X-linked polymorphisms in <i>TLR7</i> and <i>TLR8</i> genes are associated with protection against Chikungunya fever

Gotay, Wilker Jose Perez; Maciel, Mariella Sousa Coêlho; Rodrigues, Raphael de Oliveira; Cardoso, Cynthia Chester; Oliveira, Caroline Nobre; Montenegro, Artur Fontenelle Lima; Yaochite, Juliana Navarro Ueda

doi:10.1590/0074-02760230224

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RESEARCH ARTICLE • Mem. Inst. Oswaldo Cruz 120 • 2025 • https://doi.org/10.1590/0074-02760230224 linkcopy

X-linked polymorphisms in TLR7 and TLR8 genes are associated with protection against Chikungunya fever

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

BACKGROUND Chikungunya virus (CHIKV) causes an infection that leads to the activation of the innate immune response, triggering receptor pathways such as toll-like receptors (TLRs).

OBJECTIVE The present study aimed to investigate the association of single nucleotide polymorphisms (SNPs) in genes encoding toll-like receptors 3, 7, and 8 and IRF5 in susceptibility to CHIKV infection and persistent joint pain.

METHODS A case-control study was carried out. The study included 121 symptomatic cases, 29 asymptomatic cases, and 182 healthy controls matched for age and sex. Polymorphisms were identified by TaqMan^® SNP Genotyping assays.

FINDINGS The G allele of the TLR7 variant (rs3853839 G/C) and the G allele of TLR8 (rs3764879 G/C) were associated with protection against CHIKV infection [_adjusted odd ratio (OR) = 0.64; p = 0.02 and _adjusted OR = 0.54; p = 0.001, respectively]. Moreover, individuals who presented the G allele in the rs3764879 variant have a greater chance of developing the asymptomatic form (_adjusted OR =2.88; p =0.004). The development of persistent joint pain was not associated with any investigated SNPs in positive anti-CHIKV IgG individuals.

MAIN CONCLUSIONS This study identified TLR7 and TLR8 gene polymorphisms as protective factors for Chikungunya infection.

Key words:
Chikungunya; single nucleotide polymorphisms; toll-like receptors (TLRs); interferon regulatory factor 5 (IRF-5); immune response

Characteristic	Study subjects, Nº. (%)				p-value^b
Characteristic	SYM (n = 121)	ASYM cases (n = 29)	Healthy controls (n = 182)	p-value^a	p-value^b	p-value^c
Sex
Male	35 (29)	15 (51.7)	51 (28)	0.027^*	0.89	p-value^c	0.016^*
Female	86 (71)	14 (48.3)	131 (72)
Age years (median and IQR)	57 (48 - 68)	58 (40 - 70.5)	51 (27 - 63)	0.82	0.0002^*	0.12
Chronic diseases
Yes	75 (62)	20 (69)	30 (16)	0.52	p < 0.0001^*	p < 0.0001^*
No	46 (38)	09 (31)	152 (84)
Household contacts with CHIKV
Yes	90 (74)	8 (27.6)	124 (68)	p < 0.0001^*	0.25	p < 0.0001^*
No	31 (26)	21 (72.4)	58 (32)

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Instituto Oswaldo Cruz, Ministério da Saúde Av. Brasil, 4365 - Pavilhão Mourisco, Manguinhos, 21040-900 Rio de Janeiro RJ Brazil, Tel.: (55 21) 2562-1222, Fax: (55 21) 2562 1220 - Rio de Janeiro - RJ - Brazil
E-mail: [email protected]

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[TFN1] Characteristic analyses were performed using Fisher’s exact test and Mann-Whitney test for age analysis, ^*p < 0.05. p-value^a: SYM cases versus ASYM cases; p-value^b: SYM cases versus health controls; p-value^c: ASYM cases versus healthy controls. Data represent No. (%) of study subjects, unless otherwise specified; p-values, IQR: interquartile range and chronic diseases including hypertension, diabetes, asthma, or arthritis; SYM: symptomatic; ASYM: asymptomatic; CHIKV: Chikungunya virus.

Frequency of symptoms
Symptoms	SYM cases (n = 121)	Female (%) (n = 86)	Male (%) (n = 35)	Prevalence of Chikungunya symptoms (%)	p-value
Fever	103	75 (87)	28 (80)	103 (85)	0.40
Headache	87	63 (73)	24 (69)	87 (72)	0.66
Myalgia	81	61 (71)	20 (57)	81(67)	0.20
Rash	51	37 (43)	14 (40)	51 (42)	0.84
Joint pain	120	85 (99)	35 (100)	120 (99)	1.00
Persistent joint pain	86	63 (73)	21 (60)	86 (71)	0.19
Retro-ocular pain	53	41 (48)	12 (34)	53 (44)	0.23
Oedema	67	51 (59)	16 (48)	67 (55)	0.23
Vomiting/ Nausea	48	35 (41)	13 (37)	48 (55)	0.84
Weakness	75	55 (64)	20 (57)	75 (62)	0.54
Diarrhoea	80	50 (93)	30 (86)	80 (66)	0.01^*

