Association between polymorphisms in the genes encoding toll-like receptors and dectin-1 and susceptibility to invasive aspergillosis: a systematic review

Cunha, Daiane de Oliveira; Leão-Cordeiro, Jacqueline Andréia Bernardes; Paula, Hellen da Silva Cintra de; Ataides, Fábio Silvestre; Saddi, Vera Aparecida; Vilanova-Costa, Cesar Augusto Sam Tiago; Silva, Antonio Márcio Teodoro Cordeiro

doi:10.1590/0037-8682-0314-2018

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Mini Review • Rev. Soc. Bras. Med. Trop. 51 (06) • Nov-Dec 2018 • https://doi.org/10.1590/0037-8682-0314-2018 copy

Association between polymorphisms in the genes encoding toll-like receptors and dectin-1 and susceptibility to invasive aspergillosis: a systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Invasive aspergillosis is a common fungal infection in immunocompromised individuals. Some studies have shown that toll-like receptor and dectin-1 genetic polymorphisms may alter signaling pathways, thus increasing an individual’s susceptibility to invasive aspergillosis. We investigated the pertinent literature to determine whether polymorphisms in the genes encoding toll-like receptors and dectin-1 increase the susceptibility to invasive aspergillosis. This study systematically reviewed the literature using the databases PubMed/PMC, Scopus, and Web of Science using the keywords invasive aspergillosis, polymorphism, Toll-like, and Dectin-1. From the initial search, 415 studies were found and according to our inclusion and exclusion criteria, eight studies were selected. Several studies described single-nucleotide polymorphisms (SNPs) that are associated with a greater susceptibility to invasive aspergillosis. These SNPs were found in the genes that encode toll-like receptors 1, 3, 4, and 5 and the gene that encodes dectin-1; upon activation, both cellular receptors initiate a signaling cascade that can result in the production of cytokines and chemokines. Thus, our literature review uncovered a significant association between polymorphisms in the genes that encode toll-like receptors and dectin-1 and invasive aspergillosis. More studies should be performed to better understand the relationship between toll-like receptor and dectin-1 genetic polymorphisms and invasive aspergillosis susceptibility.

Keywords:
Invasive aspergillosis; Genetic polymorphism; Toll-like; Dectin-1; Susceptibility

Authors	Year	Title	Type of Study	Study Location
Carvalho et al.¹⁴14. Sainz J, Lupiáñez CB, Segura-Catena J, Vazquez L, Ríos R, Oyonarte S, et al. Dectin-1 and DC-SIGN polymorphisms associated with invasive pulmonary Aspergillosis infection. PLoS One. 2012;7(2):e32273.	2008	Polymorphisms in Toll-Like Receptor Genes	Cohort study	United Kingdom
		and Susceptibility to pulmonary Aspergillosis
Cunha et al.¹1. Cunha C, Di Ianni M, Bozza S, Giovannini G, Zagarella S, Zelante T, et al. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood. 2010;116(24):5394-402.	2010	Dectin-1 Y238X polymorphism associates with	Control case	Italy
		susceptibility to invasive aspergillosis in
‘		hematopoietic transplantation through
		impairment of both recipient and donor
		dependent mechanisms of antifungal immunity
Boer et al.¹⁹19. Lin YT, Verma A, Hodgkinson CP. Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. Curr Genomics. 2012;13(8):633-45.	2011	Influence of Polymorphisms in Innate Immunity Genes on Susceptibility to Invasive	Cohort study	Netherlands
		Aspergillosis after Stem Cell Transplantation
Chai et al.¹⁸18. Rødland EK, Ager-Wick E, Halvorsen B, Müller F, Frøland SS. Toll like receptor 5 (TLR5) may be involved in the immunological response to Aspergillus fumigatus in vitro. Med Mycol . 2011;49(4):375-9.	2011	The Y238X Stop Codon Polymorphism in th	Control case	Belgium
		e Human b-Glucan Receptor Dectin-1 and
		Susceptibility to Invasive Aspergillosis
Carvalho et al.²⁰20. Pamer EG. TLR polymorphisms and the risk of invasive fungal infections. N Engl J Med . 2008;359(17):1836-38.	2012	TLR3 essentially promotes protective	Retrospective cohort study	Italy
		class I-restricted memory CD8_ T-cell responses to
		Aspergillus fumigatus in hematopoietic
		transplanted patients
Sainz et al.¹¹11. Elia N, von Elm E, Chatagner A, Pöpping DM, Tramèr MR. How do authors of systematic reviews deal with research malpractice and misconduct in original studies? A cross-sectional analysis of systematic reviews and survey of their authors. BMJ Open. 2016;6(3):e010442.	2012	Dectin-1 and DC-SIGN Polymorphisms	Prospective cohort study	England
		Associated with Invasive Pulmonary
		Aspergillosis Infection
Grube et al.¹³13. Bochud PY1, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359(17):1766-77.	2013	TLR5 stop codon polymorphism is associated	Control case	Germany
		with invasive aspergillosis after allogeneic
		stem cell transplantation
Smith et al.²¹21. Chai LY, de Boer MG, van der Velden WJ, Plantinga TS, van Spriel AB, Jacobs C, et al. The Y238X stop codon polymorphism in the human β-glucan receptor dectin-1 and susceptibility to invasive aspergillosis. J Infect Dis . 2011;203(5):736-43.	2014	Reduced expression of TLR3, TLR10 and	Control case	Italy
		TREM1 by human macrophages in Chronic
		cavitary pulmonary aspergillosis, and novel
		associations of VEGFA, DENND1B and PLAT

