Genetic association of key Th1/Th2 pathway candidate genes, IRF2, IL6, IFNGR2, STAT4 and IL4RA, with atopic asthma in the Indian population.

Abstract

Asthma is a complex, multifactorial disease resulting due to dysregulated immune responses. Genetic factors contribute significantly to asthma pathogenesis, and identification of these factors is one of the major goals in understanding the disease. Th1/Th2 helper differentiation has a critical role in modulating the phenotypes associated with atopic asthma. This study was aimed at identifying genetic modifiers of asthma in selected genes involved in T helper differentiation. A total of 354 single-nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped in a case-control cohort (cases=147, controls=199) and families (n=247) using Illumina's Golden Gate Assay. Five SNPs, rs3733475A/C (IRF2), rs2069832A/G (IL6), rs2012075G/A (IFNGR2) and rs1400656G/A (STAT4) and rs1805011C/A (IL4RA) were found to be associated with asthma in family based as well as in case-control analyses (P=0.002, P=0.001, P=0.004, P=0.003 and P=0.001, respectively). Interestingly, the minor alleles at these loci showed a protective effect. A five loci haplotype, TAACG, in IRF2 gene, was significantly associated with asthma in families (P=1.1 × 10(-6)) and in case-control cohort (P=0.01). In conclusion, our studies led to identification of some key candidate genes, namely IRF2, IL6, IFNGR2, STAT4 and IL4RA that modulate genetic susceptibility to asthma in the Indian population. Also, this is the first report of independent association of IL6 gene polymorphism with atopic asthma.