Polymorphisms in the interleukin 3 gene show strong association with susceptibility to Graves' disease in Chinese population.

Graves' disease (GD) is a common organ-specific autoimmune disorder, which is multifactorial and develops in genetically susceptible individuals. We had earlier mapped a susceptibility locus for GD to chromosome 5q31-33 in a linkage study. Here we used tag single-nucleotide polymorphisms (SNPs) to search for genetic variants associated with GD, and examined 19 functional candidate genes in this chromosomal region. We identified 192 polymorphisms by re-sequencing the candidate genes, and selected 51 tagSNPs to genotype in a case-control collection of 1118 south Han Chinese subjects (428 cases and 690 controls). Initial analysis suggested that a non-synonymous SNP rs40401 (P27S) of interleukin 3 (IL3) was associated with GD, and further fine-mapping showed that rs40401, or its perfect proxy SNP rs31480 in the 5' flanking region of IL3, fully accounted for the association signal at this locus. We replicated significant association of rs40401 with GD in an independent sample collection of 839 north Han Chinese subjects. A combined analysis revealed strong validation of this association (odds ratio (OR(common))=1.63, combined P (P(comb))=4 x 10(-6) in the Recessive disease model). This study provides convincing evidence that the IL3 gene is a susceptibility locus for GD in the Chinese population.