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Massachusetts Team Finds Diabetes-Precursor SNPs

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Researchers at the Joslin Diabetes Center and the Children’s Hospital Boston Informatics Program claim to have identified a group of genes linked to type 2 diabetes, and have shown that the expression of these genes change before diabetic sequelae develops.

The results may lead to molecular diagnostics that might help physicians determine which individuals are at a greater risk for the developing the disease, which affects around 15 million people in the United States.

Mary-Elizabeth Patti, an endocrinologist and scientist and director of the Genomics Laboratory at Joslin, and colleagues used microarrays and bioinformatics tools from the CHIP to measure the activity of more than 7,000 genes in muscle tissue from Mexican-Americans, an ethnic group the team said has a “very high risk” for developing diabetes. The researchers compared three groups: those with diabetes, those without diabetes, and high-risk individuals with what the team termed “prediabetes” — diabetes in family members.

The researchers found that two genes, PCG1-alpha and PCG1-beta, showed reduced expression in the diabetic cohort as well as the prediabetic group. These genes code for proteins in the mitochondria, so a reduction in their expression may impact an individual’s ability to use insulin properly.

“This decreased activity appeared to lead to reduced activity of a larger group of genes involved in the metabolism of fats and carbohydrates,” according to the authors. The study appears in the July Proceedings of the National Academy of Sciences.

Patti’s team initially compared patterns of gene expression in people with diabetes against the nondiabetics and found that 187 genes were expressed differently between the two groups. They then compared the nondiabetics with the prediabetics and found differences in expression for 166 genes. Additional analysis uncovered 55 mutated genes in both the diabetics and the prediabetics.

“What’s interesting is that we can see these changes in gene expression even before the diagnosis of diabetes is made,” said Atul Butte, a co-investigator from the CHIP. “This tells us that the process of getting to diabetes may be a continuum.”

The researchers eventually discerned that “many of the genes” altered in diabetes encode for proteins in the mitochondria, and that “the majority” of these genes is regulated by another gene, NRF-1. “That gave the clue to look at PCG-1 alpha and beta, genes that work with NRF-1 and may function as master controllers for many metabolic genes important in insulin resistance and diabetes,” according to the Joslin center.

“If we can identify people at high risk for diabetes ... we may be able to find better methods for both treatment and prevention of diabetes,” Patti said.

— KL

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