Gene	SNP(s)	Chromosome	Nucleotide /	Population	Cases	Controls	Odds ratio	p Value	Ref
		Location	Amino Acid Exchange				(CI 95%)
TLR1	rs4833095	4p14	239G>C	Italy	112	277	0.58 (0.36-0.95)	0.029	Smith et al.²¹21. Chai LY, de Boer MG, van der Velden WJ, Plantinga TS, van Spriel AB, Jacobs C, et al. The Y238X stop codon polymorphism in the human β-glucan receptor dectin-1 and susceptibility to invasive aspergillosis. J Infect Dis . 2011;203(5):736-43.
TLR1	rs4833095	4q14	239G>C	Netherlands	43	61	1.02 (0.53-1.96)	0.096	Boer et al.¹⁹19. Lin YT, Verma A, Hodgkinson CP. Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. Curr Genomics. 2012;13(8):633-45.
TLR1	rs5743611	4q14	743A>G	Netherlands	42	59	1.10 (0.39-3.08)	0.86	Boer et al.¹⁹19. Lin YT, Verma A, Hodgkinson CP. Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. Curr Genomics. 2012;13(8):633-45.
TLR2	rs5743708	4q31.3	Arg753Gln	United Kingdom	40	80	0.795 (0.151-4.150)	1.000	Carvalho et al.¹⁴14. Sainz J, Lupiáñez CB, Segura-Catena J, Vazquez L, Ríos R, Oyonarte S, et al. Dectin-1 and DC-SIGN polymorphisms associated with invasive pulmonary Aspergillosis infection. PLoS One. 2012;7(2):e32273.
TLR2	rs5743708	4q31.3	Arg753Gln	Germany	41	109	-	0.16	Grube et al.¹³13. Bochud PY1, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359(17):1766-77.
TLR3	rs3775296	4q35.1	95C/A	Italy	42	147	2.41(1.27-4,58)	0.007	Carvalho et al.²⁰20. Pamer EG. TLR polymorphisms and the risk of invasive fungal infections. N Engl J Med . 2008;359(17):1836-38.
TLR4	rs4986790	9q33.1	Asp299Gly	United Kingdom	40	80	3.462 (1.477-8.110)	0,03	Carvalho et al.¹⁴14. Sainz J, Lupiáñez CB, Segura-Catena J, Vazquez L, Ríos R, Oyonarte S, et al. Dectin-1 and DC-SIGN polymorphisms associated with invasive pulmonary Aspergillosis infection. PLoS One. 2012;7(2):e32273.
TLR4	rs4986790	9q33.1	Asp299Gly	Germany	41	107	-	0,13	Grube et al.¹³13. Bochud PY1, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359(17):1766-77.
TLR4	rs4986791	9q33.1	Thr399Ile	Germany	41	109	-	0,15	Grube et al.¹³13. Bochud PY1, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359(17):1766-77.
TLR4	rs4986791	9q33.1	1363C>T	Netherlands	42	61	2.81 (0.91-8.70)	0.06	Boer et al.¹⁹19. Lin YT, Verma A, Hodgkinson CP. Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. Curr Genomics. 2012;13(8):633-45.
TLR4	rs4986790	9q33.1	1063A>G	Netherlands	43	61	4.33 (1.33-14,1)	0.01	Boer et al.¹⁹19. Lin YT, Verma A, Hodgkinson CP. Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. Curr Genomics. 2012;13(8):633-45.
TLR5	rs5744168	1q41	Arg392Ter	Germany	41	109	3.285 (1.20-8.99)	0.007	Grube et al.¹³13. Bochud PY1, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359(17):1766-77.
TLR6	rs5743810	4p14	745C>T	Netherlands	42	59	1.14 (0.65-2.00)	0.67	Boer et al.¹⁹19. Lin YT, Verma A, Hodgkinson CP. Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. Curr Genomics. 2012;13(8):633-45.
TLR9	rs5743836	3q21.2	T-123C	United Kingdom	40	80	0.927 (0.362-2.373)	0.43	Carvalho et al.¹⁴14. Sainz J, Lupiáñez CB, Segura-Catena J, Vazquez L, Ríos R, Oyonarte S, et al. Dectin-1 and DC-SIGN polymorphisms associated with invasive pulmonary Aspergillosis infection. PLoS One. 2012;7(2):e32273.
TLR9	rs352140	3q21.2	P545P	Germany	41	110	-	0.19	Grube et al.¹³13. Bochud PY1, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359(17):1766-77.

