HLA-DRB1∗15:01 and HLA-DRB3∗02:02 in PLA2R-related membranous nephropathy

Abstract

Idiopathic membranous nephropathy (MN) is associated with HLA; however, the HLA allele involved remains unknown. To identify the HLA risk alleles associated with phospholipase A2 receptor (PLA2R)- related MN in the Chinese population, we sequenced the entire MHC region in DNA samples from 99 patients with PLA2R-related MN, 50 patients with PLA2R-unrelated MN, and 100 healthy subjects. Two HLA risk alleles, HLA-DRB1∗15:01 and HLA-DRB3∗02:02, independently and strongly associated with an increased risk of PLA2R-related MN. After adjusting for HLA-DRB1∗15:01 and HLA-DRB3∗02:02, no other alleles showed significant association with PLA2R-related MN. A replication study in an independent cohort of 293 participantswith PLA2R-relatedMNand 285 healthy controls validated these findings. In a joint analysis, a multivariate logistic regression model confirmed that HLA-DRB1∗15:01 (odds ratio [OR], 24.9; 95% confidence interval [95% CI], 15.3 to 42.6; P52.3310-35) and HLA-DRB3∗02:02 (OR, 17.7; 95% CI, 11.0 to 30.3; P58.0310-29) independently and strongly associated with PLA2R-related MN. As many as 98.7% of patients with PLA2R-related MN, compared with 43.9% of control subjects, carried at least one HLA risk allele. Subjectswith either risk allele had higher odds of developing PLA2R-relatedMNthan those without a risk allele (OR, 98.9; 95%CI, 44.4 to 281.7; P52.5310-23). These HLA risk alleles also associated with the age at disease onset in patients with PLA2R-related MN. In conclusion, our findings provide clear evidence that the HLA-DRB1∗15:01 and HLA-DRB3∗02:02 alleles independently and strongly associate with PLA2R-related MN in the Chinese population.