Title |
Rare and Common Variants in CARD14, Encoding an Epidermal Regulator of NF-kappaB, in Psoriasis
|
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Published in |
American Journal of Human Genetics, April 2012
|
DOI | 10.1016/j.ajhg.2012.03.013 |
Pubmed ID | |
Authors |
Catherine T. Jordan, Li Cao, Elisha D.O. Roberson, Shenghui Duan, Cynthia A. Helms, Rajan P. Nair, Kristina Callis Duffin, Philip E. Stuart, David Goldgar, Genki Hayashi, Emily H. Olfson, Bing-Jian Feng, Clive R. Pullinger, John P. Kane, Carol A. Wise, Raphaela Goldbach-Mansky, Michelle A. Lowes, Lynette Peddle, Vinod Chandran, Wilson Liao, Proton Rahman, Gerald G. Krueger, Dafna Gladman, James T. Elder, Alan Menter, Anne M. Bowcock |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 50% |
Unknown | 1 | 50% |
Demographic breakdown
Type | Count | As % |
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Scientists | 1 | 50% |
Science communicators (journalists, bloggers, editors) | 1 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United States | 1 | <1% |
Germany | 1 | <1% |
Unknown | 185 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 31 | 17% |
Student > Ph. D. Student | 28 | 15% |
Student > Master | 21 | 11% |
Student > Bachelor | 19 | 10% |
Other | 15 | 8% |
Other | 30 | 16% |
Unknown | 43 | 23% |
Readers by discipline | Count | As % |
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Medicine and Dentistry | 38 | 20% |
Agricultural and Biological Sciences | 34 | 18% |
Biochemistry, Genetics and Molecular Biology | 29 | 16% |
Immunology and Microbiology | 14 | 7% |
Pharmacology, Toxicology and Pharmaceutical Science | 10 | 5% |
Other | 8 | 4% |
Unknown | 54 | 29% |