EFFECTIVENESS of an anti-diabetic drug depends on small, natural differences in DNA among individuals, a discovery that has paved the way towards the tailoring of disease treatment to individual patients.
Led by Prof Mitchell Lazar, Professor of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA, a research team has shown in their study that small variations in DNA sequences, including minute changes as small as a single letter, can have a great impact on switches that manage genes that determine how cells and proteins respond to drugs. Furthermore, the DNA sequences where variations occur do not need to be in the same location as the affected coding genes – they may be found in the so-called “dark matter” or non-coding section of the genome.
The researchers focussed on the nuclear receptor PPAR-gamma. This fat cell molecule is the target of a class of Type 2 diabetes drugs called thiazolidinediones (TZDs). TZDs are the only diabetes drugs that target fat cells and boost the patient’s own response to insulin. However, they have recently fallen into disuse because they can trigger side-effects such as bone loss and oedema, while there have also been reports of increased risk of bladder cancer and heart attack.
In addition, around 20% of patients with Type 2 diabetes fail to improve their control of the disease on TZDs, something that is particularly relevant to the findings. The team proved that natural genetic differences in the DNA of the switches may influence the effectiveness of PPAR-gamma and TZDs as switch activators. These conclusions were reached through a series of experiments conducted at first in mice and then in human fat tissue from obese bariatric surgery patients, while also referring to genome-wide association studies to accompany and confirm some of the findings.
“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,” said Prof Lazar. “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.”
The team indicate that approaches such as those used in this study will eventually be used as part of precision medicine to predict which patients are most likely to benefit from drugs such as TZDs.