Second-generation association study of the 5q31 cytokine gene cluster and the interleukin-4 receptor in asthma

We have analyzed a dense set of single-nucleotide polymorphisms (SNPs) and microsatellites spanning the T-helper cytokine gene cluster (interleukins 3 , 4, 5, 9, and 13, interferon regulatory factor-1, colony-stimulating facto r-2, and T-cell transcription factor-7) on 5q31 and the gene encoding the i nterleukin-4 receptor (IL4R) on 16p12 among Finnish families with asthma. A s shown by haplotype pattern mining analysis, the number of disease-associa ted haplotype patterns differed from that expected for the 129Q allele poly morphism in IL13 for high serum total immunoglobulin (Ig) E levels, but not for asthma. The same SNP also yielded the best haplotype associations. For IL4R, asthma-associated haplotype patterns, most spanning the S411L polymo rphism, showed suggestive association. However, these haplotypes consisted of the major alleles for the intracellular part of the receptor and were ve ry common among both patients and controls. The minor alleles 503P and 576R have been reported to be associated with decreased serum IgE levels and ch anges in the biological activity of the protein, especially when inherited together. In the Finnish population, these two polymorphisms segregated in strong linkage disequilibrium. Our data support previous findings regarding IL4R, indicating that 503P and 576R may act as minor protecting alleles fo r IgE-mediated disorders.