{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T02:26:30Z","timestamp":1785896790662,"version":"3.56.0"},"reference-count":53,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T00:00:00Z","timestamp":1660867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Wisconsin Foundation"},{"name":"Higher Education Commission (HEC) of Pakistan"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Psoriasis is an immune-mediated chronic and painful disease characterized by red raised patches of inflamed skin that may have desquamation, silvery-white scales, itching and cracks. The susceptibility of developing psoriasis depends on multiple factors, with a complex interplay between genetic and environmental factors. Studies have suggested an association between autosomal dominant CARD14 (caspase recruitment domain-containing protein 14) gain-of-function mutations with the pathophysiology of psoriasis. In this study, non-synonymous single-nucleotide polymorphisms (nsSNPs) of CARD14 gene were assessed to determine their association with psoriasis in Pakistani population. A total of 123 subjects (63 patients with psoriasis and 60 normal controls) were included in this study. DNA was extracted from blood, and PCR analysis was performed followed by Sanger sequencing for 18 CARD14 specific nsSNPs (14 previously reported and the 4 most pathogenic nsSNPs identified using bioinformatics analysis). Among the 18 tested SNPs, only 2 nsSNP, rs2066965 (R547S) and rs34367357 (V585I), were found to be associated with psoriasis. Furthermore, rs2066965 heterozygous genotype was found to be more prevalent in patients with joint pain. Additionally, the 3D structure of CARD14 protein was predicted using alpha-fold2. NMSim web server was used to perform coarse grind simulations of wild-type CARD14 and two mutated structures. R547S increases protein flexibility, whereas V353I is shown to promote CARD14-induced NF-kappa B activation. This study confirms the association between two CARD14 nsSNPs, rs2066965 and rs34367357 with psoriasis in a Pakistani population, and could be helpful in identifying the role of CARD14 gene variants as potential genetic markers in patients with psoriasis.<\/jats:p>","DOI":"10.3390\/ijms23169336","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T22:23:13Z","timestamp":1661120593000},"page":"9336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Association of CARD14 Single-Nucleotide Polymorphisms with Psoriasis"],"prefix":"10.3390","volume":"23","author":[{"given":"Saima","family":"Suleman","sequence":"first","affiliation":[{"name":"Department of Dermatology, University of Wisconsin, Madison, WI 53705, USA"},{"name":"Center for Research in Molecular Medicine, Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5205-7218","authenticated-orcid":false,"given":"Gagan","family":"Chhabra","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Wisconsin, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubab","family":"Raza","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Wisconsin, Madison, WI 53705, USA"},{"name":"Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 15320, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2861-013X","authenticated-orcid":false,"given":"Arslan","family":"Hamid","sequence":"additional","affiliation":[{"name":"The Life & Medical Sciences Institute (LIMES), University of Bonn, 53113 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javed Anver","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Center for Research in Molecular Medicine, Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4239-9887","authenticated-orcid":false,"given":"Nihal","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Wisconsin, Madison, WI 53705, USA"},{"name":"William S. Middleton VA Medical Center, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rendon, A., and Sch\u00e4kel, K. (2019). Psoriasis pathogenesis and treatment. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061475"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1111\/j.1365-4362.1996.tb03687.x","article-title":"Skin disease and socioeconomic conditions in rural Africa: Tanzania","volume":"35","author":"Gibbs","year":"1996","journal-title":"Int. J. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"J314","DOI":"10.1016\/j.jaut.2009.12.001","article-title":"Geoepidemiology and environmental factors of psoriasis and psoriatic arthritis","volume":"34","author":"Chandran","year":"2010","journal-title":"J. Autoimmun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00403-016-1637-8","article-title":"The German National Program on psoriasis health care 2005\u20132015: Results and experiences","volume":"308","author":"Augustin","year":"2016","journal-title":"Arch. Dermatol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Capon, F. (2017). The genetic basis of psoriasis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122526"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1086\/377159","article-title":"The International Psoriasis Genetics Study: Assessing linkage to 14 candidate susceptibility loci in a cohort of 942 affected sib pairs","volume":"73","author":"Consortium","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1046\/j.1523-1747.1999.00710.x","article-title":"Characterization of the major susceptibility region for psoriasis at chromosome","volume":"113","author":"Balendran","year":"1999","journal-title":"J. Investig. