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 = 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.
Song
Huai-Dong
HD
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
Liang
Jun
J
Shi
Jing-Yi
JY
Zhao
Shuang-Xia
SX
Liu
Zhi
Z
Zhao
Jia-Jun
JJ
Peng
Yong-De
YD
Gao
Guan-Qi
GQ
Tao
Jiong
J
Pan
Chun-Ming
CM
Shao
Li
L
Cheng
Feng
F
Wang
Yi
Y
Yuan
Guo-Yue
GY
Xu
Chao
C
Han
Bing
B
Huang
Wei
W
Chu
Xun
X
Chen
Yi
Y
Sheng
Yan
Y
Li
Rong-Ying
RY
Su
Qing
Q
Gao
Ling
L
Jia
Wei-Ping
WP
Jin
Li
L
Chen
Ming-Dao
MD
Chen
Sai-Juan
SJ
Chen
Zhu
Z
Chen
Jia-Lun
JL
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
D005819:Genetic Markers; C490460:MARCO protein, human; D011506:Proteins; D011971:Receptors, Immunologic; C449940:SCGB3A2 protein, human; C449818:Scgb3a2 protein, mouse; D060765:Secretoglobins; D014598:Uteroglobin