1 Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China, 2 The Key Laboratory of Gene Resource Utilization for Severe Diseases, Ministry of Education and Anhui Province, Hefei, Anhui, China, 3 Chinese National Human Genome Center at Shanghai, Shanghai, China, 4 Department of Dermatology of Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, China, 5 Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada, 6 Human Genetics, Genome Institute of Singapore, Singapore
SOURCE: http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000523
ABSTRACT
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 = 2.94×10−6, 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.
Author Summary
Vitiligo is a genetically complex skin disorder that afflicts 0.1%–2% of
the population throughout the world. Linkage and association studies in
different populations have implicated several genomic regions and
candidate genes that are linked to the development of vitiligo. Our
previous genome-wide linkage analysis identified a genetic
susceptibility locus for vitiligo on 22q12 in a Chinese population. In
this study, we conducted a genetic and molecular study of a biologically
plausible candidate gene, XBP1, within the region. We first performed a
progressive association analysis in three independent samples of
vitiligo, which revealed significant association between a putative
promoter polymorphism, rs2269577, and vitiligo. Then, our functional
analysis also demonstrated that the risk-associated allele of this
variant has a stronger promoter activity and was associated with a
significantly elevated expression of XBP1 in lesional skins in patients
carrying the risk-associated allele. Our findings have provided the
first evidence for XBP1 to play an important role in the development of
vitiligo.
Citation: Ren Y, Yang S, Xu S, Gao M, Huang W, et al. (2009) Genetic Variation of Promoter Sequence Modulates XBP1 Expression and Genetic Risk for Vitiligo. PLoS Genet 5(6): e1000523. doi:10.1371/journal.pgen.1000523
Editor: Derry C. Roopenian, The Jackson Laboratory, United States of America
Received: December 9, 2008; Accepted: May 18, 2009; Published: June 19, 2009
Copyright: © 2009 Ren et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported in part by the Key Project of National Natural Science Foundation (No. 30530670), the Cooperation Project of Chinese Key National Natural Science Foundation for Overseas Youth (No. 30628021), Anhui Provincial Special Scientific Program (2007-7), and Constructive Foundation from the Key Laboratory of Gene Resource Utilization for Severe Diseases, Anhui province and Ministry of Education, P.R China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: liuj3@gis.a-star.edu.sg (JL); ayzxj@vip.sina.com (XZ)