title: Functional SNPs in the SCGB3A2 promoter are associated with susceptibility to Graves' disease.
abstract: 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 approximately -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.
authors.affiliation: Ruijin Hospital, State Key Laboratory of Medical Genomics, Shanghai Institute of Endocrinology, Shanghai Jiao Tong University (SJTU), School of Medicine, Shanghai 20025, China. huaidong_s1966@163.com
authors.forename: Huai-Dong
authors.initials: HD
authors.lastname: Song
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Shi
authors.forename: Shuang-Xia
authors.initials: SX
authors.lastname: Zhao
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Jia-Jun
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Yong-De
authors.initials: YD
authors.lastname: Peng
authors.forename: Guan-Qi
authors.initials: GQ
authors.lastname: Gao
authors.forename: Jiong
authors.initials: J
authors.lastname: Tao
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Pan
authors.forename: Li
authors.initials: L
authors.lastname: Shao
authors.forename: Feng
authors.initials: F
authors.lastname: Cheng
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Guo-Yue
authors.initials: GY
authors.lastname: Yuan
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Xun
authors.initials: X
authors.lastname: Chu
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Sheng
authors.forename: Rong-Ying
authors.initials: RY
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Su
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Jia
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Ming-Dao
authors.initials: MD
authors.lastname: Chen
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Jia-Lun
authors.initials: JL
authors.lastname: Chen
mesh_terms: D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006111:Graves Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060765:Secretoglobins; D014598:Uteroglobin / Q000235:genetics* / Q000378:metabolism
chemical_list: D005819:Genetic Markers; C490460:MARCO protein, human; D011506:Proteins; D011971:Receptors, Immunologic; C449940:SCGB3A2 protein, human; C449818:Scgb3a2 protein, mouse; D060765:Secretoglobins; D014598:Uteroglobin