Psoriasis is a multifactorial immune-mediated skin disease with a strong genetic background. Previous studies reported that psoriasis with a family history (PFH) and sporadic psoriasis (SP) have a distinct manifestation and genetic predisposition. However, the genetic heterogeneity of PFH and SP in the major histocompatibility complex (MHC) region has not been fully elucidated. To explore genetic variants in the MHC region that drive family aggregation of psoriasis, we included a total of 8,127 psoriasis cases and 9,906 healthy controls from Han Chinese and divided psoriasis into two subtypes, PFH () and SP (). Then, we calculated the heritability of PFH and SP and performed a large-scale stratified association analysis. We confirmed that variants in the MHC region collectively explained a higher heritability of PFH (16.8%) than SP (13.3%). Further stratified association analysis illustrated that HLA-C06:02 and NOTCH4:G511S contribute to the family aggregation of psoriasis, and BTNL2:R281K specifically confers risk for SP. HLA-C06:02 and NOTCH4:G511S could partially explain why patients with PFH have a stronger genetic predisposition, more complex phenotypes, and more frequent other autoimmune diseases. The identification of the SP-specific variant BTNL2:R281K revealed that the genetic architecture of SP is not just a subset of PFH.

中文翻译：

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NOTCH4和HLA-C基因的两个变体有助于银屑病家族聚集

牛皮癣是一种具有强大遗传背景的多因素免疫介导的皮肤病。先前的研究报道，具有家族史（PFH）的牛皮癣和散发性牛皮癣（SP）具有明显的表现和遗传易感性。但是，尚未完全阐明主要组织相容性复合体（MHC）区域中PFH和SP的遗传异质性。为了探索MHC地区导致牛皮癣家族聚集的遗传变异，我们纳入了总共8,127例牛皮癣病例和9,906名来自汉族的健康对照，并将牛皮癣分为两种亚型PFH（）和SP（）。然后，我们计算了PFH和SP的遗传力，并进行了大规模分层关联分析。我们证实，MHC地区的变异总体上解释了PFH（16.8％）比SP（13.3％）更高的遗传力。进一步的分层关联分析表明， HLA-C 06:02和NOTCH4：G511S有助于牛皮癣的家族聚集，而BTNL2：R281K特别赋予SP风险。HLA-C 06:02和NOTCH4：G511S可以部分解释为什么PFH患者具有更强的遗传易感性，更复杂的表型以及更常见的其他自身免疫性疾病。SP特定变体BTNL2：R281K的标识 揭示了SP的遗传结构不仅是PFH的子集。