The genetic material we carry in our cells is unique to us, and the field of personalized medicine studies how those individual differences affect our health, and the therapeutics that we use. Now, scientists from the University of Copenhagen and the MRC Laboratory of Molecular Biology in Cambridge have assessed the genetic differences between individuals in an important class of receptors, GPCRs. Drugs frequently target those receptors, and they wanted to know how drug efficacy may change depending on changes in the GPCR gene. Their work was reported in Cell.
“We estimate that an average of three percent of the population have receptors that contain mutations which can alter the effect of medicine,” noted the first author of the study, Alexander Hauser, a postdoctoral fellow at the Department of Drug Design and Pharmacology at the University of Copenhagen.
People that carry these mutations still have functional receptors, but the mutations have a varying effect on how well drugs work. “This might mean that the medicine simply works less efficiently. It can also mean that the medicine does not work at all or causes adverse effects on patients,” explained the senior author of the work, Madan Babu, from the MRC Lab of Molecular Biology in Cambridge.
For this research, the investigators utilized whole genome sequencing to assess mutations in human GPCRs. They used data from about 2,500 individuals included in the 1,000 Genomes project, in addition to exome data, assessing the portions of the genome that are transcribed into RNA, from 60,000 participants of the ExAC project. Structural data was then employed to reveal the mutations that were most likely to change how medicine would work.
“The three percent of the affected population is an average. For some important receptors, it is way more. For instance, the relevant mutations occur in 69 percent of people in the GLP1 receptor that is the target of diabetes medicine and in 86 percent of people in the CNR2 receptor that is used as a target for medicine to relieve nausea induced by chemotherapy. But of course, we cannot know every person's genome and so these are estimates based on the data sets available,” said Hauser.
The researchers used their data to find out how many people were spending money on drugs that probably were not having any effect. In the UK, it resulted in an economic burden of at least 14 million pounds, or around 19 million dollars annually, when taking people with mutations in important places in both copies of their GPCR gene into account.
“The prevalence and potential impact of variation in drug response between individuals is a strong argument for further researching this field. It also constitutes a fine example of why personalized medicine might be the way forward; even when we are talking about common drugs,” said Hauser.
Learn more about how genetics can be used to tailor therapies to the individual in this video about pharmacogenomics, from Mayo Clinic.