DNA Variations May Signal Lupus Risk, Offer New Therapeutic Targets
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Identifying SNPs associated with SLE is the initial step in determining how molecular pathways contribute to disease.
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UAB investigators and colleagues participating in the International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) have uncovered new genetic risk factors for SLE. This study is the largest to date examining the genetic basis of lupus. An interaction of genetic and environmental factors causes SLE, which now appears to be associated with more than 20 genes. Pinpointing each genetic variant requires costly and labor-intensive research in large cohorts of patients—challenges that, until recently, were not addressable.
The research success of SLEGEN is due in part to the Program Project in the Genetics of SLE (PPG) at UAB, a multiinstitutional collaboration of investigators. UAB's PPG, a cross-campus cooperative effort, provided SLEGEN with leadership, investigative support, and, critically, access to large repositories of biological samples and data from well-characterized lupus patients from various ethnic groups.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases funds the PPG, which aims to identify the genes responsible for susceptibility and severity of SLE in ethnic minorities. Immunologist and rheumatologist Robert P. Kimberly, MD, leads UAB's longstanding PPG, which currently involves initiatives at eight collaborating centers. These projects include creating and maintaining a large patient specimen and data repository and analysis effort called PROFILE.
Rheumatologist Graciela S. Alarcón, MD, MPH, principal investigator of PROFILE, says "Collaboration between UAB's Program Project PROFILE and SLEGEN is crucial for success. It allows cross-typing of samples from various patient cohorts for the same markers in the same genes. Researchers can determine the relative impact of each variant on disease risk."
Genome-wide association technologies allow researchers to scan and test hundreds of thousands of single nucleotide polymorphisms (SNPs)—locations on chromosomes where a single building block of DNA may vary—distributed across the entire genome to find variants predisposing to disease. The SLEGEN study looked at the genomes of 720 women of European descent with lupus and 2337 without lupus. They scanned complete genomes for 317,501 SNPs to identify those linked to lupus. Researchers then validated findings in an independent set of 1846 women with and 1825 without lupus (Nat Genet. 2008;40[2]:152-154;204-210).
Investigators found associations with SLE in four new chromosomal regions and in genes previously connected with autoimmune diseases. "Identification of implicated genes is the initial step in determining how molecular pathways contribute to disease. Each of these genes represents an opportunity for therapeutic targeting," Kimberly says. "These findings will accelerate our understanding of the causes of lupus and aid development of genetic tests to discover those most at risk."
More than 2 million Americans have SLE. Most cases are in women. Blacks, Hispanics (particularly those with significant Amerindian background), Asians, and Native Americans have higher rates of disease than other ethnicities; prevalence in black women aged 15 to 64 years is 1 in 245.
"This study opens the door for similar studies to determine if the same gene variants signal high lupus risks in certain ethnic or racial groups and how these genetic pathways contribute to lupus development," he says.
For more information contact Dr. Robert Kimberly at 1-800-UAB-MIST or at mist@uabmc.edu.