This study goes firmly into the file marked “You never could have done this one a few years ago, sonny”. We already know that there’s genetic variation in every population and in every individual. And we know that a large number of marketed drugs (about a third of them) target G-protein coupled receptors (GPCRs). But do we know how much genetic variation there is in GPCRs across a large sample of individual patients, and how that might affect their treatment?
We do now. This paper in Cell (open access) analyzed over 64,000 people (data from the Exome Aggregation Consortium) for the sorts of variants most likely to make themselves felt: mis-sense and loss-of-function mutations (frameshift, stop codons, etc.) as well as copy number variation. Previous studies had turned up some of these, and the statistics suggested that there would be more of them as sample sizes were increased. That there are. Looking across 108 GPCRs that are targeted by known drugs, the team found over 14,000 variants, and the distribution was long-tailed indeed: any individual receptor had an average of 3 or 4 common variations across the 64,000 patients (more than one in a thousand minor allele frequency) and 128 rare ones. The estimate is that at least 120 people out of the 60,000 had what looks like a loss-of-function mutation in a GPCR somewhere.
Of course, not all mutations are created equal. What looks like a nasty shift might honestly not matter as much as you’d think if it hits in a part of a protein that is just taking up some space between the really functional regions. So the paper zoomed in a bit more and found that about two thousand of those fourteen thousand fall into what are very likely to be functional sites. In addition to changes in allosteric regions and drug-binding pockets themselves, there seem to be many mutations on the intracellular regulatory surfaces of the receptors, which suggests that there are a good number of patients out there who will not respond in the ways that you’d expect to a given drug.
The paper shows this experimentally with variations in the mu-opioid receptor (which is already known to be rather variable). Looking at the mutant forms that were predicted to have changes in functional regions, they showed that some of them have less effective signaling across the board (agonists, partial agonists, and antagonists alike), but others showed real variations between the different classes. So there are apparently people out there who are more sensitive to (say) morphine than average, or will show unexpected effects between different synthetic opioids, or greater or lesser susceptibility to a dose of an opioid antagonist. Other receptors that show a lot of natural variation include CCKA, dopamine D5, the calcitonin receptor, and somatostatin SSR5. As the authors put it, “a substantial fraction of the population might carry variant receptors and remain healthy but have the potential to display differences in drug response when treated with a drug.” Among the drugs that the paper flags (in table S5) for a high chance of variable response are Belsomna (suvorexant), targeting orexin receptors, all the natural and synthetic cannabinols, and all the GLP-1 targeting compounds, such as Byetta (exenatide).
So perhaps we’re finally heading for that era of personalized medicine that everyone keeps talking about. As it stands, there are no GPCR-targeting drugs with any human genetic variants flagged by regulatory agencies on the label, but that is surely going to change as sequencing gets relentlessly cheaper and more widespread. It’s worth realizing, though, that most of the stories about personalized medicine seem to assume that we’ll sequence someone’s genome and find the drug or combination that will be much more likely to work. But what this paper suggests (and what has always seemed statistically more likely) is that it’s going to be mostly about telling people that the drugs that work for the rest of the population won’t work for them. What then? Avoiding useless or even harmful treatments is definitely a good thing, but that doesn’t seem to be what the general public is picturing as the most likely outcome.