Genetic Variation of Promoter Sequence Modulates XBP1 Expression and Genetic Risk for Vitiligo

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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. 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.