OKLAHOMA CITY, Oklahoma, UPPSALA, Sweden, SOUTH SAN FRANCISCO, California—A collaboration of lupus researchers spread across two continents and drawing on resources from academic centers, government agencies, research foundations, and industry has discovered four new lupus-related genes and other genetic changes likely to dramatically alter basic understanding of the pathology of systemic lupus erythematosus (SLE) and to redirect some aspects of therapeutic research.

Genome-wide association, international collaborations push SLE research forward

Papers released January 20 online in Nature Genetics and in The New England Journal of Medicine include work by

• the International Consortium for Systemic Lupus Erythematosus (SLEGEN), led by John B. Harlen, MD, of the Oklahoma Medical Research Foundation in Oklahoma City, identifying variants in or near the genes encoding integrin α_M (ITGAM), KIAA1542, and PXK, as well as a so-called "gene desert" on chromosome-1 and a possible association with B-lymphoid tyrosine kinase (BLK)¹
• Swapan K. Nath, MD, of the Oklahoma Medical Research Foundation, et al also showing an association between lupus and ITGAM²
• Sergey V. Kozyrev, MD, et al from Uppsala University in Sweden, reporting an association between SLE and variants in the B-cell scaffold protein with ankyrin repeats 1 (BANK1)³
• Geoffrey Horn, PhD, from Genentech, South San Francisco, California, reporting associations between SLE and BLK, as well as with genes encoding C8orf13 (chromosome 8p23.1).⁴

Much of this work using genome-wide association technologies was made possible by the Alliance for Lupus Research, which formed and supported SLEGEN.

In an accompanying New England Journal of Medicine editorial, Mary K. Crow, MD, director of rheumatology research at the Hospital for Special Surgery in New York, said, "The genetic diversity that is described in these and other recent studies can be viewed as essential for maintaining adequate host defense against infectious microbes at the level of the aggregate human population. When the combination of variants favors immune-system activation, inflammation, and vascular damage, SLE can result."⁵

New studies suggest new targets for treatment research

Dr. Crow pointed to the B-cell receptor-signaling pathway and to the ways inflammatory cells adhere to the vasculature as potentially fruitful areas for future research.

The protein encoded by the BLK gene is involved in adaptive immunity. BANK1 links activation of Src tyrosine kinases by B-cell receptor ligation to activation of calcium channels. ITGAM is thought to modify intercellular adhesion molecule-1 in a way that would alter binding and might play a role in SLE-related vasculopathy and vasculitis.

"The identification of ITGAM as a lupus-associated gene should rekindle interest in and investigation of the mechanisms underlying many characteristic clinical and pathologic features of SLE including ‘onion skinning' of splenic arterioles, retinopathy livedo reticularis, wire-loop lesions of glomerular capillaries, and premature atherosclerosis (the latter being one of the most important causes of morbidity and mortality associated with SLE)," Dr. Crow said.

A limitation of these studies is that three of the four included only patients of European descent. Further work is needed on SLE genetics in patients of African, Hispanic, or Asian descent, who typically have more severe disease.

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