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Research to explore how genes, other factors affect cardiometabolic disease risk

$8.8 million to fund research into interaction of specific genes with demographic, lifestyle factors

by Gerry Everding August 11, 2021

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Researchers at Washington University School of Medicine in St. Louis have received a four-year, $8.8 million grant to ramp up research aimed at unraveling how an individual’s risks of cardiometabolic diseases, such as heart disease and Type 2 diabetes, are influenced by the interaction of specific genes with demographic and lifestyle factors.

Going beyond the small percentage of disease risk explained by genes alone, this study will explore how an individual’s gender, race, ethnicity, smoking, alcohol use, diet and exercise levels may combine with genetic risks to trigger the metabolic processes that underlie heart disease.

“By investigating genomic and lifestyle contributors to cardiometabolic health through their interactions across genders and diverse populations, our research can help advance the emerging field of precision medicine,” said principal investigator D.C. Rao, PhD, professor of biostatistics, of genetics, of psychiatry and of mathematics.

Rao’s key co-investigators at the School of Medicine include cardiologist Lisa de las Fuentes, MD, professor of medicine and of biostatistics, and statistical geneticist C. Charles Gu, PhD, associate professor of biostatistics and of genetics.

Precision medicine uses information about a person’s genetic makeup, metabolism and other biological and lifestyle factors to optimize strategies that potentially can prevent or treat a health condition. Such personalized approaches to treatment are more likely to be successful for individual patients, rather than a one-size-fits-all approach.

Funded by the National Institutes of Health (NIH), this new investigation will be the third in a series of similar studies in which Rao and his team use statistical analysis to identify gene-lifestyle interactions associated with cardiovascular and cardiometabolic diseases — the leading causes of death in the United States and worldwide.

Their original study identified promising gene-lifestyle interactions, including several tied to African ancestry, but the study lacked the sample size necessary to robustly validate the interactions as statistically significant.

The current study, involving investigators from within and outside the U.S., will overcome that hurdle by expanding the sample size tenfold to include data from more than 1 million individuals, including people from several countries outside the United States. With a sample of 912,000 people of European ancestry, 231,000 of Asian ancestry, 91,000 of African ancestry and 33,000 of Hispanic ancestry, it will be the largest, most diverse investigation of gene-lifestyle interactions attempted.

By focusing heavily on gene-lifestyle interactions, Rao’s study represents a shift from traditional genomewide association studies (GWAS), which rapidly scan the genomes of many people to find genetic variations associated with a particular disease. His approach, known as a genomewide interaction study (GWIS), adds the potential to show how smoking, alcohol consumption, physical activity, obesity, sleep duration and other lifestyle factors interact with genes to influence high blood pressure, diabetes, cholesterol levels and other metabolic traits that may increase the risk of a heart attack or stroke.

“The study aims to identify new gene-lifestyle interactions that contribute to cardiometabolic disease risk, and to better understand the molecular mechanics underlying these interactions,” Gu said. “By detailing associated molecular biomarkers and traits, such as DNA methylation, gene expression and metabolites, the study could reveal new opportunities for disease intervention.”

Added de las Fuentes: “Our findings could reveal new diagnostic and therapeutic tools, identify targets for novel drug development and serve as the foundation for a more precise, more personalized approach to health care for heart disease, diabetes, and other metabolic diseases. This project has high potential to move the field forward.”

Washington University School of Medicine’s 1,700 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, consistently ranking among the top medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.