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1126\/science.8178173","article-title":"Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q","volume":"264","author":"Tomfohrde","year":"1994","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/ng.313","article-title":"Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis","volume":"41","author":"Zeeuwen","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1086\/503821","article-title":"Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene","volume":"78","author":"Nair","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.1002\/jcp.22667","article-title":"Alternative splicing of CARMA2\/CARD14 transcripts generates protein variants with differential effect on NF-\u03baB activation and endoplasmic reticulum stress-induced cell death","volume":"226","author":"Scudiero","year":"2011","journal-title":"J. Cell. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.ajhg.2012.03.012","article-title":"PSORS2 is due to mutations in CARD14","volume":"90","author":"Jordan","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.ajhg.2012.05.010","article-title":"Familial pityriasis rubra pilaris is caused by mutations in CARD14","volume":"91","author":"Sarig","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1111\/bjd.12313","article-title":"Genetic associations of psoriasis in a Pakistani population","volume":"169","author":"Shaiq","year":"2013","journal-title":"Br. J. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.molimm.2014.11.015","article-title":"Association analysis of GWAS and candidate gene loci in a Pakistani population with psoriasis","volume":"64","author":"Munir","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101670","DOI":"10.1016\/j.berh.2021.101670","article-title":"Clinical features of psoriatic arthritis","volume":"35","author":"Kishimoto","year":"2021","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1080\/09546634.2020.1746734","article-title":"Absolute and relative psoriasis area and severity index (PASI) treatment goals and their association with health-related quality of life","volume":"31","author":"Gerdes","year":"2020","journal-title":"J. Dermatol. Treat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.ygeno.2018.05.013","article-title":"Evaluation of computational techniques for predicting non-synonymous single nucleotide variants pathogenicity","volume":"111","author":"Hassan","year":"2019","journal-title":"Genomics"},{"key":"ref_19","first-page":"7","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2","volume":"76","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: An ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.ajhg.2018.08.005","article-title":"ClinPred: Prediction tool to identify disease-relevant nonsynonymous single-nucleotide variants","volume":"103","author":"Alirezaie","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.3389\/fimmu.2018.02239","article-title":"Clinical and genetic heterogeneity of CARD14 mutations in psoriatic skin disease","volume":"9","author":"Israel","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1590\/S0100-879X2009000600012","article-title":"Interleukin-6 promoter polymorphisms (-174 G\/C) in Malaysian patients with systemic lupus erythematosus","volume":"42","author":"Chua","year":"2009","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4862","DOI":"10.1093\/bioinformatics\/btz422","article-title":"AlphaFold at CASP13","volume":"35","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Mulder, N., and Apweiler, R. (2007). Interpro and interproscan. Comparative Genomics, Springer.","DOI":"10.1002\/047001153X.g306310.pub2"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1042\/BCJ20160270","article-title":"Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-\u03baB activation","volume":"473","author":"Howes","year":"2016","journal-title":"Biochem. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.3389\/fimmu.2018.02167","article-title":"CARD14\/CARMA2 signaling and its role in inflammatory skin disorders","volume":"9","author":"Zotti","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.immuni.2018.05.012","article-title":"Gain-of-function mutation of Card14 leads to spontaneous psoriasis-like skin inflammation through enhanced keratinocyte response to IL-17A","volume":"49","author":"Wang","year":"2018","journal-title":"Immunity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1111\/bjd.17392","article-title":"Variants of CARD14 are predisposing factors for generalized pustular psoriasis (GPP) with psoriasis vulgaris but not for GPP alone in a Chinese population","volume":"180","author":"Li","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12041-020-01219-5","article-title":"Updating and identifying three novel variants of the CARD14 gene in Chinese Han patients with psoriasis","volume":"99","author":"Huang","year":"2020","journal-title":"J. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1038\/jid.2014.46","article-title":"CARD14 c. 526G > C (p. Asp176His) is a significant risk factor for generalized pustular psoriasis with psoriasis vulgaris in the Japanese cohort","volume":"134","author":"Sugiura","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1089\/dna.2013.2109","article-title":"SNP rs11652075 in the CARD14 gene as a risk factor for psoriasis (PSORS2) in a Spanish cohort","volume":"32","author":"Penedo","year":"2013","journal-title":"DNA Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.1038\/jid.2015.186","article-title":"Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with loss-of-function mutations in IL36RN in European patients","volume":"135","author":"Frambach","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1590\/abd1806-4841.20164016","article-title":"Variants of CARD14 gene and psoriasis vulgaris in southern Chinese cohort","volume":"91","author":"Zhu","year":"2016","journal-title":"An. Bras. De Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/1346-8138.13065","article-title":"CARD 14 gene polymorphism c. C2458T (p. Arg820Trp) is associated with clinical features of psoriasis vulgaris in a Chinese cohort","volume":"43","author":"Feng","year":"2016","journal-title":"J. Dermatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/bjd.14158","article-title":"CARD 14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts","volume":"174","author":"Ammar","year":"2016","journal-title":"Br. J. Dermatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1016\/j.jid.2018.05.001","article-title":"Psoriasis plays a wild CARD","volume":"138","author":"Afonina","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1016\/j.jid.2018.03.1525","article-title":"CARD14 gain-of-function mutation alone is sufficient to drive IL-23\/IL-17\u2013mediated psoriasiform skin inflammation in vivo","volume":"138","author":"Mellett","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.3389\/fimmu.2018.01564","article-title":"Nuclear factor \u03baB activation in a Type V pityriasis rubra pilaris patient harboring multiple CARD14 variants","volume":"9","author":"Danis","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1038\/jid.2014.269","article-title":"Variant analysis of CARD14 in a Chinese Han population with psoriasis vulgaris and generalized pustular psoriasis","volume":"134","author":"Qin","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1111\/jdv.15455","article-title":"The management and genetic background of pityriasis rubra pilaris: A single-centre experience","volume":"33","author":"Danis","year":"2019","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e1430","DOI":"10.1002\/mgg3.1430","article-title":"Genetic and pathological findings in a boy with psoriasis and C3 glomerulonephritis: A case report and literature review","volume":"8","author":"Wei","year":"2020","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1177\/1203475415586332","article-title":"The Relationship of Obesity With the Severity of Psoriasis: A Systematic Review","volume":"19","author":"Fleming","year":"2015","journal-title":"J. Cutan. Med. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"493","DOI":"10.2147\/CCID.S147236","article-title":"Associations between body mass index and severity of psoriasis","volume":"10","author":"Sobhan","year":"2017","journal-title":"Clin. Cosmet. Investig. Derm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1093\/embo-reports\/kvf139","article-title":"CARD games in apoptosis and immunity","volume":"3","author":"Martin","year":"2002","journal-title":"EMBO Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1002\/bies.950190606","article-title":"PDZ domains: Targeting signalling molecules to sub-membranous sites","volume":"19","author":"Ponting","year":"1997","journal-title":"Bioessays"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/0022-2836(92)90474-X","article-title":"Refined structure of the complex between guanylate kinase and its substrate GMP at 20 \u00c5 resolution","volume":"224","author":"Stehle","year":"1992","journal-title":"J. Mol. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1016\/j.jmb.2013.07.012","article-title":"The effects of non-synonymous single nucleotide polymorphisms (nsSNPs) on protein\u2013protein interactions","volume":"425","author":"Yates","year":"2013","journal-title":"J. Mol. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e115","DOI":"10.1093\/nar\/gks596","article-title":"Primer3\u2014New capabilities and interfaces","volume":"40","author":"Untergasser","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1093\/bib\/3.2.146","article-title":"Genetic association studies: Design, analysis and interpretation","volume":"3","author":"Lewis","year":"2002","journal-title":"Brief. Bioinform."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/s41594-021-00650-1","article-title":"AlphaFold2 and the future of structural biology","volume":"28","author":"Cramer","year":"2021","journal-title":"Nat. Struct. Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9336\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:12:09Z","timestamp":1760141529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9336"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,19]]},"references-count":53,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23169336"],"URL":"https:\/\/doi.org\/10.3390\/ijms23169336","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,19]]}}}