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At the Forefront of Genetics Research
CHORI Scientist Leads Natural Killer Cell Research with 3 New Grants

"What we do know for sure is that genome wide association studies have shown a very strong association of MS with chromosome 19, which is the same region where the KIR complex is located."

Multiple sclerosis (MS) is a debilitating autoimmune disorder in which the body’s own cells attack the nervous system, and for which there is currently no cure. Although patients’ life expectancy is not significantly reduced, MS results in progressive loss of physical and neurological function with very few available effective treatment options, and disease progression is very difficult to predict.

Dr. Trachtenberg’s study, led in concert with CHORI scientist Henry Erlich, PhD, and University of California at San Francisco’s Jorge Oksenberg, PhD, will be the first study to investigate the role of NK and KIR in MS, although previous studies of MS have suggested the potential for a connection between NK activity and MS.

“Although there is no definitive connection between NK and MS, what we do know for sure is that genome wide association studies have shown a very strong association of MS with chromosome 19, which is the same region where the KIR complex is located,” says Dr. Trachtenberg.

While it has been known for almost 30 years that the HLA complex influences the risk for MS, a very thorough analysis of both HLA class I and II heterogeneity in MS has yet to be performed. Dr. Trachtenberg’s study, however, will significantly broaden the analysis of HLA in MS.

“We hope to identify which genetic variations explain differences in disease risk, age of onset and progression. It’s very likely that the addition of KIR and HLA/KIR interactions to the study of MS pathogenesis will bring important new developments to MS research” Dr. Trachtenberg says.

Dr. Okesenberg has already compiled the cohort of 500 MS patients and 500 controls who have no inflammatory or autoimmune disease for the study, which is undertaken with strict confidentiality, with samples coded and other measures taken so that no personal identifiers are available to the investigators. The study will use multifactorial gene association analysis on the two groups in order to identify which KIR genes and KIR/HLA ligand combinations exists that may predispose people to disease, have an effect on age of onset, and/or correlate with disease progression.

“Our overall goal," says Dr. Trachtenberg, "is to understand the role of the NK, KIR and HLA heterogeneity in MS disease and disease progression.
"NK cells are emerging as innate effector cells with both cell killing and immune re-sponse tuning functions, so a more detailed understanding of the under-lying genetics of the KIR receptors will significantly enhance our knowledge.”
In addition to utilizing their own assay, Dr. Trachenberg will also be using a novel HLA sequencing assay pioneered by her collaborator, Dr. Erlich, (of CHORI and Roche Molecular Systems) using the Roche 454 platform, a high through-put sequencing method capable of sequencing all of the HLA genes concurrently.

“We’ll be using the 454 platform to analyze 8 different loci on one thousand samples in a one year period. You could never do a study like this without this kind of high-throughput analysis,” says Dr. Trachtenberg.

Such information could be critical in diagnosing both disease and disease severity which may help clinicians with treatment regimens and management of their MS patients. In the long term, the elucidation of KIR/HLA function in MS could also provide a potential avenue for developing treatments that target the alleviation of inflammation. In the mean time, however, Dr. Trachtenberg is ready to start the hard work that comes before such breakthroughs.
“It’s very exciting to be working on this grant with other colleagues who are at the top of their fields,” says Dr. Trachtenberg. “It’s an honor to be working with them.”

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Tuesday, May 17, 2011 8:19 AM

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