increases the risk of fever and rash.	(¹¹11. Dutta SK, Tripathi A. Association of toll-like receptor polymorphisms with susceptibility to Chikungunya virus infection. Virology 2017; 511: 207-213, doi: 10.1016/j.virol.2017.08.009. https://doi.org/10.1016/j.virol.2017.08.... )
	rs574880 [G/T]				(¹¹11. Dutta SK, Tripathi A. Association of toll-like receptor polymorphisms with susceptibility to Chikungunya virus infection. Virology 2017; 511: 207-213, doi: 10.1016/j.virol.2017.08.009. https://doi.org/10.1016/j.virol.2017.08.... )
TLR8	rs3764880 [A/G]	Chr.X	Transversion Substitution	AG genotype is associated with susceptibility to CHIKV infection.	(⁶⁸68. Sengupta S, Mukherjee S, Bhattacharya N, Tripathi A. Differential genotypic signatures of Toll-like receptor polymorphisms among dengue-chikungunya mono-and co-infected Eastern Indian patients. Eur J Clin Microbiol Infect Dis 2021; 1-13, doi: 10.1007/s10096-020-04125-x. https://doi.org/10.1007/s10096-020-04125... )
	rs3764879 [G/C]			Association with increased risk of CHIKV infection.	(¹¹11. Dutta SK, Tripathi A. Association of toll-like receptor polymorphisms with susceptibility to Chikungunya virus infection. Virology 2017; 511: 207-213, doi: 10.1016/j.virol.2017.08.009. https://doi.org/10.1016/j.virol.2017.08.... ,⁶⁸68. Sengupta S, Mukherjee S, Bhattacharya N, Tripathi A. Differential genotypic signatures of Toll-like receptor polymorphisms among dengue-chikungunya mono-and co-infected Eastern Indian patients. Eur J Clin Microbiol Infect Dis 2021; 1-13, doi: 10.1007/s10096-020-04125-x. https://doi.org/10.1007/s10096-020-04125... )
HLA II	DQB103: 03/ DRB111	Chr.6	Insertion/Deletion (Indels)	Protection against CHIKV infection.	(⁷⁷77. Chaaithanya IK, Muruganandam N, Anwesh M, Rajesh R, Ghosal SR, Kartick C, et al. HLA class II allele polymorphism in an outbreak of Chikungunya fever in middle Andaman, India. Immunology 2013; 140: 202-210, doi: 10.1111/imm.12128. https://doi.org/10.1111/imm.12128... ,⁷⁸78. Thanapati S, Hande A, Das R, Gurav Y, Tripathy AS. Association of human leukocyte antigen class II allele and haplotypes in Chikungunya viral infection in a western Indian population. Trans R Soc Trop Med Hyg 2014; 108: 277-282, doi: 10.1093/trstmh/tru030. https://doi.org/10.1093/trstmh/tru030... )
-DQB1 -DRB1	DQB103DRB14			Susceptibility to CHIKV infection.	(⁷⁸78. Thanapati S, Hande A, Das R, Gurav Y, Tripathy AS. Association of human leukocyte antigen class II allele and haplotypes in Chikungunya viral infection in a western Indian population. Trans R Soc Trop Med Hyg 2014; 108: 277-282, doi: 10.1093/trstmh/tru030. https://doi.org/10.1093/trstmh/tru030... )
TNF	rs1800629 [A/G]	Chr.6	Transition Substitution	Associated with decreased persistent joint pain in patients with Chikungunya disease.	(¹³13. Bucardo F, Reyes Y, Morales M, Briceão R, González F, Lundkvist Å, et al. Association of genetic polymorphisms in DC-SIGN, toll-like receptor 3, and tumor necrosis factor α genes and the Lewis-negative phenotype with Chikungunya infection and disease in Nicaragua. J Infect Dis 2021; 223: 278-286, doi: 10.1093/infdis/jiaa364. https://doi.org/10.1093/infdis/jiaa364... )
IL1RN	1/	Chr.2	Tandem Repeat	Association with increased risk of CHIKV infection.	(⁸²82. Tripathy AS, Ganu MA, Sonam L, Alagarasu K, Walimbe AM, Thanapati S, et al. Association of IL1RN VNTR polymorphism with Chikungunya infection: a study from Western India. J Med Virol 2019; 91: 1901-1908, doi: 10.1002/jmv.25546. https://doi.org/10.1002/jmv.25546... )
