The interaction between farming/rural environment and TLR2, TLR4, TLR6 and CD14 genetic polymorphisms in relation to early- and late-onset asthma

Abstract

Asthma phenotypes based on age-of-onset may be differently influenced by the interaction between variation in toll-like receptor (TLR)/CD14 genes and environmental microbes. We examined the associations between single-nucleotide polymorphisms (SNP) in the TLR/CD14 genes and asthma, and their interaction with proxies of microbial exposure (childhood farm exposure and childhood rural environment). Ten SNPs in four genes (TLR2, TLR4, TLR6, CD14) were genotyped for 1,116 participants from the Tasmanian Longitudinal Health Study (TAHS). Using prospectively collected information, asthma was classified as never, early- (before 13 years) or late-onset (after 13 years). Information on childhood farm exposure/childhood rural environment was collected at baseline. Those with early-onset asthma were more likely to be males, had a family history of allergy and a personal history of childhood atopy. We found significant interaction between TLR6 SNPs and childhood farm exposure. For those with childhood farm exposure, carriers of the TLR6-rs1039559 T-allele (p-interaction = 0.009) and TLR6-rs5743810 C-allele (p-interaction = 0.02) were associated with lower risk of early-onset asthma. We suggest the findings to be interpreted as hypothesis-generating as the interaction effect did not withstand correction for multiple testing. In this large, population-based longitudinal study, we found that the risk of early- and late-onset asthma is differently influenced by the interaction between childhood farming exposure and genetic variations.

Shared and Distinct Genetic Risk Factors for Childhood Onset and Adult Onset Asthma: Genome- and Transcriptome-wide Studies

“…S100A12 has been previously implicated in asthma 38 and FLG variants have been associated with atopic dermatitis and food allergies, and asthma in the context of other allergic diseases 21, 28–34 . Other childhood onset specific genes previously implicated in asthma but not previously reported in asthma GWASs are CCL20 39 at 2q36.3 and TLR10 40 at 4p14 in whole blood, and TLR6 41, 42 at 4p14, AP5B1 at 11q13.1 and SERPINB7 43 at 18q21·33 in skin.…”

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

“…TLR2 SNPs have not been associated directly with EoE, but have been associated with closely linked atopic diseases. Specifically, there are TLR2 SNPS which predispose to the development of asthma in Puerto Rican, Norwegian, Danish, and Caucasian African populations and development of severe atopic dermatitis in Italian and German populations . Interestingly, several of the SNPs decrease TLR2 signaling activity .…”

Genetics and Gene-Environment Interactions in Childhood and Adult Onset Asthma

“…Effect modification by farm exposure in childhood on the association between polymorphism in TLR genes and asthma have been shown. Being exposed to a farm environment in childhood was protective against childhood-onset asthma for those with TLR2/-16934 T-allele (86), TLR6-rs1039559 T-allele and TLR6-rs5743810 C-allele (87). The most comprehensive GWIS in 1708 children from 4 rural regions of Central Europe for childhood asthma in relation to farm-related exposures did not reveal any significant interaction with common SNPs (88); however, strong interactions were found for rarer variants in 15 genes, particularly of the glutamate receptor, metabotropic 1 gene (GRM1).…”