Gene	SNP(s)	Chromosome Location	Nucleotide / Amino Acid Exchange	Population	Cases	Controls	Odds ratio (CI 95%)	p Value	Ref
CLEC7A	rs16910526	12p13.2	aY238X	Italy	39	166	3.39(1.5-10.0)	0.005 (D+R)	Cunha et al.¹1. Cunha C, Di Ianni M, Bozza S, Giovannini G, Zagarella S, Zelante T, et al. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood. 2010;116(24):5394-402.
							(D+R) 2.5(1.0-6.5) (D)	0.05(D)
CLEC7A	rs16910526	12p13.2	aY238X	Belgium	71	108	1.79(0.77-4.19)	0.017	Chai et al.¹⁸18. Rødland EK, Ager-Wick E, Halvorsen B, Müller F, Frøland SS. Toll like receptor 5 (TLR5) may be involved in the immunological response to Aspergillus fumigatus in vitro. Med Mycol . 2011;49(4):375-9.
CLEC7A	rs7309123	12p13.2	-	England	57	125	4.91(1.52-15.89)	0.05	Sainz et al.¹¹11. Elia N, von Elm E, Chatagner A, Pöpping DM, Tramèr MR. How do authors of systematic reviews deal with research malpractice and misconduct in original studies? A cross-sectional analysis of systematic reviews and survey of their authors. BMJ Open. 2016;6(3):e010442.
CLEC7A	rs7309123	12p13.2	-	Spain	112	279	0.59(0.35-0.99)	0.046	Smith et al.²¹21. Chai LY, de Boer MG, van der Velden WJ, Plantinga TS, van Spriel AB, Jacobs C, et al. The Y238X stop codon polymorphism in the human β-glucan receptor dectin-1 and susceptibility to invasive aspergillosis. J Infect Dis . 2011;203(5):736-43.
CLEC7A	rs3901533	12p13.2	-	England	57	125	5.59(1.37-22.77)	0.012	Sainz et al.¹¹11. Elia N, von Elm E, Chatagner A, Pöpping DM, Tramèr MR. How do authors of systematic reviews deal with research malpractice and misconduct in original studies? A cross-sectional analysis of systematic reviews and survey of their authors. BMJ Open. 2016;6(3):e010442.

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[1] Corresponding author: Prof. Dr. Antonio Márcio Teodoro Cordeiro Silva. e-mail:marciocmed@gmail.com