A research team led by investigators at Vanderbilt University Medical Center has identified a set of inflammatory genes that contribute to severe obesity — a condition of being 100 pounds or more overweight.
The findings, published in the journal Cell Genomics, reveal novel targets for prevention, intervention and treatment of severe obesity.
People with severe obesity, defined as a body mass index (BMI) of 40 or more, have been mostly excluded from population-based genetic studies and clinical trials, noted Jennifer (Piper) Below, PhD, professor of Medicine in the Division of Genetic Medicine at VUMC.
“Individuals with severe obesity experience profound, debilitating adverse health outcomes, but because they’ve been excluded from most research, we know little about the underlying physiology,” said Below, who holds the Robert A. Goodwin Jr., MD Directorship in Medicine. “We decided to focus on this population in order to understand the genetic drivers of severe obesity risk.”
Severe obesity has doubled in the United States over the past two decades to 9.2%, with the greatest increases among women and Latino populations.
Below, co-corresponding author Kari North, PhD, professor of Epidemiology at the University of North Carolina, and colleagues studied samples from participants in the Cameron County Hispanic Cohort, a group of 5,000 individuals from households in Brownsville, Texas, on the U.S.-Mexico border.
“This is a really incredible population of participants who were not ascertained in a hospital or clinic,” Below said. “We went household by household on randomly selected census blocks and enrolled everyone who was willing to participate.”
The population is 100% Latino and about 96% Mexican American.
“This is a population that experiences high levels of obesity, starting at younger ages, and negative cardiometabolic health outcomes,” Below said.
The researchers examined gene expression in blood samples from 49 participants with severe obesity compared to 81 participants with a BMI less than 25. They found a set of dysregulated genes associated with severe obesity and replicated the findings in another group from the same population cohort.
Using statistical approaches, they determined which genes could be causal for severe obesity versus a consequence of the condition and examined which molecular biomarkers were also dysregulated in protein form.
“What we found was a really important set of genes that are primarily involved in signatures of inflammation, and that these molecular biomarkers are identifying patterns of dysregulation that make physiological sense as preceding other obesity-related consequences,” Below said. “We’re seeing a profile in the state of severe obesity that is shining a light on a progressive pathway toward cardiometabolic adverse health outcomes.”
The team’s integrative, multiomics approach — studies that span genomics (genes), transcriptomics (gene expression) and proteomics (proteins) — complement previous studies of genetic susceptibility factors, allowing the researchers to “disentangle cause and consequence,” Below said.
The researchers also examined the broader clinical significance of the genes they identified by conducting a phenome-wide association study (PheWAS) that linked genetic regulation of the identified genes to a range of traits including obstructive sleep apnea, bone fractures and hyperaldosteronism (excessive production of the hormone aldosterone).
“The traits that emerged in the PheWAS are illuminating important potential shared biology and potential risk mechanisms,” Below said.
“This phenotype (severe obesity) is growing, and we need to not ignore it or cluster it with everyone else across the BMI spectrum. Understanding the physiology of severe obesity is important, particularly for populations that are at such high risk for severe obesity and its negative health outcomes.”
Hung-Hsin Chen, PhD, who was a postdoctoral fellow in Genetic Medicine at VUMC and is now an assistant research fellow at Academia Sinica in Taipei, Taiwan, and Heather Highland, PhD, assistant professor of Epidemiology at the University of North Carolina, are co-first authors of the study.
The research was supported by the National Institutes of Health (grants UL1TR000371, U01CA288325, R01HL142302, R35HG010718, R01HG011138, R01GM140287, R01DK127084, R01AG078452, R01HL163262, R01HL151152, R01DK122503, R01HD057194, R01HG010297 and R01HL143885) and the American Heart Association.
