association analysis identifies znf750 regulatory variants in psoriasis关联分析确定znf750监管变体牛皮癣.pdfVIP

Birnbaum et al. BMC Medical Genetics 2011, 12:167 /1471-2350/12/167 RESEARCH ARTICLE Open Access Association analysis identifies ZNF750 regulatory variants in psoriasis 1,2,3† 4† 3 2,5 4 2,5 Ramon Y Birnbaum , Genki Hayashi , Idan Cohen , Annie Poon , Haoyan Chen , Ernest T Lam , Pui-Yan Kwok2,5, Ohad S Birk3 and Wilson Liao4* Abstract Background: Mutations in the ZNF750 promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. ZNF750 encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene. Methods: We examined whether ZNF750 variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of ZNF750 in 716 Caucasian psoriasis cases and 397 Caucasian controls. Results: We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two ZNF750 haplotypes associated with psoriasis (p 0.05). We also identified an excess of rare promoter and 5’untranslated region (UTR) variants in psoriasis cases compared to controls (p = 0.041), whereas there was no significant difference in the number of rare coding and rare 3’ UTR variants. Using a promoter functional assay in stimulated human primary keratinocytes, we showed that four ZNF750 promoter and 5’ UTR variants displayed a 35-55% reduction of ZNF750 promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a ZNF750 promoter variant. However, the rare promoter and 5’ UTR variants identified in this study did not s