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

摘要: Our previous genome-wide linkage analysis identified a susceptibility locus for generalized vitiligo on 22q12. To search genes within the locus, we investigated biological candidate gene, X-box binding protein 1(XBP1). First, sequenced all exons, exon-intron boundaries as well some 5' and 3' flanking sequences of XBP1 in 319 cases 294 controls Chinese Hans. Of 8 common variants identified, significant association was observed at rs2269577 (p_(trend) = 0.007, OR 1.36, 95% CI 1.09-1.71), putative regulatory polymorphism promoter region XBP1. We then variant an additional 365 404 found supporting evidence 0.008, 1.31, 1.07-1.59). further validate association, genotyped another independent sample 1,402 1,288 controls, including 94 parent-child trios, confirmed by both case-control 0.003, 1.18, 1.06-1.32) family-based transmission disequilibrium test (TDT, p 0.005, 1.93, 1.21-3.07). The combined 2,086 1,986 provided highly 2.94x10(-6), 1.23, 1.13-1.35). Furthermore, also suggestive epistatic effect between HLA-DRB1*07 allele development (p 0.033). subsequent functional study showed that risk-associated C had stronger activity than non-risk G allele, there elevated expression lesional skins patients carrying allele. Therefore, our has demonstrated transcriptional modulation germ-line impact vitiligo.