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PLA2R-associated membranous glomerulopathy is modulated by common variants in PLA2R1 and HLA-DQA1 genes

M Saeed1, M L Beggs1, P D Walker1

  • 1Department of Genomics, Nephropath, Little Rock, AR, USA.

Genes and Immunity
|September 5, 2014
PubMed

Insights

Genetic variants in PLA2R1 strongly associate with phospholipase A2 receptor-positive membranous glomerulopathy (MG), particularly in Caucasians. This study highlights PLA2R1 SNP rs35771982 as a key factor, with potential for discovering new genes for PLA2R-negative MG.

Area of Science:

  • Nephrology
  • Genetics
  • Immunology

Background:

  • Membranous glomerulopathy (MG) is frequently autoimmune, often linked to antibodies against the podocyte phospholipase A2 receptor (PLA2R1).
  • Common genetic variants within the PLA2R1 gene are known risk factors for MG.

Purpose of the Study:

  • To investigate the association of PLA2R1 variants with specific pathological subtypes of MG.
  • To determine the extent of genetic association in PLA2R-positive versus PLA2R-negative MG.
  • To identify potential novel genetic factors for PLA2R-negative MG.

Main Methods:

  • A large case-control association study (n=1512) was conducted.
  • Analyses included single-nucleotide polymorphisms (SNPs) and haplotypes within PLA2R1.
  • Joint analysis and trans-ethnic mapping were employed to enhance statistical power.

Main Results:

  • The PLA2R1 SNP rs35771982 showed the strongest association with PLA2R-positive MG (P=1.4 × 10⁻¹⁴, OR=1.98).
  • Other PLA2R1 SNP associations were attributed to linkage disequilibrium with rs35771982.
  • PLA2R1 variants were significantly associated with PLA2R-positive MG predominantly in Caucasians, but not in African Americans.
  • Strong epistasis was observed between HLA-DQA1 SNP rs2187668 and PLA2R1 variant rs35771982.

Conclusions:

  • Common PLA2R1 variants, especially rs35771982, significantly influence PLA2R-positive MG risk in Caucasians, interacting with HLA-DQA1.
  • PLA2R1 variants do not associate with MG in African Americans.
  • PLA2R-negative MG, particularly in African Americans, represents a promising area for identifying novel causative genes.

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