Psoriasis (Ps) is a common chronic inflammatory skin disease affecting approximately 2-3% of individuals of European ancestry. 10-40% of the time it is accompanied by a disabling psoriatic arthritis (PsA). Other co-morbidities include metabolic syndrome and an increased risk for cardiovascular disease and stroke. Genome-wide association studies have identified over 20 predisposing loci, but account for less than 20% of disease heritability. We recently used a combination of linkage analysis and NexGen sequencing to identify mutations in caspase recruitment domain protein 14 (CARD14) in two families with highly penetrant forms of Ps and PsA, thereby successfully identifying the PSORS2 locus on human chromosome 17q25. Screening of over 5,000 cases and controls revealed additional rare variants in CARD14 and an excess of variants in cases versus controls. We also identified a single severe psoriasis case with a de-novo mutation in CARD14. Ps/PsA associated mutations enhanced NF- kB activation and altered the transcriptome of keratinocytes, leading to the production of chemokines and other psoriasis-associated inflammatory markers. In the current application we will extend our genetic analyses of CARD14 in an extended cohort of Ps/PsA patients and controls. We will also perform exome capture or whole genome sequencing on cases with sporadic and familial forms of Ps and PsA to screen for additional genes with rare highly penetrant variants predisposing to disease. By targeting cases or families with both Ps and PsA we hope to reduce possible genetic heterogeneity. Genes will be prioritized for follow up on the basis of known biological roles/pathway altered in Ps/PsA or if they are enriched for deleterious variants. Additional variants in these genes will be identified with targeted capture (4 genes per year). Those with additional variants in cases versus controls will be genotyped in a larger cohort of >5,000 cases and 5,000 controls. Statistical analyzes will then be performed to examine the contribution of rare variants in specifi genes to Ps and PsA susceptibility. Functional studies of novel variants will be performed to complement the genetic studies. By identifying rare highly penetrant mutations leading to these diseases, we will increase our understanding of disease pathogenesis and identify novel therapeutic targets lying within pathways altered in Ps/PsA.

Public Health Relevance

Psoriasis and psoriatic arthritis are chronic inflammatory diseases of the skin and joints for which there are no cures. Total direct and indirect health care costs are ~ $11.25 billion annually with work loss accounting for 40% of the cost burden. Psoriasis can cause as much disability as other major diseases, including diabetes, heart disease, hypertension and depression accompanied by thoughts of suicide. It goes hand-in- hand with myriad co-morbid conditions such as obesity, metabolic syndrome, diabetes, cardiovascular disease, renal failure, non-alcoholic fatty liver disease, Crohn's disease, hypertension, stroke, and hypertension. Current treatments present a challenge for patients and their health care providers because no one treatment works for everyone, some treatments lose effectiveness over time, many treatments used are in combination with other treatments, and all treatments are associated with a unique set of side effects. The goal of the current study is to identify rare mutations leading to these diseases, thereby increasing our understanding of their genetic basis and their altered pathways. These are expected to provide novel targets for therapies for these devastating diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Cibotti, Ricardo
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U of L Imperial Col of Sci/Technlgy/Med
United Kingdom
Zip Code
SW7 2-AZ
Okada, Yukinori; Han, Buhm; Tsoi, Lam C et al. (2014) Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. Am J Hum Genet 95:162-72
Lu, Yingchang; Chen, Haoyan; Nikamo, Pernilla et al. (2013) Association of cardiovascular and metabolic disease genes with psoriasis. J Invest Dermatol 133:836-9
Zeng, Xue; Chen, Haoyan; Gupta, Rashmi et al. (2013) Deletion of the activating NKG2C receptor and a functional polymorphism in its ligand HLA-E in psoriasis susceptibility. Exp Dermatol 22:679-81
Roberson, Elisha D O; Liu, Ying; Ryan, Caitriona et al. (2012) A subset of methylated CpG sites differentiate psoriatic from normal skin. J Invest Dermatol 132:583-92
Landreville, Solange; Agapova, Olga A; Matatall, Katie A et al. (2012) Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res 18:408-16
Ellinghaus, Eva; Stuart, Philip E; Ellinghaus, David et al. (2012) Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL. J Invest Dermatol 132:1133-40
Lai, Olivia Y; Chen, Haoyan; Michaud, Henri-Alexandre et al. (2012) Protective effect of human endogenous retrovirus K dUTPase variants on psoriasis susceptibility. J Invest Dermatol 132:1833-40
Jordan, Catherine T; Cao, Li; Roberson, Elisha D O et al. (2012) Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. Am J Hum Genet 90:796-808
Jordan, Catherine T; Cao, Li; Roberson, Elisha D O et al. (2012) PSORS2 is due to mutations in CARD14. Am J Hum Genet 90:784-95
Chen, Haoyan; Poon, Annie; Yeung, Celestine et al. (2011) A genetic risk score combining ten psoriasis risk loci improves disease prediction. PLoS One 6:e19454

Showing the most recent 10 out of 18 publications