RESUMEN
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.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/genética , Guanilato Ciclasa/genética , Proteínas de la Membrana/genética , FN-kappa B/genética , FN-kappa B/metabolismo , Psoriasis/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Estudios de Casos y Controles , Epidermis/metabolismo , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Guanilato Ciclasa/metabolismo , Antígenos HLA-C/genética , Antígenos HLA-C/metabolismo , Humanos , Queratinocitos , Proteínas de la Membrana/metabolismo , Mutación Missense , Polimorfismo Genético , Piel/patología , Transcriptoma , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Población Blanca/genéticaRESUMEN
SIRE1 is a 2000-copy member of the Ty1/copia retroelement family found in the soybean genome and is closely related to sireviruses found in the genomes of other legumes. Although these elements closely resemble typical plant members of the Ty1/copia family, they are unusual in that they possess an envelope-like coding region immediately downstream of the reverse transcriptase gene. Despite its copy number, very few members of the SIRE1 family are currently present in publicly available genomic assemblies or draft contigs. However, fragments of family members are well-represented as BAC-ends in the GenBank Genome Survey Sequence database. This database was queried using the 5' and 3' ends of SIRE1 in order to catalog sequences into which SIRE1 members have integrated. Seven hundred and eighty-one unique SIRE1 insertions were identified and the majority of insertion sites constituted other repetitive elements, including Class I and Class II transposable elements and satellite DNAs. Ninety-four insertions were in single- or low-copy number sequences and three of these were homologous to characterized protein-coding genes. Examination of the ten bases flanking either side of SIRE1 revealed no clear consensus sequence, but the the distributions of A, C, G, and T at most of the positions were biased with strong statistical significance.