HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-Related Membranous Nephropathy

J Am Soc Nephrol. 2017 May;28(5):1642-1650. doi: 10.1681/ASN.2016060644. Epub 2016 Dec 27.

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 participants with PLA2R-related MN and 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; P=2.3×10-35) and HLA-DRB3*02:02 (OR, 17.7; 95% CI, 11.0 to 30.3; P=8.0×10-29) 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. Subjects with either risk allele had higher odds of developing PLA2R-related MN than those without a risk allele (OR, 98.9; 95% CI, 44.4 to 281.7; P=2.5×10-23). 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.

Keywords: HLA Typing; Target sequencing; autoimmune disease; human leukocyte antigen; membranous nephropathy.

MeSH terms

  • Adult
  • Alleles
  • Asian Continental Ancestry Group
  • Female
  • Glomerulonephritis, Membranous / genetics*
  • Glomerulonephritis, Membranous / immunology
  • HLA-DRB1 Chains / genetics*
  • HLA-DRB1 Chains / immunology
  • HLA-DRB3 Chains / genetics*
  • HLA-DRB3 Chains / immunology
  • Humans
  • Male
  • Middle Aged
  • Receptors, Phospholipase A2 / physiology*
  • Young Adult

Substances

  • HLA-DRB1 Chains
  • HLA-DRB3 Chains
  • Receptors, Phospholipase A2