Resumen: |
Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1. 25, P = 3. 4 × 10 −12) and IRF4 (rs9405192, OR = 1. 29, P = 1. 4 × 10 −14), fine-map the PLA2R1 locus (rs17831251, OR = 2. 25, P = 4. 7 × 10 −103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3. 81, P = 2. 0 × 10 −49), DQA1*0501 in Europeans (OR = 2. 88, P = 5. 7 × 10 −93), and DRB1*0301 in both ethnicities (OR = 3. 50, P = 9. 2 × 10 −23 and OR = 3. 39, P = 5. 2 × 10 −82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk. Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects. |