Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis

Am J Hum Genet. 2012 May 4;90(5):796-808. doi: 10.1016/j.ajhg.2012.03.013. Epub 2012 Apr 19.

Abstract

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× 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-α) 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 × 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • CARD Signaling Adaptor Proteins / genetics*
  • CARD Signaling Adaptor Proteins / metabolism
  • Case-Control Studies
  • Epidermis / metabolism
  • European Continental Ancestry Group / genetics
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Guanylate Cyclase / genetics*
  • Guanylate Cyclase / metabolism
  • HLA-C Antigens / genetics
  • HLA-C Antigens / metabolism
  • Humans
  • Keratinocytes
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mutation, Missense
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism*
  • Polymorphism, Genetic
  • Psoriasis / genetics*
  • Skin / pathology
  • Transcriptome
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • CARD Signaling Adaptor Proteins
  • HLA-C Antigens
  • Membrane Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • CARD14 protein, human
  • Guanylate Cyclase