Department of Dermatology, University of Wisconsin, Madison, WI 53705, USA.
Center for Research in Molecular Medicine, Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan.
Int J Mol Sci. 2022 Aug 19;23(16):9336. doi: 10.3390/ijms23169336.
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.
银屑病是一种免疫介导的慢性、疼痛性疾病，其特征为红色凸起的炎症性斑块，可能有脱皮、银白色鳞屑、瘙痒和裂缝。发生银屑病的易感性取决于多种因素，遗传和环境因素之间存在复杂的相互作用。研究表明，常染色体显性 CARD14（半胱氨酸丰富域蛋白 14）功能获得性突变与银屑病的病理生理学有关。在这项研究中，评估了 CARD14 基因的非同义单核苷酸多态性（nsSNP），以确定它们与巴基斯坦人群中银屑病的关系。本研究共纳入 123 例受试者（63 例银屑病患者和 60 例正常对照）。从血液中提取 DNA，进行 PCR 分析，然后对 18 个 CARD14 特定的 nsSNP（之前报道的 14 个和使用生物信息学分析鉴定的 4 个最致病的 nsSNP）进行 Sanger 测序。在测试的 18 个 SNP 中，只有 2 个 nsSNP，rs2066965（R547S）和 rs34367357（V585I），与银屑病有关。此外，rs2066965 杂合基因型在有关节痛的患者中更为常见。此外，使用 alpha-fold2 预测了 CARD14 蛋白的 3D 结构。使用 NMSim 网络服务器对野生型 CARD14 和两种突变结构进行粗磨模拟。R547S 增加了蛋白质的灵活性，而 V353I 被证明可以促进 CARD14 诱导的 NF-kappa B 激活。这项研究证实了两个 CARD14 nsSNP，rs2066965 和 rs34367357 与巴基斯坦人群中银屑病的关系，这可能有助于确定 CARD14 基因突变作为银屑病患者潜在遗传标志物的作用。
