Thursday, May 19, 2011

Kidney disease linked to putative autoantigen + HLA

Idiopathic membranous nephropathy is a progressive disease involving the thickening of the basement membranes in glomeruli, which are key blood filtration units in the kidneys. Membranous nephropathy can be caused by exposure to toxins (gold, mercury, some medicines) or autoimmunity, such as lupus. Deposits of antibody-antigen (immune) complexes with complement components can be observed in the glomerulus.

These authors sought genetic associations in 556 biopsy-proven patients (British, French, & Dutch) by comparison of about 300,000 SNPs with matched healthy subjects. They found strong associations with a membrane protein previously implicated in autoimmunity, M-type phospholipase A2 receptor (PLA2R1, p~10E-28), and a histocompatibility gene (HLA-DQA1, p~10E-92). PLA2R1 is normally expressed in human glomeruli, exactly where immune complexes are found in membranous nephropathy patients. PLA2R1 was implicated only recently in autoantibody studies (Beck 2009) and is now known as the major autoantigen in idiopathic membranous nephropathy. The DQA1 association is not surprising, having been discovered by Vaughn et al using the relatively crude restriction fragment length polymorphism (RFLP) analysis and reported way back in 1989. The odds ratio for a single PLA2R1 risk allele is about 2 and for HLA-DQA1 about 6, modest but typical for such association studies. It is therefore astonishing that the risk to individuals possessing homozygous risk alleles at both loci is practically determinate – a 78.5-fold increased risk! – with 42 patients out of the 55 subjects possessing this combination.

How might this happen? The authors’ model is that perhaps the DQA1 molecule binds the PLA2R1 variant peptide and triggers T lymphocytes to help B cells make anti-PLA2R1 autoantibodies that bind to glomerular cells. They could have looked whether any PLA2R1 peptides has anchor residues that determine whether they can fit one of the 35 different allelic forms of DQA1. However, as Segelmark points out in the accompanying review, the strongest SNPs lie within the first introns for both PLA2R1 and DQA1 and (therefore) do not alter the amino acid sequence! The authors discount this, speculating that either the associated SNP is tightly linked to a variant that does change the protein. They could have sequenced the few subjects to identify any rare variant. Segelmark proposes as “more likely” that the SNP changes a regulatory sequence, such as a transcription factor binding site or a microRNA, that increases production of the proteins. A few more facts could help resolve these possibilities.
Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, Voinescu C, Patel N, Pearce K, Hubank M, Stephens HA, Laundy V, Padmanabhan S, Zawadzka A, Hofstra JM, Coenen MJ, den Heijer M, Kiemeney LA, Bacq-Daian D, Stengel B, Powis SH, Brenchley P, Feehally J, Rees AJ, Debiec H, Wetzels JF, Ronco P, Mathieson PW, Kleta R. N Engl J Med. 2011 Feb 17;364(7):616-26.