Functional SNPs in the SCGB3A2 promoter are associated with susceptibility to Graves' disease

Graves’ disease (GD) is one of the most common human autoimmune diseases, and recent data estimated a prevalence of clinical hyperthyroidism of 0.25–1.09% in the population. Several reports have linked GD to the region 5q12–q33; and a locus between markers D5s436 and D5s434 was specifically linked to GD susceptibility in the Chinese population. In the present study, association analysis was performed using a large number of single-nucleotide polymorphisms (SNPs) at this locus in 2811 patients with GD recruited from different geographic regions of China. The strongest associations with GD in the combined Chinese Han cohorts were mapped to two SNPs in the promoter (pSNP) of SCGB3A2 [SNP76, rs1368408, P 5 1.43 3 10 26 , odds ratio (OR) 5 1.28 and SNP75, 2623 2622, P 5 7.62 3 10 25 ,O R5 1.32, respectively], a gene implicated in immune regulation. On the other hand, pSNP haplotypes composed of the SNP76 (rs1368408)1SNP74 (rs6882292) or SNP761SNP75 (2623 2622, AG/T) variants are correlated with high disease susceptibility (P 5 0.0007, and P 5 0.0192, respectively) in this combined Chinese Han cohort. Furthermore, these haplotypes were associated with reduced SCGB3A2 gene expression levels in human thyroid tissue, while functional analysis revealed a relatively low efficiency of SCGB3A2 promoters of the SNP761SNP75 and SNP761SNP74 haplotypes in driving gene expression. These results suggest that the SCGB3A2 gene may contribute to GD susceptibility.