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April 2006
Researchers at Boston University, led by Michael Christman and Alan Herbert, have discovered the first common genetic variant that predisposes individuals to obesity. The genetic variant, which is 10 kilobases upstream of the metabolic gene INSIG2, was identified using a whole-genome scan of DNA samples from participants in the multi-generational Framingham Heart Study, and replicated in four age and ethnicity diversified populations. The researchers estimate that up to 10 percent of individuals carry this variation.
Obesity is linked to increased risk of multiple diseases, including diabetes, stroke, heart disease and cancer. The heritability rate for body-mass index, the simplistic ratio of weight to height, is thought to be between 30 and 70 percent. Presently, 65 percent of Americans are overweight and 30 percent obese.
Participants in the Framingham Heart Study – a study that has tracked the medical history of three generations of families since 1948 – were used because they were not previously sorted for any particular genotype or phenotype. In doing so, the researchers sought to decrease the possibility that any significant finding could be based on population stratification, where individuals are culled from a larger group based on a particular characteristic. From a high-density 100K array, researchers found that the intergenic variant rs75660605 CC was associated with increased BMI in this group. The variant was also associated with increased risk of obesity in three out of four non-related groups tested, and also was more prevalent in obese children and adolescents.
rs75660605 CC is near the INSIG2 gene (insulin-induced gene). The INSIG2 protein product inhibits fatty acid and cholesterol synthesis. In the Zucker Diabetic Fatty rat model, upregulation of INSIG2 increases triglyceride turnover, and INSIG2 has been implicated as a factor in obesity by functional studies in mice and linkage studies in mice and humans.
The prevalence of the variant in both Caucasian and African American populations suggests that it may have arisen early in human history. It appears that its effects were neutral early on but only now has become deleterious given a Western diet and lack of exercise.
Reference: Watch an interview with the authors Alan Herbert and Michael Christman.
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