title: Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
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.
authors.affiliation: Division of Human Genetics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Jordan
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.forename: Elisha D O
authors.initials: ED
authors.lastname: Roberson
authors.forename: Shenghui
authors.initials: S
authors.lastname: Duan
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Helms
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Nair
authors.forename: Kristina Callis
authors.initials: KC
authors.lastname: Duffin
authors.forename: Philip E
authors.initials: PE
authors.lastname: Stuart
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.forename: Genki
authors.initials: G
authors.lastname: Hayashi
authors.forename: Emily H
authors.initials: EH
authors.lastname: Olfson
authors.forename: Bing-Jian
authors.initials: BJ
authors.lastname: Feng
authors.forename: Clive R
authors.initials: CR
authors.lastname: Pullinger
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lowes
authors.forename: Lynette
authors.initials: L
authors.lastname: Peddle
authors.forename: Vinod
authors.initials: V
authors.lastname: Chandran
authors.forename: Wilson
authors.initials: W
authors.lastname: Liao
authors.forename: Proton
authors.initials: P
authors.lastname: Rahman
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Krueger
authors.forename: Dafna
authors.initials: D
authors.lastname: Gladman
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.forename: Alan
authors.initials: A
authors.lastname: Menter
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bowcock
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D015236:HLA-C Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011565:Psoriasis / Q000235:genetics*; D012867:Skin / Q000473:pathology; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D053468:CARD Signaling Adaptor Proteins; D015236:HLA-C Antigens; D008565:Membrane Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C426243:CARD14 protein, human; D006162:Guanylate Cyclase