Extracting the Value from Human Genetics

Video Transcript

Hi, I’m Greg Michelotti, and it’s my pleasure to review an important case study that demonstrates the value of metabolomics, both to leverage the power of genomics and as a standalone modality to provide novel biological and clinical insights.

From a genomic perspective, despite the intense investment in sequencing, there has been a relatively muted impact on understanding human disease. This is also true for the identification of new drug targets, as shown in the first panel of this slide, showing the number of new drugs developed as a function of R&D spending that has steadily declined over the past six decades. Clearly, new approaches are needed to help elucidate the mechanistic basis of a wide variety of pathologies, and this is an area where metabolomics can be useful as an orthogonal modality.

Working with collaborators at King’s College, we performed metabolomic profiling on close to 4,000 female participants from the Twins UK Study and identified a significant association between the levels of the dicarboxylic fatty acid hexadecanedioate and high blood pressure. After validating results in a second independent cohort, pre-clinical studies were done to identify if the changes in hexadecanedioate levels, or HEXA for short, were a cause or an effect of hypertension.

Animals were dosed with HEXA, shown in blue, and compared to control animals treated with vehicle, shown in yellow. From the time that dosing was initiated, indicated by the blue arrow, HEXA promoted an immediate and significant increase in systolic blood pressure relative to control animals showing that this metabolite was causal for hypertension.

Independent and concurrent studies with investigators at Baylor identified that HEXA levels are associated with loss of function alleles in the gene solute transporter SLCO1B1, which include encodes a solute transporter that mediates the cellular uptake of numerous endogenous compounds and is involved in metabolism and clearance of multiple drug compounds including the popular cholesterol-lowering statins.

As can be seen in the middle panel, putative loss of function alleles of the SLCO1B1 have a profound impact on hexadecanedioate levels in a dose-dependent effect showing modest increases in circulating HEXA levels in the heterozygous state, where loss of one allele is associated with an increased risk of heart failure. Individuals with loss of both alleles exhibit a dramatic increase in circulating HEXA levels, providing a connection between genetic variants and changes in circulating levels of a key metabolite that is causal for increased blood pressure.

Now, this is particularly important because by 2020, over 1.5 billion people will have high blood pressure, and two-thirds of them will not achieve target therapeutic control with current treatments. Given that hypertension is the most prevalent modifiable risk factor for cardiovascular mortality and morbidity, these experiments offer new therapeutic insights to potential treatments for hypertension and improve outcomes. Collectively this approach reveals the power of metabolomics to functionally map genes of unknown function with associated variants of unknown significance to elucidate the role of a particular gene, in this case, SLCO1B1, in mediating adverse cardiovascular outcomes. By extension, this offers a roadmap to functionally map rare genetic variants that can play both protective and disease-promoting roles in humans.