	*2			Protection against chronic Chikungunya.	(⁸²82. Tripathy AS, Ganu MA, Sonam L, Alagarasu K, Walimbe AM, Thanapati S, et al. Association of IL1RN VNTR polymorphism with Chikungunya infection: a study from Western India. J Med Virol 2019; 91: 1901-1908, doi: 10.1002/jmv.25546. https://doi.org/10.1002/jmv.25546... )
CD209	rs4804803 [A /G]	Chr.19	Transition Substitution	Promotes susceptibility to CHIKV infection.	(²2. Chaaithanya IK, Muruganandam N, Surya P, Anwesh M, Alagarasu K, Vijayachari P. Association of oligoadenylate synthetase gene cluster and DC-SIGN (CD209) gene polymorphisms with clinical symptoms in Chikungunya virus infection. DNA Cell Biol 2016; 35: 44-50, doi: 10.1089/dna.2015.2819. https://doi.org/10.1089/dna.2015.2819... ,¹³13. Bucardo F, Reyes Y, Morales M, Briceão R, González F, Lundkvist Å, et al. Association of genetic polymorphisms in DC-SIGN, toll-like receptor 3, and tumor necrosis factor α genes and the Lewis-negative phenotype with Chikungunya infection and disease in Nicaragua. J Infect Dis 2021; 223: 278-286, doi: 10.1093/infdis/jiaa364. https://doi.org/10.1093/infdis/jiaa364... )
OAS3	rs2285932 [C/T]	Chr.12	Transition Substitution	Associated with a reduced risk of chills.	(²2. Chaaithanya IK, Muruganandam N, Surya P, Anwesh M, Alagarasu K, Vijayachari P. Association of oligoadenylate synthetase gene cluster and DC-SIGN (CD209) gene polymorphisms with clinical symptoms in Chikungunya virus infection. DNA Cell Biol 2016; 35: 44-50, doi: 10.1089/dna.2015.2819. https://doi.org/10.1089/dna.2015.2819... )
OAS1	rs1131434 [G/G]		Transition Substitution	Associated with reduced risk of edema.	(²2. Chaaithanya IK, Muruganandam N, Surya P, Anwesh M, Alagarasu K, Vijayachari P. Association of oligoadenylate synthetase gene cluster and DC-SIGN (CD209) gene polymorphisms with clinical symptoms in Chikungunya virus infection. DNA Cell Biol 2016; 35: 44-50, doi: 10.1089/dna.2015.2819. https://doi.org/10.1089/dna.2015.2819... )
OAS2	rs1732778 [G/A]rs15895 [G/A]		Transition Substitution	Associations with symptoms such as edema, fever, chills, and reduced conjunctival redness.	(²2. Chaaithanya IK, Muruganandam N, Surya P, Anwesh M, Alagarasu K, Vijayachari P. Association of oligoadenylate synthetase gene cluster and DC-SIGN (CD209) gene polymorphisms with clinical symptoms in Chikungunya virus infection. DNA Cell Biol 2016; 35: 44-50, doi: 10.1089/dna.2015.2819. https://doi.org/10.1089/dna.2015.2819... )
CRP	rs3091244 [T/C]	Chr.1	Transition Substitution	CT genotype confers protection against CHIKV infection. Patients with CC genotype present higher viral load for CHIKV.	(⁹⁰90. Sengupta S, Bhattacharya N, Tripathi A. Association of C-reactive protein polymorphisms with serum-CRP concentration and viral load among dengue-chikungunya mono/co-infected patients. Antiviral Res 2022; 197: 105225, doi: 10.1016/j.antiviral.2021.105225. https://doi.org/10.1016/j.antiviral.2021... )
	rs3093059 [T/C]rs3091244 [T/C]			Genotypes CT and TT are associated with protection against arthralgia produced by CHIKV.	(⁸⁷87. Sengupta S, Bhattacharya N, Tripathi A. Increased CRP, anti-CCP antibody, IL-2R, COMP levels in prognosis of post-chikungunya chronic arthritis and protective role of their specific genotypes against arthritic manifestation. Virus Res 2022; 23: 198998, doi: 10.1016/j.virusres.2022.198998. https://doi.org/10.1016/j.virusres.2022.... )

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[1] Correspondence: J.N.U. Yaochite: <ueda.juliana@gmail.com>