Pharmacogenomics Takes Big Step Forward with Diabetes Research

The practice of individualized medicine took another step forward recently when researchers at the University of Pennsylvania found that a patient’s genetic variations can determine how they respond to anti-diabetic drugs.

According to a press release from the school, the study (published in Cell) looked at PPAR-gamma, an “important fat cell molecule” that is the target of some forms of medications used to treat type 2 diabetes. The authors noted that the molecule “binds to DNA at switches that turn other genes on,” and that the patient’s DNA determines the efficacy of the drugs.

“The implications of this work go beyond PPAR-gamma and TZDs, to all drug targets that function directly at the genome to regulate physiology in health and disease,” noted Raymond Soccio, MD, PhD, who served as lead author and is also an instructor of medicine at the school.

The statement from the school noted that 20% of prescriptions are for “such drugs as thyroid hormone and steroids that target nuclear receptor proteins related to PPAR-gamma.” The differences have been identified as single nucleotide polymorphisms (SNP) and are “variants in the DNA alphabet of A,T, C, and G molecules that occur naturally among individually.”

While the SNP has been linked to diabetes and other diseases in the past, the authors noted it can often be found in the “dark matter” of genomes “that does not directly code for genes, but includes those switches that control genes.”

According to Mitchell Lazar, MD, PhD, and team the research showed a link that can help future treatments by finding that “SNPs in PPAR-gamma switches provide a mechanism for the disease-risk associations,” the statement continued.

The impact of this finding can have a long reaching benefit for future treatment, according to Soccio. “It’s remarkable that a single change in a DNA letter determines whether PPAR-gamma binds to one regulatory site in fat tissue, and this may alter a person’s risk of metabolic syndrome.”

With pharmacogenomics becoming a growing field, Lazar said this can help that area grow in an effort to bring patients more effective treatments even faster. “Our study provides proof-of-concept that naturally occurring regulatory genetic variation can affect nuclear receptor-mediated gene activation and, more generally, drug response in living animals,” he said. “This has special significance for TZDs, which have powerful anti-diabetic effects but limited clinical utility due to non-response, side effects, and adverse events.”

TZD medications have proven to have some adverse events like edema and bone loss and have also been linked to heart attacks and bladder cancer, the school noted, adding that 20% of type 2 patients do not see improvement in their condition with the medications. Soccio said the research they have done can help provide better care for patients who otherwise might not have seen successful results in the past.

“One day the approaches we used in this study can be used to predict who will benefit most from TZD-like drugs, so now we need to determine the pattern of SNP differences that together may show why these drugs have benefits or harms for one person and not another.” He added, “This type of precision medicine is a major goal of our research efforts.”

The research was primarily supported by the National Institute of Diabetes and Digestive Kidney Diseases and the JPB Foundation.