SNP	Genotype	SYM + ASYM cases (%) (n = 150)	Healthy controls (%) (n = 182)	Adjusted OR (95% CI)	p-value
TLR3 (L412F rs3775291;1234 C > T)	All
	Codominant
	C/C	65 (43.3)	87 (47.8)	1.0 (Reference)
	C/T	67 (44.7)	80 (44.0)	1.12 (0.71 - 1.77)	0.465
	T/T	18 (12.0)	15 (8.2)	1.61 (0.75 - 3.42)
	Dominant
	C/C	65 (43.3)	87 (47.8)	1.0 (Reference)
	C/T-T/T	85 (56.7)	95 (52.2)	1.20 (0.78 - 1.85)	0.415
	log-Additive (T)	150 (45.2)	182 (54.8)	1.23 (0.88 - 1.73)	0.23
IRF5 (198 G > T rs2004640)	All
	Codominant
	G/G	46 (30.7)	49 (26.9)	1.0 (Reference)
	G/T	73 (48.7)	89 (48.9)	0.87 (0.53 - 1.45)	0.652
	T/T	31 (20.7)	44 (24.2)	0.75 (0.41 - 1.38)
	Dominant
	G/G	46 (30.7)	49 (26.9)	1.0 (Reference)
	G/T-T/T	104 (69.3)	133 (73.1)	0.83 (0.52 - 1.34)	0.453
	log-Additive (G)	150 (45.2)	182 (54.8)	1.22 (0.89 - 1.68)	0.20
TLR7 (3′UTR G > C rs3853839)	All	(n = 150)	(n = 182)
	log-Additive (G)	150 (45.2)	182 (54.8)	0.64 (0.44 - 0.93)	0.02^*
	FEMALE	(n = 100)	(n = 131)
	Codominant
	C/C	53 (53.0)	50 (38.2)	1.0 (Reference)
	G/C	36 (36.0)	64 (48.9)	0.53 (0.30 - 0.93)	0.075
	G/G	11 (11.0)	17 (13.0)	0.61 (0.26 - 1.43)
	Dominant
	C/C	53 (53.0)	50 (38.2)	1.0 (Reference)
	G/C-G/G	47 (47.0)	81 (61.8)	0.55 (0.32 - 0.93)	0.024^*
	log-Additive (G)	100 (43.3)	131 (56.7)	0.69 (0.47 - 1.02)	0.060
TLR8 (129 C > G rs3764879)	All	(n = 150)	(n = 182)
	log-Additive (G)	150 (45.2)	182 (54.8)	0.54(0.38 - 0.78)	0.00¹*
	FEMALE	(n = 100)	(n = 131)
	Codominant
	C/C	39 (39.0)	28 (21.4)	1.0 (Reference)
	G/C	46 (46.0)	66 (50.4)	0.50 (0.27 - 0.92)	0.004^*
	G/G	15 (15.0)	37 (28.2)	0.29 (0.13 - 0.63)
	Dominant
	C/C	39 (39.0)	28 (21.4)	1.0 (Reference)
	G/C-G/G	61 (61.0)	103 (78.6)	0.43 (0.24 - 0.76)	0.003^*
	log-Additive (G)	100 (43.3)	131 (56.7)	0.54 (0.36 - 0.78)	0.001^*

