Department of Dermatovenereology, Rare Disease Center, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang Street, Chengdu, Sichuan, China, 610041.
Precision Medicine Center, State Key Laboratory of Biotherapy, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 17, Section 3, South Renmin Road, Chengdu, Sichuan, China, 610041.
Br J Dermatol. 2019 Apr;180(4):828-835. doi: 10.1111/bjd.17191. Epub 2018 Nov 1.
Pemphigus is a group of rare life-threatening mucocutaneous autoimmune diseases, presenting mainly as two subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Inherited predispositions to pemphigus have long been speculated but they remain poorly understood.
To identify common and specific nongenetic and genetic factors associated with pemphigus and its subtypes in the Chinese population.
A genome-wide association study (GWAS) was performed in 496 unrelated patients with pemphigus (including 365 with PV and 104 with PF) and 1105 controls without pemphigus.
A sex preference was observed only in PV (57·5% female) and not in PF (47·1% female). For male patients only, the mean age at diagnosis was significantly lower for PV than for PF (P < 0·001). The strongest associated single-nucleotide polymorphisms are in the human leucocyte antigen (HLA) region: rs70993900 (PV; P = 1·5 × 10 ) and rs9469220 (PF; P = 1·1 × 10 ). HLA-DQB105:03 ranks at the top (P = 4·7 × 10 ; odds ratio 12·4) in both subtypes, with significantly different risk allele frequency (RAF = 34·2% vs. RAF = 18·8% vs. RAF = 4·4%), whereas HLA-DRB114:01 and HLA-DRB104:06 are PV specific. HLA-DQB103:03 and HLA-DQB1*03:02 show significant subtype specificity in opposite directions. All of these associations were validated in the replication series with 147 cases of pemphigus and 604 controls. Multiple novel non-HLA susceptibility loci were also identified in the GWAS.
This study represents the largest GWAS on pemphigus in the Chinese population published to date, and has allowed us to identify HLA haplotypes significantly shared between or specific to the two main subtypes of pemphigus.
天疱疮是一组罕见的危及生命的黏膜皮肤自身免疫性疾病，主要表现为两型：寻常型天疱疮（PV）和落叶型天疱疮（PF）。人们长期以来一直推测天疱疮存在遗传易感性，但仍知之甚少。
鉴定与中国人群中天疱疮及其亚型相关的常见和特定的非遗传和遗传因素。
对 496 例无亲缘关系的天疱疮患者（包括 365 例 PV 和 104 例 PF）和 1105 例无天疱疮对照进行全基因组关联研究（GWAS）。
仅在 PV（57.5%为女性）中观察到性别偏好，而在 PF（47.1%为女性）中未观察到性别偏好。仅男性患者中，PV 的诊断年龄明显低于 PF（P<0.001）。最强的相关单核苷酸多态性位于人类白细胞抗原（HLA）区域：rs70993900（PV；P=1.5×10）和 rs9469220（PF；P=1.1×10）。HLA-DQB105:03 在两种亚型中均位居首位（P=4.7×10；优势比 12.4），风险等位基因频率（RAF）显著不同（RAF=34.2% vs. RAF=18.8% vs. RAF=4.4%），而 HLA-DRB114:01 和 HLA-DRB104:06 是 PV 特异性的。HLA-DQB103:03 和 HLA-DQB1*03:02 表现出相反方向的显著亚型特异性。所有这些关联在包含 147 例天疱疮和 604 例对照的复制系列中均得到验证。GWAS 还鉴定了多个新的非 HLA 易感基因座。
本研究是迄今为止发表的中国人群中天疱疮最大的 GWAS，使我们能够鉴定出两种主要天疱疮亚型之间或特定于该两种亚型的 HLA 单倍型。
