RESUMEN
BACKGROUND: Rare highly penetrant gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) can lead to psoriasis, a chronic inflammatory disease of the skin and other organs. OBJECTIVES: To investigate the contribution of rare CARD14 variants to psoriasis in the Tunisian population and to expand knowledge of CARD14 variants in the European population. METHODS: CARD14 coding exons were resequenced in patients with psoriasis and controls from Tunisia and Europe, including 16 European cases with generalized pustular psoriasis (GPP). Novel variants were evaluated for their effect on nuclear factor (NF)-κB signalling. RESULTS: Rare variants in CARD14 were significantly enriched in Tunisian cases compared with controls. Three were collectively found in 5% of Tunisian cases, and all affected the N-terminal region of the protein harbouring its caspase recruitment domain or coiled-coil domain. These variants were c.349G>A (p.Gly117Ser), c.205C>T (p.Arg69Trp) and c.589G>A (p.Glu197Lys). c.589G>A (p.Glu197Lys) led to upregulation of NF-κB activity in a similar manner to that of previously described psoriasis-associated mutations. p.Arg69Trp led to sevenfold downregulation of NF-κB activity. One Tunisian case harboured a c.1356+5G>A splice alteration that is predicted to lead to loss of exon 9, which encodes part of the coiled-coil domain. No cases of GPP harboured an interleukin-36RN mutation, but one of 16 cases of GPP with a family history of psoriasis vulgaris harboured a c.1805C>T (p.Ser602Leu) mutation in CARD14. CONCLUSIONS: These observations provide further insights into the genetic basis of psoriasis in the Tunisian population and provide functional information on novel CARD14 variants seen in cases from Tunisia and other populations.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/genética , Guanilato Ciclasa/genética , Proteínas de la Membrana/genética , Mutación/genética , Psoriasis/genética , Población Blanca/genética , Adulto , Regulación hacia Abajo/genética , Femenino , Humanos , Masculino , FN-kappa B/metabolismo , Psoriasis/etnología , Transducción de Señal , Túnez , Regulación hacia Arriba/genética , Población Blanca/etnología , Adulto JovenRESUMEN
Psoriasis is a multifactorial disease that involves genetic, immunological and environmental factors. During the last decade, several studies by genome scan on families or cases/controls helped to highlight more than ten loci "PSORS" located on different chromosomes and containing several candidate genes. Psoriasis appears as a genetic disease that follows the mixed model with the involvement of a major gene (PSORS1) and a set of minor genes with a variable penetrance depending on the locus. Genetic data have focused on the involvement of the immune system in the pathogenesis of psoriasis. It is now accepted that psoriasis is an immunological disease involving the response profiles TH1 and TH17. Much remains to be done to better elucidate the mechanisms involved in the genesis of psoriatic lesions to find new therapeutic targets.
Asunto(s)
Psoriasis/etiología , Psoriasis/fisiopatología , Animales , Diferenciación Celular , Mapeo Cromosómico , Citocinas/metabolismo , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Inflamación , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Queratinocitos/metabolismo , Queratinocitos/patología , Ratones , Ratones Noqueados , Ratones Transgénicos , Penetrancia , Psoriasis/genética , Psoriasis/inmunología , Psoriasis/patología , Células TH1/inmunología , Células Th17/inmunologíaRESUMEN
BACKGROUND: Psoriasis is a relapsing chronic inflammatory skin disease affecting all population groups, with a peak prevalence of 3% in northern European and Scandinavian caucasians. Epidemiological studies have implicated a genetic component to psoriasis. In the past 12 years multiple genome-wide linkage analyses have identified putative susceptibility loci on several chromosomes, with a major locus in the major histocompatibility complex region. OBJECTIVES: To investigate the genetic basis of familial psoriasis in the Tunisian population using a genome-wide linkage scan in seven ultiplex psoriatic families from Tunisia. METHODS: Following single nucleotide polymorphism (SNP) genotyping on the Affymetrix 10K SNP array, we performed nonparametric linkage (NPL) multipoint analyses to identify genotypes and obtain evidence for linkage with psoriasis across the genome. RESULTS: No chromosomal region gave consistent evidence for linkage, providing evidence for genetic heterogeneity in Tunisian psoriasis families. Significant evidence for linkage of psoriasis to chromosome 2p12 was seen in one family. We also identified several regions of tentative psoriasis linkage on chromosomes 2q, 4q, 6p, 11q, 12q, 9q and 13q. One family exhibiting suggestive evidence for linkage to 17q25 (PSORS2) was identified and all affected members harboured a p.Gly117Ser mutation in CARD14 (caspase recruitment domain family, member 14), recently reported to lead to psoriasis in a large family from the U.S.A. CONCLUSIONS: Our results support the genetic heterogeneity of psoriasis in the Tunisian population, provide confirmatory evidence for a novel psoriasis locus at chromosome 2p12 and reveal a psoriasis family with a mutation at PSORS2.
Asunto(s)
Cromosomas Humanos Par 2/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas/genética , Psoriasis/genética , Adolescente , Adulto , Anciano , Proteínas Adaptadoras de Señalización CARD , Niño , Femenino , Ligamiento Genético/genética , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Genotipo , Guanilato Ciclasa , Humanos , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Linaje , Túnez , Adulto JovenRESUMEN
BACKGROUND: Adiponectin has emerged over the last decade as a key adipokine linking obesity, insulin resistance, and Type 2 diabetes. However, the molecular mechanisms controlling adiponectin expression in adipose tissue are not fully elucidated. Furthermore, increasing evidence indicates that peroxisome proliferator-activated receptor- γ (PPAR-γ) plays an important, and beneficial, role in modulating adiponectin expression. AIM: The aim of the present study was to assess the separate role of obesity and Type 2 diabetes in the relationship between endogenous PPAR-γ signaling and adiponectin expression in subcutaneous adipose tissue. SUBJECTS AND METHODS: Enzyme-linked immuno sor bent assay and real time quantitative PCR analysis were carried out in overweight, obese, and/or diabetic Tunisian patients who underwent an abdominal surgery. RESULTS: These results collectively indicate that circulating levels of adiponectin were decreased in all overweight, obese, and/or diabetic (p<0.001). However, the subcutaneous mRNA expression of adiponectin was reduced only in diabetics (p<0.01) but presents some discrepancies in obese individuals. Moreover, mRNA levels of adiponectin were positively correlated with levels of mRNA encoding PPARγ and its heterodimeric partner retinoid X receptor-α (RXR-α), in both obese and diabetic patients. CONCLUSION: Our study on Tunisian patients shows impaired regulation of circulating and mRNA adiponectin levels dependent of metabolic disorders in obesity and Type 2 diabetes. The data suggest that subcutaneous adipose tissue may play an important role in modulating adiponectin expression in diabetes and obesity. Moreover, adiponectin mRNA could be potentially regulated by endogenous PPARγ/RXRα-dependent pathways.