Genetic Mutation Magnifies Risk of Diabetes, Heart Disease

Type 2 diabetes (T2D) has become increasingly common in the United States and affects millions of adults and children worldwide. Despite the prevalence, there are significant gaps in the etiology of the condition, especially regarding the connection to coronary heart disease (CHD).

Findings from a large study published by Nature Genetics may point to the causes of T2D and how it is linked to CHD. Since T2D and CHD are the leading cause of morbidity and mortality, understanding the driving factors of the conditions may lead to novel therapies.

In the new study, the authors sequenced genome information for thousands of individuals and discovered 16 new risk factors for diabetes and 1 for CHD, which may explain why the conditions are common comorbidities.

Notably, the sites on the genome linked to higher diabetes risk were also associated with an increased risk of CHD. For the 8 sites, the authors found a specific mutation that increased the risk of both conditions through immunity, cell proliferation, and heart development, according to the study.

These results add significant information to the knowledge about both conditions and could result in future targeted drugs.

"Identifying these gene variants linked to both T2D and CHD risk in principle opens up opportunities to lower the risk of both outcomes with a single drug," said study co-senior author Danish Saleheen, PhD. "From a drug development perspective, it would make sense to focus on those pathways that are most strongly linked to both diseases.”

The authors examined genome data for more than 250,000 individuals of South Asian, East Asian, or European descent. They were able to confirm common diabetes risk loci—sites on the genome where DNA mutations cause a higher diabetes risk—and discovered 16 new sites.

The authors additionally found 8 specific gene variants linked to a high risk of T2D and CHD. The eighth is a gene variant for the cholesterol-transport protein ApoE, which increased the risk of diabetes, but lowered CHD risk, according to the study. This finding was consistent with studies that found lowering LDL cholesterol may increase diabetes risk.

The investigators noted that the genetic link between the condition seems to be unidirectional, in which the risk for T2D is linked to CHD rather than the other way around, according to the study.

Interestingly, the gene variants that affect diabetes differ in their effects on CHD. For example, mutations that increase the risk of obesity or high blood pressure were found to increase the risk of CHD more than those that influence insulin or glucose levels, according to the study.

The authors hypothesize that risk of the conditions may be modifiable through prescription drugs.

"Using evidence from human genetics, it should be possible to design drugs for T2D that have either beneficial or neutral effects on CHD risk; however, it is important to identify and further de-prioritize pathways that decrease the risk of type-2 diabetes but increase the risk of CHD," Dr Saleheen said.

Some dual risk genes may be modifiable by existing drugs, such as icosapent, which is an omega-3 fatty acid that lowers cholesterol. The authors project that experimental drugs could also reduce the risk.

The authors hope to conduct further studies about the biology of the dual-risk genes by examining individuals with the mutations.

"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," said co-senior author Benjamin F. Voight, PhD.