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

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 & 6 others Proton Rahman, Gerald G. Krueger, Dafna Gladman, James T. Elder, Alan Menter, Anne M. Bowcock

Research output: Contribution to journalArticle

174 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)796-808
Number of pages13
JournalAmerican Journal of Human Genetics
Volume90
Issue number5
DOIs
StatePublished - May 4 2012

Fingerprint

NF-kappa B
Psoriasis
Mutation
Keratinocytes
Skin
Gene Expression Profiling
Transcriptome
Epidermis
Meta-Analysis
B-Lymphocytes
Tumor Necrosis Factor-alpha
Light

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Jordan, C. T., Cao, L., Roberson, E. D. O., Duan, S., Helms, C. A., Nair, R. P., ... Bowcock, A. M. (2012). Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. American Journal of Human Genetics, 90(5), 796-808. https://doi.org/10.1016/j.ajhg.2012.03.013

Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. / Jordan, Catherine T.; Cao, Li; Roberson, Elisha D O; Duan, Shenghui; Helms, Cynthia A.; Nair, Rajan P.; Duffin, Kristina Callis; Stuart, Philip E.; Goldgar, David; Hayashi, Genki; Olfson, Emily H.; Feng, Bing Jian; Pullinger, Clive R.; Kane, John P.; Wise, Carol A.; Goldbach-Mansky, Raphaela; Lowes, Michelle A.; Peddle, Lynette; Chandran, Vinod; Liao, Wilson; Rahman, Proton; Krueger, Gerald G.; Gladman, Dafna; Elder, James T.; Menter, Alan; Bowcock, Anne M.

In: American Journal of Human Genetics, Vol. 90, No. 5, 04.05.2012, p. 796-808.

Research output: Contribution to journalArticle

Jordan, CT, Cao, L, Roberson, EDO, Duan, S, Helms, CA, Nair, RP, Duffin, KC, Stuart, PE, Goldgar, D, Hayashi, G, Olfson, EH, Feng, BJ, Pullinger, CR, Kane, JP, Wise, CA, Goldbach-Mansky, R, Lowes, MA, Peddle, L, Chandran, V, Liao, W, Rahman, P, Krueger, GG, Gladman, D, Elder, JT, Menter, A & Bowcock, AM 2012, 'Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis', American Journal of Human Genetics, vol. 90, no. 5, pp. 796-808. https://doi.org/10.1016/j.ajhg.2012.03.013
Jordan, Catherine T. ; Cao, Li ; Roberson, Elisha D O ; Duan, Shenghui ; Helms, Cynthia A. ; Nair, Rajan P. ; Duffin, Kristina Callis ; Stuart, Philip E. ; Goldgar, David ; Hayashi, Genki ; Olfson, Emily H. ; Feng, Bing Jian ; Pullinger, Clive R. ; Kane, John P. ; Wise, Carol A. ; Goldbach-Mansky, Raphaela ; Lowes, Michelle A. ; Peddle, Lynette ; Chandran, Vinod ; Liao, Wilson ; Rahman, Proton ; Krueger, Gerald G. ; Gladman, Dafna ; Elder, James T. ; Menter, Alan ; Bowcock, Anne M. / Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 5. pp. 796-808.
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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.",
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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.

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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.

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