Variants of CARD14 gene and psoriasis vulgaris in southern Chinese cohort.
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ABSTRACT:
SUBMITTER: Zhu K
PROVIDER: S-EPMC4782646 | biostudies-literature | 2016 Jan-Feb
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC4227539 | biostudies-literature
Project description:PSORIASIS VULGARIS IS DEFINED BY A SERIES OF LINKED CELLULAR CHANGES IN THE SKIN: hyperplasia of epidermal keratinocytes, vascular hyperplasia and ectasia, and infiltration of T lymphocytes, neutrophils and other types of leukocytes in the affected skin. Catechol-O-methyltransferase (COMT) 158 polymorphism can reduce the activity of the COMT enzyme that may trigger defective differentiation of keratinocytes in psoriasis. Immunocytes can degrade and inactivate catecholamines via monamine oxidase (MAO) and COMT in the cells. We hypothesized that the COMT-158G > A polymorphism was associated with the risk of psoriasis vulgaris in Han Chinese people. In a hospital-based case-control study, 524 patients with psoriasis vulgaris and 549 psoriasis-free controls were studied. COMT-158 G > A polymorphism was genotyped using the PCR sequence-specific primer (PCR-SSP) technique. We found no statistically significant association between the COMT-158 allele A and the risk of psoriasis vulgaris (p = 0.739 adjusted OR = 1.03; 95% CI = 0.81-1.31). This suggests that the COMT-158 G > A polymorphism may not contribute to the etiology of psoriasis vulgaris in the Han Chinese population.
| S-EPMC3032959 | biostudies-literature
Project description: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.
| S-EPMC3376540 | biostudies-literature
Project description: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.
| S-EPMC9409305 | biostudies-literature
Project description:Mutations in the caspase recruitment domain, family member 14 (CARD14) gene have recently been described in psoriasis patients, and explain the psoriasis susceptibility locus 2 (PSORS2). CARD14 is a scaffolding protein that regulates NF-κB activation, and psoriasis-associated CARD14 mutations lead to enhanced NF-κB signaling. CARD14 is expressed mainly in epidermal keratinocytes, but also in unidentified dermal cells. In this manuscript, the identity of the dermal cell types expressing CARD14, as well the potential functional consequence of overactive CARD14 in these dermal cell types, was determined. Using two-color immunofluorescence, dermal CARD14 did not co-localize with T-cells, dendritic cells, or macrophages. However, dermal CARD14 did highly co-localize with CD31(+) endothelial cells (ECs). CARD14 was also expressed non-dermal endothelial cells, such as aortic endothelial cells, which may indicate a role of CARD14(+)ECs in the systemic inflammation and cardiovascular comorbidities associated with psoriasis. Additionally, phosphorylated NF-κB was found in psoriatic CARD14(+) CD31(+) ECs, demonstrating this pathway is active in dermal ECs in psoriasis. Transfection of dermal ECs with psoriasis-associated CARD14 mutations resulted in increased expression of several chemokines, including CXCL10, IL-8, and CCL2. These results provide preliminary evidence that CARD14 expression in ECs may contribute to psoriasis through increased expression of chemokines and facilitating recruitment of immune cells into skin.
| S-EPMC4219711 | biostudies-literature
Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an 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 was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that 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, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). 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. Keratinocytes were transfected with wildtype Cardsh or one of 16 Card14 mutations (17 total samples). The cells were collected and RNA extracted to determine the effect of these mutations compared to wildtype Card14. No replicates are included.
2012-05-08 | E-GEOD-36381 | biostudies-arrayexpress
Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an 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 was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that 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, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). 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.
