Genetic variants can simultaneously increase BMI and lower cholesterol risk, UTHealth Houston researchers find

Individuals with a genetic profile that puts them at risk of obesity may not necessarily be at risk of having high cholesterol, UTHealth Houston researchers discovered. 

The study, published in Genome Medicine, found that some genes can result in an inverse relationship between body mass index (BMI) and lipids. Lipids are the different kinds of fat found in the blood that affect a person’s health. Some lipid profiles can put an individual at a higher risk of heart attack and stroke. 

“People that have obesity tend to have a much greater risk of having cardiometabolic conditions, including high cholesterol, high blood pressure, or diabetes. But that’s not always the case,” said principal investigator Kari North, PhD, director of the Border Health Research Center and professor at UTHealth Houston School of Public Health. 

Cardiometabolic disease refers to a group of health problems, like heart disease and diabetes, that are often influenced by factors like excess body fat. 

While the genes that influence obesity generally influence a person’s risk of high cholesterol in the same way, sometimes, patients who have obesity won’t have high cholesterol. Conversely, someone with a healthy BMI, or one lower than 25, may not necessarily have a healthy lipids profile. 

By studying the genetic profiles from the UK Biobank, a large-scale prospective study of more than 500,000 people living in the UK, researchers were able to identify genomic regions that could contribute to that phenomenon. 

“Most of the variants act in the way that we expect, increasing both body mass and cholesterol, but there are some subsets that don't operate that way. These exceptions are very interesting, and we need to understand them better,” North said. 

North added that the research is especially important in the era of precision medicine, where physicians aim to more accurately determine a patient’s risk of certain diseases by analyzing their polygenic risk score. Polygenic risk scores are calculated by comparing a person’s genetic profile to known effects of genetic variants on a trait.

“Polygenic risk score models assume that the variants that we're summarizing have an effect on just one trait,” North said. “But biology is complicated, and these genes can have a cascade of effects across traits. Sometimes the effects could be counterintuitive.”

The research shows that people with BMIs less than 25, for example, should still be monitored for other risk factors of cardiometabolic disease.

This work also highlights the strengths and capabilities of team science, a central focus of the new Border Health Research Center at the School of Public Health.

“Discovering the impact of genetic variants on chronic diseases requires not only enormous sample sizes, but also the efforts of many researchers focused on the same research question. We are fortunate to work with numerous brilliant and dedicated collaborators to improve health for everyone,” said co-author Kristin Young, PhD, associate professor of epidemiology at the School of Public Health.

Other researchers on the study with UTHealth Houston School of Public Health include Heather Highland, PhD, assistant professor, and Victoria Buchanan, PhD, biostatistician.

Additionally, Myriam Fornage, PhD, professor and The Laurence and Johanna Favrot Distinguished Professor in Cardiology at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at McGovern Medical School at UTHealth Houston, is part of the study. 

Authors on the study from the University of North Carolina at Chapel Hill include: Daeeun Kim, PhD; Micah R. Hysong, PhD; Christy Avery, PhD; Penny Gordon-Larsen, PhD; Mariaelisa Graff, PhD; and Laura M. Raffield, PhD. Authors from the Fred Hutch Cancer Center include: Boya Guo, PhD, MPH; Burcu F. Darst, PhD; Charles Kooperberg, PhD; Ulrike Peters, PhD, MPH; Yanwei Cai, PhD; and Jessica Lundin, PhD, MPH. Authors from the University of Colorado include Leslie Lange, PhD; Ethan Lange, PhD; and Chris Gignoux, PhD. Other authors on the study include: Roelof Smit, MD, PhD, and Tuomas O. Kilpeläinen, PhD, of the University of Copenhagen; Chi Zhao, PhD, and Cassandra N. Spracklen, PhD, of the University of Massachusetts; Zhe Wang, PhD, and Ruth Loos, PhD, of the Icahn School of Medicine at Mount Sinai; Sonja Berndt, PharmD, PhD, of the National Cancer Institute with the National Institutes of Health; JoAnn E. Manson, MD, DrPH, MPH, of Harvard Medical School; Eirini Marouli, PhD, of the Barts and The London School of Medicine and Dentistry; Christopher Haiman, ScD, of the University of Southern California, Los Angeles; Stephen S. Rich, PhD, University of Virginia Charlottesville; and Steve Buyske, PhD, of Rutgers University.