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NEW YORK (Reuters Health) Jan 21 - Researchers have identified two new genetic loci on chromosomes 8 and 16 that appear to influence susceptibility to systemic lupus erythematosus (SLE), according to a report in the January 20th Online First issue of The New England Journal of Medicine.
In a similar study, reported in the January 20th online issue of Nature Genetics, a different research group describes the identification of additional susceptibility variants on chromosomes 11, 3, and 1. Many of the variants identified in both studies appear to affect genes with various immune functions.
"This is the first time we've been able to use the new genome-wide association technology to test over 500,000 genetic variants in lupus, and it very successfully identified new genes for this disease," Dr. Timothy W. Behrens, senior author of the first study, told Reuters Health.
"We believe we have now identified most of the major common genes contributing to lupus," Dr. Behrens, from Genentech in South San Francisco, said. "Before we were always worried about what we were missing. Now we know."
In their study, Dr. Behrens' group analyzed DNA from 1,311 cases and 1,783 controls from North America. This led to the identification of chromosome 8p23.1 and chromosome 16p11.22 as genetic loci for SLE, which was confirmed in a replication cohort involving 793 case and 857 control subjects from Sweden.
Variants on chromosome 8p23.1 increased the risk of SLE by 39% and were associated with reduced expression of B lymphoid tyrosine kinase (BLK) and increased expression of C8orf13, a gene of unknown function. Variants on chromosome 16p11.22, which occurred close to the genes for integrin alpha M (ITGAM) and integrin alpha X (ITGAX), increased the odds of SLE by 33%.
"We are starting to get a much better view of the genetics underlying lupus, and we hope that this will lead to our being able to subset patients more accurately, and ultimately to target therapies to the patients most likely to respond," Dr. Behrens said.
In the second study, Dr. Carl D. Langefeld and colleagues from the International Consortium for SLE Genetics (SLEGEN) performed a genome-wide association scan on over 300,000 variants in 720 case and 2337 control subjects of European ancestry. Disease-associated variants were then confirmed in two additional cohorts bringing the total to 1,846 case patients and 1825 control subjects.
In addition to identifying the ITGAM variant found by Dr. Behrens' team, the SLEGEN researchers identified variants on chromosomes 11p15.5 (KIAA1542), 3p14.3 (PXK), and 1q25.1 (rs10798269) that appeared to increase susceptibility to SLE.
"These findings underscore that numerous genes, which are often immune-function-related, contribute to the risk of developing lupus," Dr. Langefeld, a researcher at Wake Forest University School of Medicine in Winston-Salem, North Carolina, said in a statement.
"The new data highlight the extensive variability in genes encoding mediators of innate and adaptive immune responses, including components of the signaling pathways that regulate lymphocyte activation and the cell-surface receptors that generate tissue responses," Dr. Mary K. Crow, from the Hospital for Special Surgery in New York, writes in a related editorial.
"When the combination of (genetic) variations favors immune-system activation, inflammation, and vascular damage, SLE can result," she adds.
N Engl J Med 2008;358.
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