Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo.
Our previous genome-wide linkage analysis identified a susceptibility locus for generalized vitiligo on 22q12. To search for susceptibility genes within the locus, we investigated a biological candidate gene, X-box binding protein 1(XBP1). First, we sequenced all the exons, exon-intron boundaries as well as some 5' and 3' flanking sequences of XBP1 in 319 cases and 294 controls of Chinese Hans. Of the 8 common variants identified, the significant association was observed at rs2269577 (p_(trend) = 0.007, OR = 1.36, 95% CI = 1.09-1.71), a putative regulatory polymorphism within the promoter region of XBP1. We then sequenced the variant in an additional 365 cases and 404 controls and found supporting evidence for the association (p_(trend) = 0.008, OR = 1.31, 95% CI = 1.07-1.59). To further validate the association, we genotyped the variant in another independent sample of 1,402 cases and 1,288 controls, including 94 parent-child trios, and confirmed the association by both case-control analysis (p_(trend) = 0.003, OR = 1.18, 95% CI = 1.06-1.32) and the family-based transmission disequilibrium test (TDT, p = 0.005, OR = 1.93, 95% CI = 1.21-3.07). The analysis of the combined 2,086 cases and 1,986 controls provided highly significant evidence for the association (p_(trend) = 2.94x10(-6), OR = 1.23, 95% CI = 1.13-1.35). Furthermore, we also found suggestive epistatic effect between rs2269577 and HLA-DRB1*07 allele on the development of vitiligo (p = 0.033). Our subsequent functional study showed that the risk-associated C allele of rs2269577 had a stronger promoter activity than the non-risk G allele, and there was an elevated expression of XBP1 in the lesional skins of patients carrying the risk-associated C allele. Therefore, our study has demonstrated that the transcriptional modulation of XBP1 expression by a germ-line regulatory polymorphism has an impact on the development of vitiligo.
Ren
Yunqing
Y
Institute of Dermatology and Department of Dermatology at No 1 Hospital, Anhui Medical University, Hefei, Anhui, China.
Yang
Sen
S
Xu
Shengxin
S
Gao
Min
M
Huang
Wei
W
Gao
Tianwen
T
Fang
Qiaoyun
Q
Quan
Cheng
C
Zhang
Chi
C
Sun
Liangdan
L
Liang
Yanhua
Y
Han
Jianwen
J
Wang
Zhimin
Z
Zhang
Fengyu
F
Zhou
Youwen
Y
Liu
Jianjun
J
Zhang
Xuejun
X
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014820:Vitiligo / Q000235:genetics* / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D055815:Young Adult
D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human