Meta-analysis of sib pair linkage studies of asthma and the interleukin-9 gene (IL9)

Asthma is a complex disease, with an etiology that includes both genetic and environmental influences that may interact. The moderate heritability of asthma has led researchers to investigate its molecular genetic basis using both exploratory investigations of linkage via genome scans, as well as targeted studies of specific candidate genes. Promising candidate genes include the cytokine genes on chromosome 5q23-31. Both genome scans and association studies of these candidate genes/genomic regions have yielded mixed findings, which raise the possibilities of a true relation that emerges more strongly in certain samples simply due to sampling variability, as well as of genetic heterogeneity. Meta-analytic approaches that combine data across samples and examine how findings may vary as a function of effect modifiers can address both of these possibilities. In this study, we used a meta-analytic approach to examine linkage between the interleukin-9 gene (IL9), one of the cytokine genes located on chromosome 5q31, and asthma diagnoses and serum IgE levels in four samples. We analyzed IBD allele sharing for affected, unaffected, and discordant sib pairs, and as a function of sibling differences in IgE levels. We used a recently developed logistic regression-based method that allows for the inclusion of covariates and/or effect modifiers in the analysis of allele sharing in sib-pairs [Rice et al., Genet Epidemiol 17(Suppl. 1):S691-5, 1999]. Sex of the siblings and transmitting parent were considered both as covariates and effect modifiers in analyses. The results provided little evidence for linkage, or for heterogeneity therein due to sex or transmitting parent, either within or across samples.