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Researchers Find Genetic Link Between Type 2 Diabetes, Coronary Heart Disease

NEW YORK (GenomeWeb) – An international study led by researchers from the Perelman School of Medicine at the University of Pennsylvania has identified new loci with ties to the etiology of both type 2 diabetes (T2D) and coronary heart disease (CHD).

The team conducted a genome-wide, multi-ancestry study of genetic variation for T2D and CHD in order to evaluate the shared genetic origin of the two diseases.

T2D is a major risk factor for CHD, which is the leading cause of death worldwide. The research team explained that CHD patients with T2D have twice the risk of mortality compared to individuals who do not have T2D.

While previous work has shown a genetic correlation between several dozen loci for T2D and CHD, no study has directly examined individual variants beyond established sites along the genome or compared pathways that both outcomes share.

In the study, published yesterday in Nature Genetics, the researchers assembled a discovery association set for T2D comprising 73,337 T2D cases and 192,341 controls to find new loci for T2D. Then they used additional genetic data on 90,831 CHD cases and 169,534 controls to potentially identify genetic pathways connected to both outcomes.

Examining sets of genome data on more than 250,000 people of South Asian, East Asian, or European descent, the researchers confirmed most of the known diabetes risk loci. More importantly, they found 16 new loci for diabetes and one new CHD genetic risk factor. For eight of these sites, the researchers discovered several new genetic pathways, including immunity, cellular proliferation and cardiovascular development, that link the outcome of both diabetes and CHD.

"Identifying these gene variants linked to both type 2 diabetes and CHD risk in principle opens up opportunities to lower the risk of both outcomes with a single drug," co-senior author Danish Saleheen said in a statement.  

Seven of the eight genetic sites appeared to increase risk for both diseases.

The researchers also found that the eighth site, a variant of the gene for the cholesterol-transport protein ApoE, was associated with higher diabetes risk but lower CHD risk. Salaheen noted that the contrasting association was consistent with recent studies that show that lowering LDL cholesterol can lead to a moderate risk of diabetes.

Saleheen and his team also reported a new locus for CHD and identified genetic loci shared by T2D and CHD, of which a subset colocalized to the same genetic variant. On the whole, the genetic link between the disease appears to work in one direction, in that the risk genes for T2D are much more likely associated with higher CHD risk than vice-versa.

Using a bivariate scan for both T2D and CHD, the researchers examined genetic association data that pointed to new pathways that are implicated in the causes of both diseases. The researchers identified loci that were enriched for disease ontologies related to vascular resistance, T2D, cardiovascular disease, fatty liver, obesity, gestational hypertension, and preeclampsia. The 79 gene intervals involve targets of existing drugs, highlighting more direct connections of the dual-risk loci than expected.

"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 T2D but increase the risk of CHD," Saleheen added.

The dual-effect risk also includes the region covering FABP4, which is currently being investigated for its potential as a diabetes and heart disease drug target. Inhibition of this gene's protein in mice has been shown to reduce atherosclerosis, glucose, and insulin levels.    

The authors wrote that "overall, identification of genetic loci associated with both T2D and CHD risk in a directionally consistent manner could provide therapeutic opportunities to lower the risk of both outcomes."

Saleheen noted that his team plans to further investigate the dual-risk genes uncovered in the study by observing patients who have mutations in those genes.

"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 said in a statement.