Toll-like receptors and microbial exposure: gene-gene and gene-environment interaction in the development of atopy

Abstract

Environmental and genetic factors contribute to atopy development. High microbial exposure may confer a protective effect on atopy. Toll-like receptors (TLRs) bind microbial products and are important in activating the immune system.To assess whether interactions between microbial exposures and genes encoding TLRs (and related genes) result in atopy, genes, environmental factors and gene-environment interactions of 66 single-nucleotide polymorphisms (SNPs) of 12 genes (TLR 1-6, 9 and 10, CD14, MD2, lipopolysaccharide-binding protein (LBP) and Dectin-1), and six proxy parameters of microbial exposure (sibship size, pets (three different parameters), day-care and intrauterine and childhood tobacco smoke exposure) were analysed for association with atopic phenotypes in 3,062 Dutch children (the Allergenic study).The presence of two or more older siblings increased the risk of developing high total immunoglobulin (Ig)E levels at different ages. This risk increased further in children aged 1-2 yrs carrying the minor allele of TLR6 SNP rs1039559. Furthermore, novel two-and three-factor genegene and gene-environment interactions were found (e.g. between sibship size, day-care and LBP SNP rs2232596).Larger sibship size is associated with increased total IgE levels. Furthermore, complex two-and three-factor interactions exist between genes and the environment. The TLRs and related genes interact with proxy parameters of high microbial exposure in atopy development.

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

“…We have also shown previously that early- and late-onset asthma exhibit different clinical characteristics in our study21. Our findings were also consistent with several other studies that have also found some evidence of an association between TLR6 -rs5743810 T-allele and atopic asthma9, allergic rhinitis22 and allergic sensitisation23 in children.…”

“…We are aware of only one previous study that examined the interaction between TLR6 SNPs and proxies of microbial exposure and allergic disease outcomes23. In contrast to our finding of a lower risk of asthma in individuals with the TLR6 -rs1039559 T-allele and early farm exposure, their study found higher IgE levels at age two years in individuals with the TLR6 -rs1039559 CC-genotype and exposure to two or more older siblings.…”

Polymorphisms in the TLR6 gene associated with the inverse association between childhood acute lymphoblastic leukemia and atopic disease

“…23 Although several candidate gene studies did find TLR6 polymorphisms to be associated with atopy, 5,8,24 this has to date not yet been confirmed in genome-wide association studies. However, Figure 1.…”

Polymorphism in the gene encoding toll-like receptor 10 may be associated with asthma after bronchiolitis

“…Innate immunity, which is highly regulated by genes, plays a crucial role in both infection and inflammation 3 . The development of asthma is a complicated and multifactorial process in which genes interact with the environment 4 . In early life, the Th2-dominated immune responses shift towards Th1-dominated responses 5 , but among genetically susceptible individuals, environmental factors like viruses may lead to the persistence of Th2-dominated immunity and to subsequent atopy and asthma 6 .…”