New Study IDs Genes Linking Type 2 Diabetes and Heart Disease

Veronica Hackethal, MD

September 11, 2017

New research has provided fresh insight into genetic contributions to type 2 diabetes and heart disease and how the two diseases are linked. Results were published online on September 4 in Nature Genetics.

"This study has increased our knowledge about what causes type 2 diabetes and heart attacks. We have been able to identify genomic regions that connect both these outcomes," co–senior author Danish Saleheen, PhD, commented via email. Dr Saleheen is an assistant professor at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

The scientists identified 16 previously unidentified genetic variants that appear to increase the risk for type 2 diabetes and one new genetic variant that increases the risk for heart disease. They also confirmed previously identified risk loci for diabetes and pinpointed seven genetic variants that increase the risk for both type 2 diabetes and heart disease.

The findings could potentially affect drug development for both diseases. Some of the genetic regions linked to both type 2 diabetes and heart disease risk are targets of existing drugs, for example.

Also, having a better understanding of how heart disease and type 2 diabetes are linked is important for developing drugs that have neutral or beneficial effects on both diseases, according to Dr Saleheen.

"We would certainly like to stay away from the drugs that confer protection from one disease but increase the risk of the other," he commented.

For instance, statins lower cholesterol and can decrease the risk of heart disease but can increase the risk of type 2 diabetes.

Diabetes and Heart Disease Are Grave Threats to Public Health

Both diabetes and heart disease pose grave threats to global health. Experts estimate that diabetes will affect half a billion people in the next 2 decades, while heart disease is currently the leading cause of death worldwide. And people with type 2 diabetes have double the risk of developing heart disease, stressed Dr Saleheen.  

Initial studies have pointed to genetic pathways connecting heart disease and type 2 diabetes. But finding them is like looking for a needle in a haystack and requires large sample sizes. To expand the search, the researchers evaluated genomic data in a multiethnic sample that included at least 250,000 participants for each disease. Participants were of South Asian, East Asian, and European descent.  

The analysis found eight genetic variants strongly linked to risk for both type 2 diabetes and heart disease, with seven of these linked to increased risk for both diseases.

The eighth was a variant of the cholesterol-transport protein ApoE and was associated with increased type 2 diabetes risk but decreased heart disease risk. While the last finding may seem paradoxical, it is consistent with studies suggesting that using statins to lower LDL may modestly increase risk for diabetes, Dr Saleheen explained.

Further analysis identified a new shared gene, CCDC92, that appears to increase risk for both type 2 diabetes and heart disease at a single locus.

Researchers also evaluated these genetic variants against a range of physical traits and biomarkers. Using genetic risk scores, they discovered that genes linked to increased diabetes risk and certain physical traits or biomarkers appear to have different effects on heart-disease risk. For example, genetic variants linked to increased risk for obesity or high blood pressure appear to boost CHD risk more strongly than variants linked to abnormal glucose or insulin levels.

Finally, the researchers performed a joint analysis that identified 79 genetic regions involved in type 2 diabetes and heart disease. In addition to being involved in other disease pathways, like vascular resistance and fatty-liver disease, the results suggested that these regions may also be involved in immunity, cell proliferation, and cardiovascular development.

Findings May Help Development of Therapeutics

The results also showed that many of these regions may be targets of existing drugs.

One such drug is icosapent ethyl, a polyunsaturated fatty acid found in some fish oils that is already prescribed in concentrated form for lowering cholesterol.

Another candidate that could be the basis of a future therapeutic is FABP4, a gene that codes for the adipocyte fatty-acid binding protein and may play a role in the development of atherosclerosis. FABP4 is currently being studied as a potential target for diabetes and heart-disease medications.

The researchers plan to use their findings as a springboard for further research.

"I'm hopeful that with the advanced genomic engineering techniques now available, we'll be able to quickly convert our human genetics observations into concrete details regarding the molecular mechanisms involved in both heart disease and diabetes," co–senior author Benjamin Voight, PhD, an associate professor at the University Pennsylvania, said in a press release from his institution.

Future studies will examine individuals who are naturally deficient in these gene variants, which naturally protects them from both type 2 diabetes and heart disease. By studying such people, the researchers hope to determine whether they are free of other, perhaps related, disorders.

The authors report financial interests from their affiliations with Pfizer, Regeneron Pharmaceuticals, Genenetech, and Eli Lilly.

Nat Genet. Published online September 4, 2017.   Abstract

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