Membranous Nephropathy (MN) is one of the leading causes of end-stage renal
disease (ESRD). MN is an autoimmune disease in which autoantibodies target
antigens at the level of the glomerular basement membrane. The nature of these
antibodies and the reason why they develop are not fully understood.
One of the strategies towards a better understanding of the disorder is genetic
analysis, of which two approaches have been attempted: linkage mapping, based
on a family suggestive for X-linked transmission of the MN trait; and whole
genome association mapping, based on three case-control cohorts. The first
cohort (335 cases and ethnically matched controls from the UK) was genotyped
using SNP markers and analysed in an exploratory study which led to the
identification of two highly significant loci of association. Two cohorts (146
biopsy proven MN cases and ethnically matched controls from the Dutch
research group in Nijmegen and 75 biopsy proven cases and ethnically matched
controls from the French research group in Paris) were used to successfully
replicate the results.
The two loci which we identified and independently confirmed are located on
chromosome 2 and on chromosome 6.
The chromosome 2 locus includes the PLA2R gene, confirming the hypothesis of
Beck et al. which identified PLA2R as a key antigen in idiopathic MN by using
an immunological approach [1].
The chromosome 6 locus lies within the extended Human Leukocyte Antigene
(HLA) system locus, with the highest significance for association reached by
alleles of HLA-DQA1.
Our results suggest that the susceptibility to membranous nephropathy is
associated to genetic variants at the level of both PLA2R1 and HLA loci. The
causative variants could be some of the polymorphisms captured by the
genotyping array which was analysed or, more likely variants (single nucleotide
or copy number variant type) situated nearby (and therefore in linkage
disequilibrium)
