Obesity, Diabetes-Linked Gene Found

French researchers have identified a gene associated with increased risk of obesity and type 2 diabetes in children and adults. Dr. Philippe Froguel of the Institute Pasteur de Lille, stated that, “The gene, ENPP1 (ectonucleotide pyrophosphatase phosphodiesterase, also known as plasma cell glycoprotein 1), blocks insulin-induced changes in insulin receptor conformation.
Variants in the gene may promote obesity by increasing ENPP1 expression, they hypothesize, which in turn boosts insulin resistance and leads to excessive accumulation of fat.

"These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions," Dr. Froguel and his team write.

In a study of several thousand people, beginning with an area on chromosome 6 that they had linked to childhood obesity, Dr. Froguel and his team identified a three-single nucleotide polymorphism (SNP) haplotype of ENPP1, QdelTG, that conferred a strongly increased risk of severe obesity in adults. It was associated with a 50% increased risk of morbid obesity in adults and a 69% increased risk of childhood obesity.

The gene was also linked to a 37% increased risk of less-severe obesity (BMI between 30 and 40).

An analysis of 279 children of varying weights identified a positive association between BMI and serum ENPP1 protein levels, while the researchers also identified an association between the obesity-linked haplotype and increased levels of the protein.
The findings suggest that QdelTG both impairs insulin binding and increases EHPP1 expression, according to Dr. Froguel and colleagues.

The researchers also found children with the obesity-linked haplotype had higher fasting glycemia and were more than three times as likely to have glucose intolerance and type 2 diabetes, while the haplotype conferred a more than doubled risk of type 2 diabetes among parents.

"This study strongly supports a genetic link between ENPP1 gene variants and chromosome 6q-linked childhood polygenic obesity and adult obesity and T2D," the researchers conclude. "This provides an insight into the molecular basis for the physiologic association between insulin resistance and obesity and presents a new perspective for prevention and treatment of these conditions."

Nature Genetics, 2005 July 17.
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