Genetics news:
Kidney Disorder Linked to Gene Variants

By Michael Smith, North American Correspondent, MedPage Today
Published: February 16, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

The rare kidney disorder known as idiopathic membranous nephropathy may be an autoimmune disease, according to a large genome-wide association study.

In three different cohorts totaling more than 550 white European patients, the disease was linked to a single-letter genetic variation in the human leukocyte antigen (HLA) complex -- which plays a central role in immunity, reported Robert Kleta, MD, PhD, of Royal Free Hospital in London, and colleagues.

The genome-wide association study also replicated aprevious finding, linking the disease to the so-called M-type phospholipase A2 receptor -- determining that variants in the gene for this receptor were linked to an increased risk of the illness, Kleta and co-authors wrote in the Feb. 17 issue of the New England Journal of Medicine.

Having two copies of the risk alleles in both genes increased the likelihood of the disease by a factor of 78, they reported, and -- although the exact mechanism remains unknown -- it could be an interaction between the immune system and the receptor that leads to autoimmunity.

The condition has an annual incidence of about one in 100,000 people, the researchers noted, and it can lead to end-stage renal disease, although its cause remains unclear.

To help clarify the issue, the researchers undertook a genome-wide analysis of three separate groups of European patients of white ancestry -- 75 French, 146 Dutch, and 335 British patients -- and compared them with 2,339 racially matched controls.

The cohorts and their controls were analyzed separately but -- since they were racially homogenous -- they also could be analyzed together, Kleta and colleagues reported.

In all three cohorts, the researchers found a significant association with an HLA-DQA1 allele on chromosome six, while in the Dutch and British groups, they also found a significant link with the gene coding for the M-type phospholipase A2receptor.

When the groups were analyzed together, Kleta and colleagues reported, the links remained significant. Specifically:

- A single nucleotide polymorphism dubbed rs2187668 within HLA-DQA1 was significant at P=8.0x10-93.
- And a single nucleotide polymorphism called rs4664308 within the gene for the receptor was significant at P=8.6x10-29.

Carrying the risk alleles of the two genes had an additive effect, Kleta and colleagues found.

Compared with having two copies of the protective allele within HLA-DQA1, having one copy of the risk allele increased the odds of the disease by a factor of 6.07 and having two copies by a factor of 20.24.

Similarly, having one copy of the risk allele within the receptor gene increased the odds of the disease by a factor of 2.22 and having two copies by a factor of 4.19, compared with having two copies of the protective allele.

Having risk alleles in each of the genes increased the risk still more, the researchers found: Those with all four risk alleles had an odds ratio for the disease of 78.46 compared with people who had only the protective alleles.

Kleta and colleagues cautioned that the findings "do not establish causality" but they suggest that an interaction between the immune system and glomerular components form the basis for the development of the disease.

On that hypothesis, they argued, the immune system variants in HLA-DQA1 are a "trigger" while those in the receptor gene establish autoantibodies -- "a bullet" -- that target glomerular antigens.

Indeed, the findings "may redirect research toward finding a remedy for this troublesome disease," argued Marten Segelmark, MD, PhD, of the Linkoping University Hospital in Linkoping, Sweden.

In an accompanying editorial, Segelmark wrote that the study lends credence to the notion that recently discovered autoantibodies to the M-type phospholipase A2 receptor play a pathogenic role in membranous nephropathy.

The study also suggests that -- if and when effective prevention or treatments become available -- screening for people who have two copies of each of the risk variants might be a useful public health measure, he argued.

Link to the NEJM article by Stanescu and Others.

Primary source: New England Journal of Medicine
Source reference: Stanescu HC, et al "Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy" N Engl J Med 2011; 364: 616-626. 

Additional source: New England Journal of Medicine
Source reference: Segelmark M "Genes that link nephritis to autoantibodies and innate immunity" N Engl J Med 2011; 364: 679-680.

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