People with certain rare gene mutations could be seven times more likely to develop type 2 diabetes than those without, according to research published in the Proceedings of the National Academy of Sciences of the United States of America.
Boston researchers estimate that one in every 1,000 individuals carries a variant in peroxisome proliferator-activated receptor gamma (PPARG) that may reduce function in adipocyte differentiation and increase the risk for developing the disease.
Amit R. Majithia, MD, of the Broad Institute of Harvard and MIT, Massachusetts General Hospital and Harvard Medical School, and colleagues sequenced PPARG in 19,752 individuals (9,070 with type 2 diabetes, 10,682 controls) of European, East Asian, South Asian, European American, African American and Hispanic ancestries.
Amit R. Majithia
“With a common disease like type 2 diabetes that is caused by dysfunction in many genes, there are rare individuals in the general population whose disease risk is strongly influenced by dysfunction in a single gene,” Majithia told Endocrine Today. “For the gene we studied, PPARG, there is a known class of drugs that activate it (thiazoledinediones). It is possible that individuals who have the types of mutations we found in PPARG may benefit from specific pharmacotherapy tailored to PPARG.”
The scientists characterized each nonsynonymous variant; 49 previously unidentified protein-altering mutations were uncovered. Collectively, with or without computational prediction of functional outcome, the variants were not associated with type 2 diabetes (P=.17).
High-throughput human adipocyte differentiation assay was used to evaluate the variants’ cellular function in human cells; nine variants were found to cause a loss-of-function (LOF).
After comparing type 2 diabetes risk in individuals carrying benign variants and LOF variants, the team found participants who carried any of the nine LOF mutations were at a substantially higher risk for the disease (P=.0005).
“While genome sequencing is becoming more routinely accessible, the key to making sense of this sequence for health and disease is interpreting the mutations we find from sequencing,” Majithia said. “Our study shows that even when we look at a well-studied gene, merely finding the mutations by sequencing does not yield insight. Direct experimental characterization of each mutation was required to separate benign mutations from those that increase risk for diabetes.” — by Allegra Tiver
Disclosures: The researchers report no relevant disclosures.