Family-Based Association Study of Tim-1 and Tim-3 Gene Polymorphisms with Childhood Asthma in Chinese Trios

Abstract

Background: Asthma is a complex genetic disease, caused by the interaction of multiple genetic and environmental factors. T cell immunoglobulin domain and mucin domain (Tim) genes are located in chromosome 5q31–33, a region repeatedly linked to asthma or asthma-related phenotypes in several populations. Two members of Tim families, Tim-1 and Tim-3, which are expressed on T cell surface and potentially involved in T cell proliferation and differentiation, are good candidate genes for asthma. We investigated whether genetic variants or haplotypes in Tim-1 and Tim-3 genes confer susceptibility to asthma in a Chinese population. Methods: A total of 9 polymorphisms were selected by using the HapMap Han Chinese population data and a haplotype-tagging single nucleotide polymorphism approach. Polymerase chain reaction fragment length polymorphism was adapted to determine the genotype in 118 complete Chinese trios of asthma. Then, transmission disequilibrium test (TDT), haplotypic relative risk (HRR), linkage disequilibrium and haplotype analysis were performed. Results: The single locus TDT and HRR analysis showed the 9 polymorphisms were not transmitted preferentially to asthma-affected children (all p > 0.05). However, in both the haplotypic TDT and HRR analysis, the haplotype G-A-ins-C-G consisting of 5 Tim-1 polymorphisms was found to be overtransmitted to affected offspring (χ² = 4.51, p = 0.03) and the haplotype G-G-G consisting of 3 Tim-3 polymorphisms was found to be undertransmitted to asthma children (χ² = 8.24, p = 0.004). Conclusions: We conclude that it is unlikely that the Tim-1 or Tim-3 polymorphisms influence asthma susceptibility individually, but that the haplotypes of variants may be functional or may be in linkage disequilibrium with other functional single nucleotide polymorphisms.