Membranous nephropathy (MN) is an autoimmune kidney disease that has an underlying genetic component; however, the only genome-wide association study (GWAS) to date was of limited size and included only individuals of European ancestry. Now, a large, multinational GWAS has provided greater insights into the genetic architecture of MN. “Our GWAS identified novel risk loci for MN, refined ethnicity-specific effects at the HLA locus and supports a regulatory function of the PLA2R1 risk haplotype,” says Krzysztof Kiryluk. “Moreover, we were able to generate a genetic risk score (GRS) that had excellent diagnostic properties when combined with an anti-PLA2R serum test.”

Kiryluk explains that their study required a large-scale international collaboration to assemble biopsy-diagnosed cohorts of sufficient size. “This study included 3,782 cases and 9,038 controls recruited across East Asia, Europe and North America.” The researchers identified two novel risk loci: NFKB1 and IRF4. “These genes participate in a common immune regulatory pathway; our findings clearly establish a role of this pathway in MN pathogenesis,” says Kiryluk. They also identified ethnicity-specific effects at the HLA locus, defining DRB1*1501 as a major risk allele in East Asians, DQA1*0501 in Europeans and DRB1*0301 in both ethnicities, which the researchers propose could suggest the presence of different immunological triggers in different populations. Fine mapping of the PLA2R1 locus showed that the risk variant intersects a predicted regulatory element. Although this variant was associated with suppressed antigen expression across multiple tissues, it seems to increase expression of PLA2R1 in the kidney.

Development of a GRS showed that the identified variants were highly predictive of disease status, explaining 29% of disease risk across the cohorts. Finally, the researchers show that combining the GRS with an anti-PLA2R ELISA enabled re-classification of 20–37% of cases in which the ELISA test was either negative or inconclusive. “The complementary information provided by the GRS could potentially spare the need for a kidney biopsy in this large subgroup of patients,” explains Kiryluk. “However, future efforts to test this strategy in more diverse populations will be important.”