When Precision Medicine Gets Lost in Translation
By Charles Dinerstein, MD, MBA, FACS
Precision medicine—the promise of highly targeted, customized care—is so alluring, but much of its promise is lost in the translation from science to practical care. Two recent studies demonstrate how the hoped-for translation is tantalizingly close and elusive.
High blood pressure, or hypertension, is a dominant, non-communicable disease globally, and it is a well-known risk factor for both stroke and coronary artery disease. It has been extensively studied, with many family studies showing it to result from both genetic and lifestyle factors. If there is any disease where we will see precision medicine work to separate the effects of nature and nurture, this should be a front-runner.
Genetics
Our friends the UK Biobank have produced another genome-wide association study (GWAS) in this instance on hypertension. (You can catch up on previous Biobank and GWAS studies in general here and here.) In short, a GWAS study identifies genes associated with particular outcomes, like hypertension or the need to wear glasses, or even doing well in school. Prior studies of high blood pressure have suggested and identified 274 genetic alterations accounting for 3% to 4% of patients with hypertension.
The UK Biobank coupled with additional data from the U.S. based Million Veteran Program and Estonian Genome Centre Biobank expand the study population to over 1 million individuals, resulting in a 3-fold increase in identified loci and increasing the genetic “explanation” of hypertension to 11%. As with any genetic study, the findings are restricted to the gene pool, in this instance, Europeans or their descendants. Hypertension was defined by elevated systolic or diastolic blood pressures as well as pulse pressure or pulse width. This later measurement describes the difference between systolic and diastolic pressures and is a more subtle measure of what is driving the underlying pathophysiology.
As with most GWAS studies, the researchers developed a composite genetic risk score. Taking all 901 loci into account generated scores that demonstrated a 10mmHg elevation between the highest and lowest population segments, in this instance quintiles. They extrapolated that 10mmHg rise in blood pressure between the lowest and highest quintiles into clinical events demonstrating that their genetic risk score identified patients at increased risk of stroke (37% higher) and high attacks (44% increase).
Some genes were associated with one component of hypertension, others with multiple — as the overlap in this Venn-type diagram demonstrates. The identified genes had roles in modulating vascular tone, the constriction, and dilation of blood vessels, as well as genes involved in adrenal tissue — which has a role in fluid retention through the production of aldosterone.
These pathways we already knew or suspected. But there were additional paths that were surprising. Genes involved in the remodeling of vessels, reshaping the heart wall, sodium handling by the kidneys, as well as genes associated with type 2 diabetes, elevated cholesterol and atherosclerosis all demonstrated associations with hypertension. The chart below shows just how many genes are involved in hypertension overlap with other diseases. Epistasis is a term used to describe the impact of alterations of one gene upon another. The combinatorial possibilities of these interactions are huge.
The variability in the expression of the phenotype by genes—a generic way of saying a patient has hypertension—accounts for only 11% of cases in this study, which is a common percentage in the GWAS literature. When the same risk score was applied to an Asian population, its predictive value dropped, to about 6% which is not surprising given that Asian and European genetic variations would be expected to be similar, not identical. This study shows that many hundreds of genes are involved and interact in the expression of the phenotype we call high blood pressure. Not only is there no easily-defined “genetic basis” for hypertension, but the combinatorial possibilities are also so great as to be considered, at this point, infinite. Given our current understanding, these genetic variants are better described as a “background effect”—or a necessary but not sufficient cause of hypertension.
Environment
Scientists have investigated the “background effect” of genes on phenotypes and have found, not surprisingly, that in addition to multiple genetic variants interacting with one another, they also respond to their environment. Understanding the additional complexity of the role of environmental or in the case of medicine lifestyle factors along with genetic variation is a very tough knot to untie and untangle. We are not going to be making inroads in that medical Gordian knot, but research on yeast helps outline the bigger picture.
Researchers investigated these genetic background effects in yeast, looking at 7 genetic variants in 10 various environments. They identified over 1,000 epistatic genetic interactions for those 7 genetic variants. Some alterations affected 100 or so other genes, while other alterations impacted over 500. And the interactions resulted in both enhanced and reduced phenotypic expression. In their words, phenotypic expression was “complicated, highly contextual.” And the context was the yeast’s environment, which accounted for 50% of expression in this study. Their findings echo the UK Biobank’s report on genetics and hypertension at a far smaller scale. A back of the envelope calculation places the possible interaction of hypertension 900 loci at well over 100,000 possibilities; and the number of our environments, based on diet and activity is far greater than 10.
Precision medicine is an aspirational, not pragmatic goal. These two studies, taken together, make it clear that the possible genetic and environmental interactions underlying the phenotypes we call disease are not going to result in one or even a few medical answers. How and where we live our lives are the only variables we can control. The deeper we look into our biology, the more precise our findings, the more we realize that health results from our choices in the world, not from some preordained genes.
Dr. Charles Dinerstein is a retired vascular surgeon and senior fellow at the American Council on Science and Health where he writes on contemporary health issues. His more philosophical thoughts can be found at Surgical Analytics. He is a 2017–2018 Doximity Fellow.
