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Researchers have identified a common genetic variant, present in ten percent of individuals

Boston University : 13 April, 2006  (Technical Article)
An international team of scientists led by researchers in the Genetics and Genomics Department at Boston University School of Medicine have identified a common genetic variant, present in ten percent of individuals studied, that is associated with an elevated risk of obesity in populations of both European and African ancestry. The risk of obesity is increased for both adults and children. The study appears in the April 14th issue of the journal Science.
The variant was identified by examining over 100,000 single nucleotide polymorphisms in each individual in DNA samples from participants in the Framingham Heart Study cohort. The Genetics and Genomics Department team analyzed the genetic variation using the Affymetrix GeneChip Mapping 100K DNA microarray technology. The resulting dataset contained roughly a terabyte of information, or about two billion printed pages. Drs. Marc Lenburg and Norman Gerry of BUSM spearheaded the gathering and management of these huge datasets. The study used BMI measurements the Framingham Heart Study participants gathered over a period of 24 years under a contract from the National Heart Lung and Blood Institute administered by Boston University.

“This study may allow us to design better drugs to treat obesity by identifying the biochemical pathways that make us fat,” said lead author *Alan Herbert, MBChB, PhD, at BUSM. “In today’s world of caloric excess this variant may elevate your risk of obesity. However, 75,000 years ago in hunter gatherer groups, it may have had little impact on body weight,” said senior author *Michael Christman, PhD, professor and Chair of the Department of Genetics and Genomics at BUSM. The obesity variant is ancient and most likely arose prior to human migration out of Africa. “In many cases a predisposing genetic signature such as the one we have found may also require a specific environment to show its effects,” he explained.

Using families from the Framingham Heart Study, the Genetics and Genomics investigators performed a genome-wide analysis to identify the common genetic variants associated with obesity, which led to the discovery of a variant near the INSIG2 gene (insulin-induced-gene 2) reported in the Science paper. The BUSM researchers collaborated with researchers from Harvard School of Public Health, led by Drs. Nan Laird and Christoph Lange, who developed methods used in the analysis. The finding was then tested in several other populations by collaborators in Germany (KORA study led by Erich Wichmann and Thomas Meitinger ) and Essen study led by Johannes Hebebrand), Chicago (Loyola University study led by Richard Cooper) and Boston (Nurses Health Study led by David Hunter, Frank Hu and Graham Colditz, Children’s Hospital study led by Joel Hirschhorn and SeraCare study led by Kristen Ardlie). Collectively, the studies found that those ten percent of individuals who possessed the common genetic risk factor were heavier and showed an elevated risk of being obese, regardless of their sex and age. The association was also observed in children and adolescents.

'The identification of this new gene variant for obesity highlights the continued importance of the Framingham Heart Study in cutting edge research on risk factors for cardiovascular disease,' said Elizabeth G. Nabel, M.D., director of the National Heart, Lung, and Blood Institute of the National Institutes of Health. 'It is particularly exciting that this finding was replicated in samples from other populations. This suggests that the variant may be involved in the basic underlying pathways leading to obesity, a finding that could have substantial public health impact.'

Roughly half of obesity risk is genetically determined and the remainder is due to environmental factors such as diet and exercise. Obesity is also a risk factor for many common diseases such as type 2 diabetes, heart disease, hypertension, stroke and some forms of cancers. Presently, sixty-five percent of Americans are overweight, and thirty percent are considered obese. The study is ongoing and the authors hope to identify other genetic variants that elevate the risk of obesity and even those that are associated with thinness.

Support for this work was obtained from a Leadership Award from the Whitaker Foundation, grants from the American Diabetes Association, an ADA Smith Family Pinnacle Program Project, NIH grants, German Ministry of Education and Research through the National Genome Research Network, Bioinformatics for the Analysis of Mammalian Genomes, and National Cancer Institute. DNA samples and phenotypic data were provided by NHLBI-Framingham Heart Study investigators.
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