2012-05-09 | GSE36381 | GEO
Project description:Psoriasis is a lifelong disorder characterized by approximately 8-fold reduction of the duration of normal skin keratinocyte cell cycle and 2-fold increase of the number of dividing cells. Multiple genes, several environmental factors, and immune system alterations are involved in the pathogenesis of psoriasis. Hyperleptinemia is associated with psoriasis and leptin acts as an angiogenic factor. Angiogenetic processes precede the epidermal hyperplasia in psoriasis, indicating possible involvement of leptin in the pathogenesis of psoriasis. Leptin gene polymorphisms and their association with psoriasis have been given very little attention. We present a study of the rs2060713C/T genetic polymorphism in the pathogenesis of psoriasis vulgaris in 263 vulgaris patients and 252 unrelated matched healthy controls. No statistically significant differences were observed between patients and controls. A statistically nonsignificant trend was observed in males with the early onset type of psoriasis (11.1% C/T in patients versus 5.6% in controls) and in females with the late onset type of the disease (12.8% C/T in patients versus 3.3% in controls). Still, there is no hard evidence on correlation of psoriasis vulgaris with this polymorphism. Possible association with specific forms of the disease and either gender needs further investigation in larger studies.
| S-EPMC3926229 | biostudies-literature
Project description:BackgroundIncreased transforming growth factor beta 1 (TGF-β1) in the epidermis and serum has been found in psoriatic patients. The mechanism for this increase remains unclear.ObjectiveTo study the TGF-β1 gene polymorphism at codon 10 and its relation to psoriasis susceptibility in a sample of Egyptian patients.Materials and methodsThis cross-sectional study involved 70 patients with psoriasis vulgaris and 100 age- and sex- comparable healthy volunteers as a control group. Genomic DNA was prepared from peripheral blood lymphocytes from all subjects using QIAamp DNA mini kit (QIAGEN Inc., Germany). The TGF-β1 polymorphism was genotyped by PCR-based restricted fragment length polymorphism (PCR-RFLP) analysis. Amplification of codon 10, located in exon 1 of TGFβ1 gene was done through PCR reaction using gene-specific primers.ResultsStatistically significant difference was found between psoriasis patient and controls as regards TGF-β1 (T869C) polymorphism (P=0.045). The presence of TT genotype was associated with a 3-fold risk of psoriasis compared to CC genotype (P=0.016, OR: 3.13 95% CI: 1.24-7.88). T allele was significantly more frequent in psoriasis patients (P=0.017). TGF-β1 gene mutation was significantly higher among psoriasis patients with positive family history (P=0.007).ConclusionTGF-β1 gene polymorphism at codon 10 (T869C) is significantly associated with susceptibility to psoriasis in Egyptian patients. This polymorphism is more common in patients with a positive family history of psoriasis.
| S-EPMC6110268 | biostudies-literature
Project description:BackgroundPsoriasis is an incurable, chronic skin disorder with considerable impact on the quality of life. No drugs are available for treating the disease. Clarifying the progression, exploring the risk factors affecting progression, and finding effective treatments with few side-effects and low recurrence rates is critical. This protocol describes a future study that will analyze psoriasis vulgaris progression risk factors and trends, establish a multicenter clinical registration platform, evaluate clinical evidence for Chinese Medicine (CM) intervention for psoriasis, and evaluate therapeutic effectiveness and recurrence rate advantages of CM.MethodsThe study is a prospective cohort clinical trial planned for October 2019 to September 2021 involving 20 clinics. The trial will enroll 1,500 participants in a psoriasis vulgaris group, and 500 healthy participants in a control group (no intervention). The psoriasis vulgaris group will be divided into three equal-sized subgroups: blood heat syndrome group (BHS), blood stasis syndrome group (BSS), and non-blood heat nor blood stasis syndrome group (NHS) group. Participants will be grouped according to CM syndrome classification and receive oral CM herbal medication (according to the CM syndrome classification, and tailored to the participant's disease progression). Medication will be administered twice every day during the intervention phase (eight weeks of intervention, and eight weeks of follow-up). Exposure measures include demographic variables, risk factors, and intervention factors.DiscussionThe primary outcome measures include improvement in both the psoriasis and severity index scores after eight weeks of intervention. Secondary outcome measures include body surface area affected, Physician Global Assessment scores, Dermatology Life Quality Index, pain-relat ed quality of life, pain on visual analog scale, CM syndromes, and recurrence. Other outcome measures include CM physical scale, personal history, medical expenses, and patient satisfaction. The number, nature, and severity of adverse events will be carefully recorded.Trial registrationThe trial has been registered at ClinicalTrials.gov (ID: NCT03942185).
| S-EPMC6944550 | biostudies-literature