Rare and Common Variants in CARD14, Encoding an Epidermal Regulator of NF-kappaB, in Psoriasis

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• 作者：Catherine  ; T. Jordan¹ ; Li Cao¹ ; Elisha  ; D.O. Roberson¹ ; Shenghui Duan¹ ; Cynthia  ; A. Helms¹ ; Rajan  ; P. Nair² ; Kristina  ; Callis Duffin³ ; Philip  ; E. Stuart² ; David Goldgar³ ; Genki Hayashi⁴ ; Emily  ; H. Olfson¹ ; Bing-Jian Feng³ ; Clive  ; R. Pullinger⁵ ; John  ; P. Kane⁶ ; Carol A. Wise⁷ ; Raphaela Goldbach-Mansky⁸ ; Michelle  ; A. Lowes⁹ ; Lynette Peddle¹⁰ ; Vinod Chandran¹¹ ; Wilson Liao⁴ ; Proton Rahman¹⁰ ; Gerald  ; G. Krueger³ ; Dafna Gladman¹¹ ; James  ; T. Elder² ; Alan Menter¹² ; Anne  ; M. Bowcock¹ ; ^{bowcock@genetics.wustl.edu}
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 期刊代码：P22_00029297
• 类别：bio
• 出版时间：4 May, 2012
• 卷：90
• 期：5
• 页码：796-808
• 文件大小：798 K

摘要

Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5脳 higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-伪) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1聽脳 10^鈭?). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw^{鈭?/sup>0602} (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.