Human Molecular Genetics Advance Access originally published online on January 6, 2009
Human Molecular Genetics 2009 18(6):1156-1170; doi:10.1093/hmg/ddn442
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Functional SNPs in the SCGB3A2 promoter are associated with susceptibility to Graves' disease
,
1 Ruijin Hospital, State Key Laboratory of Medical Genomics, Molecular Medicine Center, Shanghai Institute of Endocrinology, Shanghai Jiao Tong University (SJTU), School of Medicine, Shanghai 20025, China 2 Shanghai Center for Systems Biomedicine, SJTU, 800 Dong Chuan Road, Shanghai 200240, China 3 Department of Endocrinology, Shandong Province Hospital, Shandong University, 324 Jing 5 Road, Jinan 250021, China 4 Department of Endocrinology, The First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, China 5 Department of Endocrinology, The People's Hospital of Linyi, Shandong Province, 27 Liberation Road, Linyi 276003, China 6 Centre of Anthropology, Fudan University, 220 Handan Road, Shanghai 200433, China 7 Department of Endocrinology, Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China 8 Chinese National Human Genome Center at Shanghai, Zhang Jiang High Tech Park, 250 Bi Bo Road, Shanghai 201203, China 9 Department of Endocrinology, Xin Hua Hospital, Shanghai Jiao Tong University (SJTU), School of Medicine, Shanghai 20092, China 10 Shanghai Diabetes Institute, Shanghai Jiaotong University, No. 6 Hospital, Shanghai 200233, China
* To whom correspondence should be addressed. Tel: +86 2164370045 Ext. 610808; Fax: +86 2164743206; Email: huaidong_s1966{at}163.com
Received November 14, 2008; Revised December 22, 2008; Accepted December 30, 2008
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 = 1.43 x 10–6, odds ratio (OR) = 1.28 and SNP75, –623
–622, P = 7.62 x 10–5, OR = 1.32, respectively], a gene implicated in immune regulation. On the other hand, pSNP haplotypes composed of the SNP76 (rs1368408)+SNP74 (rs6882292) or SNP76+SNP75 (–623–622, AG/T) variants are correlated with high disease susceptibility (P = 0.0007, and P = 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 SNP76+SNP75 and SNP76+SNP74 haplotypes in driving gene expression. These results suggest that the SCGB3A2 gene may contribute to GD susceptibility.
The authors wish it to be known that, in their opinion, the first six authors should be regarded as joint First Authors.
Present address: Department of Endocrinology, the Fourth Hospital of Xuzhou, Jiangsu Province, China.