Pernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conducted a genome-wide association study meta-analysis in 2,166 cases and 659,516 European controls from population-based biobanks and identified genome-wide significant signals in or near the PTPN22 (rs6679677, p=1.91 x 10-24, OR=1.63), PNPT1 (rs12616502, p=3.14 x 10-8, OR=1.70), HLA-DQB1 (rs28414666, p=1.40 x 10-16, OR=1.38), IL2RA (rs2476491, p=1.90 x 10-8, OR=1.22) and AIRE (rs74203920, p=2.33 x 10-9, OR=1.83) genes, thus providing the first robust associations between pernicious anemia and genetic risk factors. We further mapped the susceptibility in the HLA region to the HLA-DR15 haplotype. Analysis of associated diagnoses and disease trajectories confirm the association between pernicious anemia and thyroid issues, vitiligo, gastritis, stomach cancer, osteoporosis and other diagnoses.

中文翻译：

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全基因组关联研究确定了恶性贫血的五个风险基因座，并暗示了HLA-DR15单倍型的作用

恶性贫血是一种罕见疾病，其特征是缺乏维生素B12缺乏性贫血，这是由于缺乏内在因素引起的，通常由自身免疫性胃炎引起。恶性贫血患者的其他自身免疫性疾病发生率较高，例如1型糖尿病，白癜风和甲状腺自身免疫性疾病。因此，尽管迄今对遗传易感性因素的研究仍很少，但该病具有明确的自身免疫基础。我们在基于人群的生物库中的2,166例病例和659,516例欧洲对照中进行了全基因组关联研究的荟萃分析，并确定了PTPN22中或附近的全基因组重要信号（rs6679677，p = 1.91 x 10-24，OR = 1.63） ，PNPT1（rs12616502，p = 3.14 x 10-8，OR = 1.70），HLA-DQB1（rs28414666，p = 1.40 x 10-16，OR = 1.38），IL2RA（rs2476491，p = 1.90 x 10-8，OR = 1.22）和AIRE（rs74203920，p = 2.33 x 10-9，OR = 1.83）基因，从而提供了恶性贫血与遗传危险因素之间的第一个强有力的关联。我们进一步将HLA地区的易感性映射到HLA-DR15单倍型。对相关诊断和疾病轨迹的分析证实了恶性贫血和甲状腺问题，白癜风，胃炎，胃癌，骨质疏松症和其他诊断之间的关联。