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Genetic Variation May Determine Anti-Diabetic Drugs Response

Investigators are targeting individualized diabetes therapy using the genetic approach…

Dr. Lazar and his team focused on a fat molecule called PPARγ, which is also the target for the thiazolidinedione (TZD) class of drugs. PPARγ binds to DNA and activates the expression of other genes. The researchers hypothesized that genetic variations in DNA may influence the effect of both PPARγ and TZD drugs. A study in mice showed that “SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, and that genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs.”

According to the lead author of the study, “The implications of this work go beyond PPARγ and TZDs, to all drug targets that function directly at the genome to regulate physiology in health and disease.” The author also pointed out drugs such as thyroid hormone and steroid are also target nuclear receptor proteins related to PPARγ.

The team showed that SNPs, a single nucleotide polymorphism, in the PPARγ is also associated with increased disease risk. The author emphasized that, “single change in a DNA letter determines whether PPARγ binds to one regulatory site in fat tissue, and this may alter a person’s risk of metabolic syndrome.” For instance, one such SNP was linked to blood lipids, including HDL (“good” cholesterol) and triglycerides, type 2 diabetes, high blood pressure, and waist-hip ratio.

TZDs are diabetes drugs that target fat cells and increase the body’s sensitivity to insulin. However, their uses are limited due to the risk of side effects such as edema, bone loss and risks for heart attacks and bladder cancer. The researchers believed that their approaches can be used to predict who will benefits the most from TZD drugs, but they still 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.

The team also examined the effect of SNP on human fat tissue. Using data of 15,000 people from Finnish database, the researchers were able to identify how many genes are “on” in fat tissue to show that SNPs affecting PPARγ binding also determine gene activity levels in the human population. Furthermore, the researchers were able to confirm that SNPs affecting PPARγ binding in fat underlie some of the risk for metabolic diseases through large human genetic analyses called genome-wide association studies (QWAS).

The authors concluded that, “Our work shines a bright light on genetic differences in PPARγ bound regulatory DNA, and how these differences among people may allow us to better predict metabolic disease and then apply precision medicine for treatment or prevention.”

Practice Pearls:

  • SNPs are highly enriched at tissue binding sites for PPARγ in mice, and that may genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs.
  • A single nucleotide polymorphism, in the PPARγ is also associated with increased disease risk.
  • Understanding the genetic differences among people may allow us to better predict metabolic disease and then apply precision medicine for treatment or prevention.

Raymond E. Soccio, Eric R. Chen, Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo. Cell, 2015; 162 (1): 33 DOI:10.1016/j.cell.2015.06.025.