SNP	Genotype	Positive anti-CHIKV IgG individuals without persistent joint pain (%) (n = 64)	Positive anti-CHIKV IgG individuals with persistent joint pain (%) (n = 86)	Adjusted OR (95% CI)	p-value
TLR3 (L412F rs3775291;1234 C > T)	All
	Codominant
	C/C	29 (45.3)	36 (41.9)	1.0 (Reference)
	C/T	28 (43.8)	39 (45.3)	1.12 (0.56 - 2.23)	0.892
	T/T	07 (10.9)	11 (12.8)	1.27 (0.44 - 3.68)
	Dominant
	C/C	29 (45.3)	36 (41.9)	1.0 (Reference)
	C/T-T/T	35 (54.7)	50 (58.1)	1.15 (0.60 - 2.21)	0.673
	log-Additive (T)	64 (42.7)	86 (57.3)	1.08 (0.66 - 1.77)	0.760
IRF5 (198 G > T rs2004640)	All
	Codominant
	G/G	19 (29.7)	27 (31.4)	1.0 (Reference)
	G/T	35 (54.7)	38 (44.2)	0.76 (0.36 - 1.61)	0.320
	T/T	10 (15.6)	21 (24.4)	1.48 (0.57 - 3.84)
	Dominant
	G/G	19 (29.7)	27 (31.4)	1.0 (Reference)
	G/T-T/T	45 (70.3)	59 (68.6)	0.92 (0.46 - 1.86)	0.822
	log-Additive (G)	64 (42.7)	86 (57.3)	1.15 (0.73 - 1.82)	0.544
TLR7 (3′UTR G > C rs3853839)	All	(n = 64)	(n = 86)
	log-Additive (G)	64 (42.7)	86 (57.3)	0.72 (0.42 - 1.26)	0.250
	FEMALE	(n = 36)	(n = 64)
	Codominant
	C/C	18 (50.0)	35 (54.7)	1.0 (Reference)
	G/C	14 (38.9)	22 (34.4)	0.81 (0.34 - 1.95)	0.893
	G/G	4 (11.1)	7 (10.9)	0.90 (0.23 - 1.88)
	Dominant
	C/C	18 (50.0)	35 (54.7)	1.0 (Reference)
	G/C-G/G	18 (50.0)	29 (45.3)	0.83 (0.37 - 1.88)	0.652
	log-Additive (G)	36 (36.0)	64 (64.0)	0.90 (0.50 - 1.64)	0.732
TLR8 (129 C > G rs3764879)	All	(n = 64)	(n = 86)
	log-Additive (G)	64 (42.7)	86 (57.3)	0.59 (0.34 - 1.01)	0.06
	FEMALE	(n = 36)	(n = 64)
	Codominant
	C/C	12 (33.3)	27 (42.2)	1.0 (Reference)
	G/C	18 (50.0)	28 (43.8)	0.69 (0.28 - 1.70)	0.680
	G/G	06 (16.7)	09 (14.1)	0.67 (0.19 - 2.30)
	Dominant
	C/C	12 (33.3)	27 (42.2)	1.0 (Reference)
	G/C-G/G	24(66.7)	37 (57.8)	0.69 (0.29 - 1.61)	0.381
	log-Additive (G)	36 (36.0)	64 (64.0)	0.79 (0.44 - 1.42)	0.429

SNP	Genotype	ASYM cases (%) (n = 29)	SYM cases (%) (n = 121)	Adjusted OR (95% CI)	p-value
TLR3 (L412F rs3775291;1234 C > T)	All
	Codominant
	C/C	11 (37.9)	54 (44.6)	1.0 (Reference)
	C/T	15 (51.7)	52 (43.0)	1.42 (0.60 - 3.37)	0.697
	T/T	3 (10.3)	15 (12.4)	0.98 (0.24 3.98)
	Dominant
	C/C	11 (37.9)	54 (44.6)	1.0 (Reference)	0.511
	C/T-T/T	18 (62.1)	67 (55.4)	1.32 (0.57 - 3.03)
	log-Additive (T)	29 (19.3)	121 (80.7)	1.17 (0.63 - 2.17)	0.62
IRF5 (198 G > T rs2004640)	All
	Codominant
	G/G	8 (27.6)	38 (31.4)	1.0 (Reference)
	G/T	16 (55.2)	57 (47.1)	1.33 (0.52 - 3.42)	0.729
	T/T	5 (17.2)	26 (21.5)	0.91(0.27 - 3.11)
	Dominant
	G/G	8 (27.6)	38 (31.4)	1.0 (Reference)	0.686
	G/T-T/T	21 (72.4)	83 (68.6)	1.20 (0.49 - 2.96)
	log-Additive (G)	29 (19.3)	121 (80.7)	0.99 (0.55 - 1.78)	0.976
TLR7 (3′UTR G > C rs3853839)	All	(n = 29)	(n = 121)
	log-Additive (G)	29 (19.3)	121 (80.7)	1.52 (0.76 - 3.06)	0.24
	FEMALE	(n = 14)	(n = 86)
	Codominant
	C/C	6 (42.9)	47 (54.7)	1.0 (Reference)
	G/C	7 (50.0)	29 (33.7)	1.89 (0.58 - 6.18)	0.499
	G/G	1 (7.1)	10 (11.6)	0.78 (0.08 - 7.24)
	Dominant
	C/C	6 (42.9)	47 (54.7)	1.0 (Reference)
	G/C-G/G	8 (57.1)	39 (45.3)	1.61 (0.51 - 5.03)	0.412
	log-Additive (G)	14 (14.0)	86 (86.0)	1.17 (0.52 - 2.62)	0.712
TLR8 (129 C > G rs3764879)	All	(n = 29)	(n = 121)
	log-Additive (G)	29 (19.3)	121 (80.7)	2.88 (1.40 - 5.94)	0.00⁴*
	FEMALE	(n = 14)	(n = 86)
	Codominant
	C/C	2 (14.3)	37 (43.0)	1.0 (Reference)
	G/C	10 (71.4)	36 (41.9)	5.14 (1.05 - 25.10)	0.071
	G/G	2 (14.3)	13 (15.1)	2.85 (0.36 - 22.31)
	Dominant
	C/C	2 (14.3)	37 (43.0)	1.0 (Reference)
	G/C-G/G	12(85.7)	49 (57.0)	4.53 (0.96 - 21.49)	0.029^*
	log-Additive (G)	14 (14.0)	86 (86.0)	1.76 (0.79 - 3.94)	0.167