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Studies Provide Greater Insight Into Molecular Pathways of Lupus

NEW YORK (GenomeWeb News) – A quartet of research papers published on lupus genetics this week may bring scientists closer to understanding the disease and could potentially lead to more effective diagnostics and treatments.
 
The four studies — including two large genome-wide SNP studies, one study investigating SNPs that specifically predict amino acid changes, and one focusing on a particular candidate gene — revealed several new genes and confirmed previously identified loci associated with lupus. The papers, three in Nature Genetics and one in the New England Journal of Medicine, were all published online on January 20th.
 
The results provide “greater insight into the particular molecular pathways that are involved in the disease,” Mary Crow, a rheumatologist with New York’s Hospital for Special Surgery and co-director of the Mary Kirkland Center for Lupus Research who wrote an invited editorial on the studies in NEJM, told GenomeWeb Daily News. “So many components of the autoimmune system are involved.”
 
Systemic lupus erythematosus is a complex autoimmune disease affecting roughly one-and-a-half million Americans — usually women. The mysterious condition causes the body’s immune system to attack itself, damaging organs such as the skin, nervous system, or cardiovascular system. Although there appear to be environmental triggers, SLE clusters strongly in families, suggesting a significant genetic component.
 
In 2005, the Alliance for Lupus Research formed the International Consortium for Systematic Lupus Erythematosus — also known as the SLEGEN Consortium — to investigate this genetic aspect of the disease. Their plan: to employ cutting edge genetic technology to study lupus genetics. In the SLEGEN study published this week in Nature Genetics, collaborators from the US, UK, Sweden, and elsewhere conducted a genome-wide association study on nearly 7,000 women of European ancestry.
 
The genotyping was performed by researchers at Boston’s Broad Institute who applied chip technologies using the Sequenom platform and an Illumina Infinium HapMap300 genotyping BeadChip system to scan nearly 320,000 SNPs. Initially, the group compared the DNA from 720 women who had SLE with 2,337 controls. They then verified their initial results in roughly 1,800 affected and unaffected women each.
 
Their work implicated at least nine different genetic markers. Some were already known to influence autoimmune diseases, while others were unexpected. “Clearly there are some here that were not anywhere near our radar screen,” Wake Forest University biostatistician Carl Langefeld, one of the corresponding authors on the SLEGEN paper, told GenomeWeb Daily News. “Many of these things weren’t on our ‘to-do’ list, which is exactly why you do this agnostic kind of a scan, if you will.”
 
For example, the group identified a region in an apparent “gene desert,” as well as ITGAM, a gene coding integrin alpha M, a protein found on the white blood cells that facilitates recruitment to red blood cells, which was also implicated in two of the other studies.
 
In another large genome-wide study, published in NEJM, American and Swedish researchers genotyped more than 500,000 SNPs from about 1,300 individuals of North American and European descent on Illumina HapMap550, 550v1, and 550v3 chips. They also incorporated data from public databases and confirmed their findings in roughly 800 Swedish SLE patients and controls. They identified genes that may be related to B-cell signaling as well as ITGAM.
 
Interestingly, ITGAM was identified not only in both genome-wide screens, but also was the gene of interest in a third lupus study published in Nature Genetics. Oklahoma Medical Research Foundation geneticist Swapan Nath and his colleagues initially identified ITGAM through linkage studies and a directed candidate gene approach.
 
A fourth group genotyped about 85,000 SNPs on samples taken from 279 Swedish subjects and 515 controls, using a 100K Affymetrix SNP array. In that case, their goal was specifically to find polymorphisms associated with non-synonymous amino acid substitutions. That work implicated BANK1, a gene coding for a B-cell scaffold protein that acts as an adaptor in the immune system, according to the findings that also were published in Nature Genetics.
 
For her part, Crow believes the ITGAM gene product’s association with blood vessels might be significant, since vascular alterations have been noted over the years with lupus but have been largely overlooked. “In the past 25 to 30 years the focus has been primarily on the immune system,” Crow said in a statement. “The new research on ITGAM, I think, will help redirect the attention of the scientific community back to this aspect of the disease.”
 
Langefeld and others anticipate that being able to increase the predictability of lupus — for example, identifying gene variants that could lead to complications as early as possible — is “really a step toward personalized medicine.”
 
“Clearly the number of genetic markers across these papers really underscores the genetic influence of lupus,” Langefeld says.

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