Rare, De Novo and Common Variants in CARD14 in Psoriasis.

摘要

Psoriasis is a common, inflammatory disorder of the skin that is associated with arthritis in up to 30% of cases. Previously, PSORS2 (psoriasis susceptibility locus 2) was independently localized with linkage analysis to chromosomal region 17q25.3-qter in two families with multiple psoriasis-affected members. One family was of European ancestry; the second was from Taiwan. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations, c.349G>A (p.Gly117Ser; in the family of European descent) and c.349+5G>A (in the Taiwanese family), altered splicing between CARD14 exons 3 and 4. A de novo mutation in CARD14, c.413A>C (p.Glu138Ala), was detected in a child with severe, early-onset, generalized pustular psoriasis. We identified fifteen additional rare, missense variants in CARD14 and determined their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls). There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). CARD14 activates nuclear factor of kappa light chain enhancer in B-cells (NF-kB), and we determined the effects of variants on NF-kB activation and the transcriptome of keratinocytes. CARD14 variants led to a range of NFkB activities; putative pathogenic variants led to levels >2.5-fold higher than did wildtype CARD14. 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 metaanalysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1x10-6). CARD14 is localized mainly in the basal layers of healthy skin epidermis, but in lesional psoriatic skin it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, which is the hallmark of psoriasis. These studies enhance our understanding of the genetics of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.