Background
Methods
Search strategy
Selection criteria
Data extraction
Data synthesis
Results
Study characteristics and quality assessment
Author, year [Ref] | SNP | Country | Setting | Age group in cases,yr | Male % in cases | Cases | Controls | Genotyping method | Consistent with HWE |
---|---|---|---|---|---|---|---|---|---|
Mockenhaupt, 2006 [20] | TLR4-A299G, T399I TLR9 T-1237C, T1486C | Ghana | H | Children | 46.6 | 290 | UM: 290 Healthy: 290 | allele-specific PCR and PCR-RT | Yes |
Leoratti, 2008 [21] | TLR4 D299G TLR9 T1237C, T1486C | Brazil | H | md 29 | 86 | 230 | 74 | PCR–RFLP | Yes |
Sam-Agudu, 2010 [22] | TLR4-A299G, T399I TLR9-T1486C, T1237C | Uganda | H | 6.2 (2.4) | 63.1 | Cases (SM): 65 | Controls (UM: 52 | PCR and LDR-FMA | Yes |
Zakeri, 2011 [23] | TLR4 D299G, T399I TLR9 T1486C, T1237C | Iran | HCs | md 28 | 65.6 | P. falciparum infected: 320 | Healthy control: 320 | PCR–RFLP | Yes |
Esposito, 2012 [24] | TLR4 A299G (rs4986790) TLR9 T1486C (rs187084), T1237C (rs5743836) | Burundi | H | Children | 57.5 | 602 | 337 | Taqman | Yes |
Munde, 2012 [25] | TLR9 T1237C | Kenya | H | Children | 47.8 | SM: 138 | UM: 163 | TaqMan | Yes |
Sawian, 2012 [26] | TLR4 A299G TLR9 T1237C, T1486C | India | H | md: 26.2 (R2-58) | SM: 136 | Controls (UM: 53 | PCR–RFLP | No | |
Kar, 2015 [27] | TLR4 D299G TLR9 T1237C, T1486C | India | H | SM: 38.0 (25.0–53.7) UM: 38.0 (24.2–55.0) | 58% | 200 | 200 | PCR–RFLP | Yes (D299G) No (T1237C and T1486C) |
Iwalokun, 2015 [28] | TLR4 A299G, T399I | Nigeria | H | Children | 62.1 | 182 | 97 | PCR–RFLP | Yes |
Costa, 2017 [29] | TLR4 A299G (rs4986790), T399I (rs4986791) TLR9-T1237C (rs187084), T1486C (rs5743836) | Brazil | 37 (19 ± 53) | 61.5 | Pv-325 | Healthy group: 274 | PCR–RFLP | Yes (A299G, T399I, T1237C) No (T1486C) | |
Rani, 2018 [30] | TLR4 A299G | Pakistan | H | 22.7 ± 13.6 | 53.5 | 228 (SM: 89, UM: 139) | 226 | Allele-specific PCR | No |
Effect of TLR 4/TLR9 on severity outcome
Polymorphisms | Variants | Number of studies included | Total cases/controls | Genetic model | Effect size, OR (95%CI) | Model |
---|---|---|---|---|---|---|
TLR 9 | T1486C | 5 | 1380/2378 | Allele | 1.26 (1.08–1.48) | F |
660/1189 | Dominant | 1.29 (0.84–1.98) | R | |||
660/1189 | Recessive | 1.27 (0.9–1.79) | F | |||
325/697 | Homozygous | 1.55 (1.08–2.28) | F | |||
585/1091 | Heterozygous | 1.26 (0.73–2.16) | R | |||
TLR 9 | T1237C | 6 | 1606/2720 | Allele | 1.01 (0.81–1.27) | R |
803/1350 | Dominant | 1.32 (0.86–2.03) | R | |||
803/1350 | Recessive | 0.71 (0.36–1.42) | R | |||
442/854 | Homozygous | 0.87 (0.45–1.7) | R | |||
722/1145 | Heterozygous | 1.57 (0.86–2.86) | R | |||
TLR 4 | T399I | 2 | 202/152 | Allele | 1.03 (0.47–2.28) | F |
104/79 | Dominant | 1.05 (0.43–2.8) | F | |||
104/79 | Recessive | 0.73 (0.1–5.31) | F | |||
85/57 | Homozygous | 0.74 (0.1–5.41) | F | |||
102/77 | Heterozygous | 1.11 (0.43–2.91) | F | |||
TLR 4 | D299G | 7 | 1463/2936 | Allele | 1.16 (0.93–1.44) | F |
773/1495 | Dominant | 1.1 (0.87–1.4) | F | |||
773/1495 | Recessive | 0.99 (0.78–1.26) | F | |||
625/1207 | Homozygous | 1.29 (0.65–2.55) | F | |||
759/1478 | Heterozygous | 1.08 (0.84–1.37) | F |
Effect of TLR 4/TLR9 on susceptibility of malaria
Polymorphisms | Variants | Number of studies included | Cases/controls | Genetic model | Effect size, OR (95% CI) | Model |
---|---|---|---|---|---|---|
TLR 9 | T1486C | 5 | 3472/2610 | Allele | 1.03 (0.91–1.16) | F |
1740/1166 | Dominant | 1.07 (0.78–1.47) | F | |||
1740/1166 | Recessive | 0.93 (0.68–1.27) | F | |||
801/533 | Homozygous | 0.85 (0.5–1.43) | R | |||
1566/1018 | Heterozygous | 1.17 (0.78–1.78) | R | |||
TLR 9 | T1237C | 5 | 2867/2217 | Allele | 0.97 (0.84–1.12) | F |
1735/1387 | Dominant | 0.87 (0.52–1.45) | R | |||
1735/1387 | Recessive | 1.53 (0.86–2.75) | R | |||
1225/859 | Homozygous | 1.28 (0.97–1.68) | R | |||
1537/1173 | Heterozygous | 0.82(0.49–1.4) | R | |||
TLR 4 | T399I | 4 | 1716/1400 | Allele | 0.95 (0.69–1.31) | F |
861/707 | Dominant | 0.99 (0.71–1.39) | F | |||
861/707 | Recessive | 1.03 (0.73–1.46) | F | |||
776/634 | Homozygous | 0.54 (0.17–1.69) | F | |||
826/700 | Heterozygous | 1.13 (0.8–1.6) | F | |||
TLR 4 | D299G | 7 | 3776/2847 | Allele | 1.05 (0.86–1.29) | F |
1959/1576 | Dominant | 1.11 (0.9–1.36) | F | |||
684/1356 | Recessive | 0.83 (0.66–1.05) | F | |||
545/1092 | Homozygous | 0.95 (0.51–1.79) | F | |||
672/1341 | Heterozygous | 1.08 (0.87–1.34) | F |
Subgroup analysis and publication bias
Discussion
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TLR 9 (T1486C) showed a significant role in severity of malaria under allele model and homozygous genetic models. These were in the absence of within-study heterogeneity. A sensitivity analysis showed the stability of the estimates.
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TLR 9 (T1486C) showed a significant role in susceptibility of malaria only in the subgroup of children from non-Asian countries under allele model.
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TLR9 (T1237C) and severity of malaria was significantly associated in the adult of Asian countries under heterogeneous model. This polymorphism was significantly associated with susceptibility of malaria in the children group of non-Asian countries under recessive and homogenous genetic models
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The reaming TLR polymorphisms showed no significant association with either severity of malaria or susceptibility of malaria under any genetic models or in any subgroups.