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Case Study

Characterizing Novel Variants Associated with Blood Pressure Regulation Through a Meta-Analysis of 1.3 Million Individuals

Researchers characterized the metabolic functions of rare variants associated with high blood pressure to shed light on this complex, heritable disease.

In a study published in Nature, researchers combined GWAS, EWAS, and metabolomics data to identify and characterize the potential metabolic functions of several novel and rare variants associated with blood pressure regulation. Their study represents a groundbreaking effort to identify metabolic pathways underlying the mechanism of how genetic factors contribute to high blood pressure, laying the foundation for further studies identifying novel therapeutic targets.

In a study published in Nature, researchers combined GWAS, EWAS, and metabolomics data to identify and characterize the potential metabolic functions of several novel and rare variants associated with blood pressure regulation. Their study represents a groundbreaking effort to identify metabolic pathways underlying the mechanism of how genetic factors contribute to high blood pressure, laying the foundation for further studies identifying novel therapeutic targets.

Characterizing Novel Variants Associated with Blood Pressure Regulation Through a Meta-Analysis of 1.3 Million Individuals

The Challenge: Better Understanding High Blood Pressure

High blood pressure is a complex, heritable condition caused by the interplay of several human genes and environmental factors. Because high blood pressure is a significant risk factor for cardiovascular disease and stroke, a better understanding of the causes of high blood pressure can improve the lives of many. Most studies have focused on common variants associated with blood pressure regulation. By performing a meta-analysis of GWAS data from over 1.3 million individuals, scientists recently identified over 100 novel and over 80 rare variants associated with blood pressure regulation.1 Working with Metabolon, the scientists linked these variants to several plasma metabolites, shedding light on the relationship between genes and metabolites in blood pressure regulation.

The Metabolon Insight: Linking High Blood Pressure-associated Variants with Metabolic Pathways

The scientists used Metabolon’s Global Discovery Panel to analyze plasma samples from 14,000 individuals from two cohorts (EPIC and INTERVAL), identifying associations between several known and unknown metabolites and newly identified blood pressure-associated variants.

The Solution: Characterizing the Phenotypic Profiles of High Blood Pressure-associated Variants

A meta-analysis of GWAS and EWAS data from over 1.3 million individuals identified several novel and rare variants associated with blood pressure regulation that, in comparison to common variants, had significantly larger average effects on blood pressure. Metabolomics data analyzed from ~14,000 individuals from the EPIC and INTERVAL cohorts identified 25 metabolites associated with nine of these newly identified blood pressure-associated variants. Most of these metabolites belonged to carbohydrate, lipid, cofactor and vitamin, nucleotide, and amino acid metabolism pathways.

Mendelian randomization analysis to understand the impact of 14 of these metabolites on blood pressure revealed that lower levels of 3-methylglutarylcarnitine were significantly associated with increased diastolic blood pressure.

The Outcome: Metabolomics Adds Essential Insights to the Big Picture

In this study, metabolomics analysis aided in characterizing novel, rare genetic variants associated with blood pressure regulation. The meta-analysis identified several novel candidate genes with potential roles in the development of high blood pressure and, given that the effect of these variants on blood pressure is higher than that of common variants, suggests that some of these novel, rare variants may represent promising therapeutic targets. Characterizing the mechanistic consequences of these variants is the foundation for advancing our understanding of this complex disease and developing effective new therapeutics.

References

1. Surendran P, Feofanova EV, Lahrouchi N et al. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. Nat Genet 2020;52(12):1314-1332. doi: 10.1038/s41588-020-00713-x

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