Rare and Common Variants in CARD14, Encoding an Epidermal Regulator of NF-kappaB, in Psoriasis
Rare and Common Variants in CARD14, Encoding an Epidermal Regulator of NF-kappaB, in Psoriasis
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DOI：
10.1016/j.ajhg.2012.03.013
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发表时间：
2012-05-04
影响因子：
9.8
通讯作者：
Bowcock, Anne M.
中科院分区：
文献类型：
--
作者：
Jordan, Catherine T.;Cao, Li;Bowcock, Anne M.
银屑病是一种皮肤及其他器官常见的炎症性疾病。我们已经确定，编码皮肤表皮内B细胞κ轻链增强子核因子（NF - κB）激活剂的CARD14基因发生突变可导致PSORS2。在此，我们描述了CARD14基因中另外15种罕见的错义变异，它们在7个银屑病队列（>6000例患者和>4000例对照）中的分布情况，以及它们对NF - κB激活和角质形成细胞转录组的影响。病例中CARD14罕见变异比对照更多（负荷检验P值 = 0.0015）。一些变异仅在单个病例中出现，其中包括推定的致病性突变（c.424G>A [p.Glu142Lys]和c.425A>G [p.Glu142Gly]）以及泛发性脓疱型银屑病突变c.413A>C（p.Glu138Ala）；这三种突变位于CARD14的卷曲螺旋结构域内。c.349G>A（p.Gly117Ser）家族性银屑病突变在欧洲血统的病例中频率为0.0005。CARD14变异导致一系列NF - κB活性；特别是，推定的致病性变异导致的水平比野生型CARD14高2.5倍以上。两种变异（c.511C>A [p.His171Asn]和c.536G>A [p.Arg179His]）需要肿瘤坏死因子α（TNF - α）刺激才能使NF - κB水平显著升高。角质形成细胞中野生型和变异型CARD14转染体的转录组分析可能将致病性突变与中性变异（如多态性）区分开来。还对20多种CARD14多态性进行了基因分型，荟萃分析显示银屑病与rs11652075（c.2458C>T [p.Arg820Trp]；P值 = 2.1×10⁻⁶）之间存在关联。在两个最大的银屑病队列中，当rs11652075以HLA - Cw*0602（PSORS1）为条件时，关联的证据增加。这些研究有助于我们理解银屑病的遗传基础，并说明了在常见疾病中鉴定致病性变异所面临的挑战。
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 >2.5x 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-alpha) 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 CARD 14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 x 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw(star)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.