Variant Analysis of CARD14 in a Chinese Han Population with Psoriasis Vulgaris and Generalized Pustular Psoriasis

TO THE EDITOR Psoriasis is a common, chronic, inflammatory, organ-specific autoimmune skin disease with a complex genetic background (Nestle et al., 2009; Zhang et al., 2013). Psoriasis vulgaris (PsV) is the most common type, accounting for approximately 85–90% of all psoriasis patients, and characterized by raised, well-demarcated, erythematous oval plaques with adherent silvery scales (Nestle et al., 2009). Generalized pustular psoriasis (GPP) is the least prevalent form of psoriasis and is considered to be a potentially lifethreatening, multi-systemic disease (Körber et al., 2013), characterized by the sudden eruption of generalized sterile pustules in a wave-like manner (Mengesha and Bennett, 2002). Genetic factors have been shown to have a critical role in the pathogenesis of psoriasis, and several genes and genomic regions have been reportedly associated with some clinical forms of this disease (http://omim.org/), including the gene for caspase recruitment domain family member 14 (CARD14), which was identified by fine-mapping of psoriasis susceptibility locus 2 (PSORS2) in European and Taiwanese patients (Hwu et al., 2005; Jordan et al., 2012a). To date, 23 variants have been reported in the CARD14 gene (Supplementary Table S3 online), mainly in patients with PsV (Jordan et al., 2012a; 2012b; Körber et al., 2013). However, most studies of CARD14 have been carried out in European populations, and studies in Chinese patients are rare. We performed direct DNA sequencing in 236 psoriasis patients (174 PsV and 62 GPP patients) and 365 controls to investigate the prevalence of CARD14 variants in the Chinese Han population. We also compared CARD14 variants between patients with GPP and PsV and between pediatricand late-onset PsV. A total of four new, rare heterozygous missense variants (allele frequency o1%) were found in the CARD14 exon, all with frequencies of 0.2% in psoriasis patients: p.Met119Val (c.355A4G) and p.Arg166His (c.497G 4A) were only seen in GPP with PsV patients, and p.Ala216Thr (c.646G4A) and p.Thr591Met (c.1772C4T) (rs200102454) were only seen in PsV patients. We predicted the effects of the four variants on protein function using the Sorting Intolerant From Tolerant (SIFT) tool (http://sift.bii.a-star.edu.sg). Only p.Thr591Met was predicted to have damaging effects (score1⁄4 0.03), whereas the other three were predicted to be tolerated (Supplementary Table S4 and Supplementary Figure S1 online). An additional known rare heterozygous variant p.Arg682Trp (c.2044C4T) (rs117918077), which was reported in 1.3% of 2169 European psoriasis patients (Jordan et al., 2012b), was only found in one GPP with PsV patient (0.2% in psoriasis patients) in this study (Supplementary Table S4 and Supplementary Figure S1 online). The overall frequency of these five rare variants was 1.1% in psoriasis patients (0.6% in PsV patients and 2.4% in GPP patients) but 0% in controls. A significant association between CARD14 rare variants and GPP was observed using Fisher’s exact test (corrected-P1⁄40.03), but there was no significant association with either psoriasis or PsV (corrected-P1⁄4 0.09, 0.998, respectively). We also conducted a gene-burden test using the sequence kernel association test package to compare the distributions of the five rare missense variants in psoriasis patients and controls, which showed a P-value of 0.00172. Subtype analysis of PsV versus GPP and pediatricversus late-onset PsV revealed no significant differences in the frequencies of the five rare variants (corrected-P1⁄40.438, 1, respectively; Table 1). One known low-frequency variant, p.Asp176His (c.526G4C) (rs144475004), was detected with frequencies of 1.9% in psoriasis patients and 1.8% in controls. Three common single-nucleotide polymorphisms (SNPs), rs2066964, rs34367357, and rs11652075, were also detected in our samples, with frequencies of 44.1 vs. 7.4 vs. 44.3% in psoriasis patients and 46.0 vs. 5.6 vs. 48.2% in controls, respectively. There were no differences between the groups in terms of these four variants (Supplementary Table S5 and Supplementary Figure S1 online). CARD14 is located within PSORS2 and encodes a nuclear factor (NF)-kB activator. Variants in CARD14 have recently been detected in association with psoriasis, mostly in patients with PsV (Jordan et al., 2012b). Particular rare variants within CARD14 could lead to psoriasis by upregulating psoriasis-associated genes in keratinocytes (Jordan et al., 2012a). The present study identified five rare variants that, in combination, were more common in psoriasis patients Accepted article preview online 7 July 2014; published online 7 August 2014 Abbreviations: CARD14, caspase recruitment domain family member 14; GPP, generalized pustular psoriasis; late-onset PsV, late-onset psoriasis vulgaris; pediatric-onset PsV, pediatric-onset psoriasis vulgaris; PsV, psoriasis vulgaris P Qin et al. CARD14, PsV, and GPP in a Chinese Population