Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Andalucía, Spain
Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Andalucía, Spain.
Ann Rheum Dis. 2021 Aug;80(8):1040-1047. doi: 10.1136/annrheumdis-2021-219884. Epub 2021 Apr 1.
The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes.
9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA).
Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with and , and revealed a novel association of . Stratified analyses showed specific associations of with lcSSc, and an exclusive association of with dcSSc. Similarly, private associations were detected in and confirmed the previously reported association of with ACA-positive patients, as opposed to the and alleles associated with ATA presentation.
This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.
系统性硬化症（SSc）报道的最大遗传效应位于主要组织相容性复合体（MHC）位点。利用最大的 SSc 全基因组关联研究，我们旨在精细定位该区域，以鉴定与 SSc 易感性及其主要临床和血清学亚型相关的新人类白细胞抗原（HLA）遗传变异。
9095 例 SSc 患者和 17584 例对照进行全基因组基因分型，以推断和测试 MHC 、经典 HLA 等位基因及其复合氨基酸残基上的单核苷酸多态性（SNP）。此外，根据患者的临床和血清学状况对其进行分层，即局限性皮肤系统性硬化症（lcSSc）、弥漫性皮肤系统性硬化症（dcSSc）、抗着丝点（ACA）、抗拓扑异构酶（ATA）和抗 RNA 聚合酶 III 自身抗体（ARA）。
顺序条件分析显示了九个 SNP、九个经典等位基因和七个氨基酸，这些 SNP、等位基因和氨基酸模拟了与 SSc 相关的观察到的关联。这证实了先前与 和 相关的关联，并揭示了 的新关联。分层分析显示了 与 lcSSc 的特定关联，以及 与 dcSSc 的独特关联。同样，在 和 中检测到了特定的关联，并证实了先前报道的与 ACA 阳性患者相关的 ，而 等位基因与 ATA 表现相关。
本研究证实了 HLA Ⅱ类的贡献，并揭示了 HLA Ⅰ类与 SSc 的新关联，提示了疾病发病机制的新途径。此外，我们描述了 SSc 临床和血清学亚型与 HLA 的特定关联，这些关联可作为疾病严重程度和进展的生物标志物。
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