Two Genetic Pathways Found To Contribute to Cardiometabolic Disease

A study published today in PLOS Medicine has identified two new genetic pathways that contribute to cardiometabolic disease, which includes heart disease, obesity and diabetes. The research, led by Dharambir Sanghera, Ph.D., of the University of Oklahoma, represents a step toward targeting the diseases more precisely.

The study analyzed how genetic differences shape the body’s range of fats (called the lipidome) and whether that interaction is linked to conditions like heart disease and diabetes. Sanghera and her team evaluated the lipidome and the body’s genetic instructions (the genome) in Asian Indians, a population that is especially susceptible to heart disease and diabetes. Most similar studies have been conducted in people of European descent.

The researchers found two genetic pathways that link specific lipid metabolites (small molecules produced when the body processes fats) to disease. One metabolite was found to be low in people with heart disease, suggesting that increasing it through diet or a treatment could prevent or lower the risk of disease. The other metabolite, when elevated, causes inflammation and increases the risk of insulin resistance, which can lead to Type 2 diabetes. This finding suggests that the genetic pathway of the metabolite could be blocked by a targeted therapy to lower the risk.

“These findings not only help us understand disease better but could be valuable in making recommendations for therapeutic interventions,” said Sanghera, a professor of pediatric genetics at the OU College of Medicine and research member of OU Health Harold Hamm Diabetes Center. “That is why studying people of different cultures is so important. The same therapies do not work for everyone. This is the way toward more personalized medicine and understanding that there can be subtypes of disease among people of different ancestries.”

Using rigorous analyses, Sanghera and her team began the study by examining 516 lipid metabolites in the blood of 3,000 individuals. They compared their findings to previous results from more than 1 million Europeans and 15,000 people with Indian ancestry. Of the 516 metabolites, about 236 were found to be associated with heart disease and diabetes. Researchers narrowed the number to 33 metabolites reported for the first time as associated with heart disease and diabetes. From there, the researchers further reduced the number to two that were found to play a direct role in the conditions.

“We would not have found these two genetic pathways and their intersecting metabolites had we not evaluated this South Asian population,” Sanghera said. “This understanding benefits everyone because we all have different genetic makeups, lifestyles and cultures.”

Sanghera plans to continue this field of study, which includes Oklahomans, who have a high burden of cardiometabolic disease.

“More studies are needed because heart disease and diabetes have different root causes and different underlying mechanisms,” she said.

Reference: Rout M, Aston E C, Duggirala R,et al. Identification of lipid quantitative trait loci linked with cardiometabolic disease in Asian Indians and Europeans: A genome-wide association study and mendelian randomization. PLOS Med. 2026.doi: 10.1371/journal.pmed.1005039 

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