Some evidence for a relation between polymorphisms of TLRs (2, 6, 9, 10) and childhood asthma
Childhood asthma in relation to polymorphisms in TLR s was addressed in 19 studies [21, 25–28, 34, 38, 39, 41, 43–45, 55–61]. The age of the population in these studies ranged from 0 to 18 years with 31 to 644 cases and 184 to 2927 controls. Outcome was defined as atopic/allergic asthma, non-atopic asthma, bronchial asthma, current asthma symptoms or asthma in general.
TLR4 is by far the most studied of all TLR s in relation to asthma in children, but only some studies showed an association (Table 3). Rs4986791 was statistically more frequent in mild atopic asthmatics , whereas rs2737190 showed an association with asthma in general and also non-atopic asthma  Rs4986790 showed no association with asthma in seven studies [41, 43–45, 55, 56, 60], but was associated with symptoms of (atopic) asthma in two other studies [34, 39]. Also, rs4986790 was associated with increased asthma severity in atopic children . However, in most studies polymorphisms of TLR4 did not show any association with asthma [21, 25, 27, 38, 41, 44, 45, 55],[56, 59, 60]. Some duplication between the studies of Reijmerink et al. and Kerkhof et al. was present as the same population was used for single nucleotide polymorphism analysis [41, 56]. Studied polymorphisms in the study of Reijmerink were not specified .
TLR2, TLR6, TLR9, and TLR10 have been associated with asthma in several studies. For TLR2, rs4696480, rs3804099, rs3804100, and rs1898830 showed association with childhood asthma in a number of studies, but not in others (Table 3) [21, 25–27, 38, 43, 56, 62]. Moreover, rs5743708 was associated with increased asthma severity in atopic children (Table 3) . Finally, rs13150331, rs4696483, rs5743704, rs7656411, rs1339, rs2289318, and rs5743708 showed no association with childhood asthma [21, 43, 59]. Two studies had an overlap in data [26, 56]. For TLR6, rs6531666, rs5743789, rs5743798, and rs5743810 significant associations with asthma and atopic asthma were found, but not with asthma in other studies (Table 3) [21, 27, 45, 57, 61]. Haplotype spanning of polymorphisms in TLR6 and TLR10 (see TLR10) revealed an association with childhood asthma, indicating no individual but a combined influence of these polymorphisms on asthma in children [21, 57]. Other TLR6 polymorphisms were not associated with asthma in children [21, 27, 45]. For TLR9, rs187084 showed a positive association with childhood asthma (Table 3) , but not in all studies [21, 45]. Other polymorphisms revealed no association with childhood asthma [21, 27, 44, 45, 60, 63]. For TLR10, out of the eight studied polymorphisms, rs4129009 and rs11096957 showed association with (atopic) asthma in some studies (Table 3) [21, 27, 45, 57]. The rs11096957 polymorphism only demonstrated association in one of the two children cohorts (Study of Asthma Genetics and Environment Cohort) studied by Daley et al . Several polymorphisms (rs4274855, rs10856839, rs11096957, rs11096956, rs11096955, rs11466657, rs4219009) showed no individual association with bronchial asthma, however, haplotype spanning together with polymorphisms in TLR6 (rs5743794, and rs5743810) did . Also rs4274855, rs10856839, rs11096957, and rs4129009 demonstrated a haplotype-based association .
TLR7 and TLR8 were only studied in two studies and TLR1, TLR3, and TLR5 in one study: For TLR7, associations with asthma phenotypes for rs179008 separately, and rs179008, rs5743781, rs864058 haplotypes were observed in one study, however, rs179008 showed no association in another study (Table 3) [27, 28]. For TLR8, association with asthma phenotype in childhood was shown for rs2407992 separately, and rs5741883, rs3764879, rs3764880, rs5744077, rs2159377, and rs2407992 haplotypes, but not rs3761624 (Table 3) [27, 28]. For TLR1, rs5743595, rs4833095, and not rs5743594 showed significant inverse effects with atopic asthma in childhood (Table 3) . For TLR3, rs3775291 showed no association with childhood asthma . Also, rs5744168, rs2072493 and rs5744174 of TLR5 showed no significant association with childhood asthma .
One study with 1105 cases and 3137 controls aged 8 to 12 years used wheeze in the past 12 months as outcome variable . For TLR4, rs11536896 showed association, but three other polymorphisms did not. In TLR2, rs1898830 showed association with more frequent wheeze. For TLR9, out of the three studied polymorphisms, rs187084 showed positive association with wheeze.