Immunogenomics Laboratory, Department of Human Genetics & Molecular Medicine, School of Health Sciences, Central University of Punjab, Ghudda, Punjab, India.
Department of Rheumatology, All India Institute of Medical Sciences, New Delhi, India.
Int J Rheum Dis. 2022 Jul;25(7):811-819. doi: 10.1111/1756-185X.14354. Epub 2022 Jun 3.
Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease. Smaller sample size and complex nature of the disease pathogenesis has made it challenging to perform well-powered genetic investigations. We performed a systematic review based meta-analysis in GPA to investigate the genetic susceptibility conferred by non-human leukocyte antigen (non-HLA) candidate genes.
A systematic review was performed using web-based literature search and eligible studies were included following inclusion-exclusion criteria. Studies were evaluated for their quality of evidence and study outcome was assessed using the Newcastle-Ottawa Scale and Grades of Research, Assessment, Development and Evaluation tools. Reviewer's agreement was accessed through Cohen's κ value. Meta-analyses were performed using RevMan 5 tool. Meta-odds ratio (meta-OR) and Z test P value were evaluated to estimate the genetic susceptibility for each of the variants.
Eighteen studies were found eligible and 7 genetic variants from only 4 genes, namely CTLA4, PRTN3, SERPINA1 and PTPN22 could be studied for meta-analysis. rs231775-G (49-G) (Meta-OR = 1.42 [1.14-1.76]; P = .001) of CTLA4 and rs7151526-A (Meta-OR = 2.70 [1.51-4.85]; P = .0008) of SERPINA1 were confirmed to be predisposing alleles, and rs5742909-C (318-C) (Meta-OR = 0.65 [0.44-0.97]; P =.03) of CTLA4 was found to be protective for GPA. In concordance with the genetic association of rs7151526-A, serological marker for the same variant "Z" allele of SERPINA1 was found to be predisposing (Meta-OR = 12.60 [5.01-31.68]; P < .00001) for GPA.
Genetic variants confirmed in this study play critical roles in T-cell mediated immune function and could be significantly implicated in GPA. Molecular pathology studies are warranted to confirm their role. These markers could be used for efficient patient classification and disease management.
肉芽肿性多血管炎（GPA）是一种罕见的系统性自身免疫性疾病。由于样本量较小和疾病发病机制复杂，使得进行强有力的遗传研究具有挑战性。我们对 GPA 进行了系统的综述和荟萃分析，以研究非人类白细胞抗原（non-HLA）候选基因所赋予的遗传易感性。
使用基于网络的文献搜索进行系统综述，纳入符合纳入排除标准的研究。研究的质量证据进行评估，并使用纽卡斯尔-渥太华量表和研究、评估、发展和评估工具的等级来评估研究结果。通过 Cohen's κ 值评估审稿人的一致性。使用 RevMan 5 工具进行荟萃分析。评估 Meta 优势比（Meta-OR）和 Z 检验 P 值，以估计每个变体的遗传易感性。
发现 18 项研究符合条件，仅来自 4 个基因的 7 个遗传变异，即 CTLA4、PRTN3、SERPINA1 和 PTPN22 可进行荟萃分析。CTLA4 的 rs231775-G（49-G）（Meta-OR=1.42[1.14-1.76]；P=0.001）和 SERPINA1 的 rs7151526-A（Meta-OR=2.70[1.51-4.85]；P=0.0008）被证实为易感等位基因，而 CTLA4 的 rs5742909-C（318-C）（Meta-OR=0.65[0.44-0.97]；P=0.03）被发现对 GPA 具有保护作用。与 rs7151526-A 的遗传关联一致，SERPINA1 的同一变异“Z”等位基因的血清学标志物被发现对 GPA 具有易感性（Meta-OR=12.60[5.01-31.68]；P<0.00001）。
本研究中证实的遗传变异在 T 细胞介导的免疫功能中起关键作用，可能对 GPA 具有重要意义。需要进行分子病理学研究来证实它们的作用。这些标志物可用于有效的患者分类和疾病管理。
