Genome-wide association study identifies five risk loci for pernicious anemia and implicates the role of HLA-DR15 haplotype

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 ⨯ 10 −24 , OR=1.63 ), PNPT1 (rs12616502, p=3.14 ⨯ 10 −8 , OR=1.70), HLA-DQB1 (rs28414666, p=1.40 ⨯ 10 −16 , OR=1.38), IL2RA (rs2476491, p=1.90 ⨯ 10 −8 , OR=1.22) and AIRE (rs74203920, p=2.33 ⨯ 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.