TY - JOUR
T1 - Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis
AU - Jordan, Catherine T.
AU - Cao, Li
AU - Roberson, Elisha D.O.
AU - Duan, Shenghui
AU - Helms, Cynthia A.
AU - Nair, Rajan P.
AU - Duffin, Kristina Callis
AU - Stuart, Philip E.
AU - Goldgar, David
AU - Hayashi, Genki
AU - Olfson, Emily H.
AU - Feng, Bing Jian
AU - Pullinger, Clive R.
AU - Kane, John P.
AU - Wise, Carol A.
AU - Goldbach-Mansky, Raphaela
AU - Lowes, Michelle A.
AU - Peddle, Lynette
AU - Chandran, Vinod
AU - Liao, Wilson
AU - Rahman, Proton
AU - Krueger, Gerald G.
AU - Gladman, Dafna
AU - Elder, James T.
AU - Menter, Alan
AU - Bowcock, Anne M.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (NIH): AR050266 and 5RC1AR058681 (A.M.B.), T32AR007279 (E.D.O.R.), T32HL083822 and T32 GM07200 (C.T.J), AR060222 (M.A.L), T32HG000045 (C.E.J), and K08AR057763 (W.L.). J.T.E., R.N., and P.S. were supported by NIH grants R01 AR042742, R01 AR050511, and AR054966 and by the Babcock Memorial Trust. J.T.E. is supported by the Ann Arbor Veterans Affairs Hospital. R.G.M. is supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Additional funding came from the Arthritis Society of Canada, the Atlantic Innovation Fund, the Canadian Institute of Health Research, the Arthritis Society, the Dana Foundation, and the Academia Sinica and National Science Council (National Clinical Core, National Genotyping Core) of Taiwan. The authors thank the many individuals with psoriasis and the controls who participated in this study. We thank Linus Schwantes-An, Weimin Duan, and Nancy Saccone for advice on statistical analyses. We also thank Mayte Suarez-Farinas for biostatistical assistance, Haoyan Chen, Olivia Lai, Fawnda Pellet, and M.J. Malloy for assembling the control population, Pui-Yan Kwok for sample procurement, Trilokraj Tejasvi for clinical evaluation of study subjects, Nikki Plass for patient scheduling and study logistics, Damaris Garcia for the management of samples, and Debbie Stone and Dawn Chapelle for patient care. Mike Lovett provided helpful comments on the manuscript. The authors are indebted to the National Psoriasis Foundation for continuing support during the course of this study.
PY - 2012/5/4
Y1 - 2012/5/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84860725325&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.03.013
DO - 10.1016/j.ajhg.2012.03.013
M3 - Article
C2 - 22521419
AN - SCOPUS:84860725325
SN - 0002-9297
VL - 90
SP - 796
EP - 808
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -