Using genome data from more than 250,000 people, scientists have identified gene variants that appear to alter the risk of both type 2 diabetes and heart disease – two leading causes of death and disease. They also suggest that the discovery could lead to treatments that use one drug to protect against both illnesses.
The international team, which was led by researchers from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, accounts for the findings in a paper published in the journal Nature Genetics.
Around 95 percent of people with diabetes have type 2 diabetes, which is a disease that develops when the body makes enough insulin but its cells lose the ability to use it to absorb blood sugar and convert it into energy.
In the United States, where it is the seventh leading cause of death, there are around 30.3 million adults with diabetes, including 25 percent of people who do not know that they have it.
The number of adult diabetes cases has more than tripled in the U.S. in the past 20 years, primarily as a result of an aging population and rising levels of obesity.
Worldwide, the prevalence of diabetes among adults has gone up from 4.7 percent in 1980 to 8.5 percent in 2014.
Diabetes is a known risk factor for heart disease, which is the leading cause of death for both men and women in the U.S., where around 630,000 people die of the disease every year.
Over half of people who die from heart disease in the U.S. die of coronary heart disease, which is caused by coronary artery disease, a condition wherein the heart’s arteries get narrower due to plaque buildup.
In their study paper, the researchers explain that patients with type 2 diabetes are twice as likely to die of coronary heart disease as patients without it. However, the genetic and molecular mechanisms that lead to this higher risk are poorly understood.
Due to a relatively new technology known as genome-wide association studies (GWAS), scientists now have a good grasp of the “genetic architecture” of coronary heart disease and type 2 diabetes.
GWAS is a sequencing method that can rapidly scan the genomes – or complete sets of DNA – of thousands of people. Scientists use it to find sites, or “loci,” in the genome that are linked to disease.
The authors note that, in the case of type 2 diabetes and coronary heart disease, GWAS has led to the discovery of “several dozen” risk loci.
But what is less well understood is the extent to which the risk genes behind the two diseases, and the molecular pathways through which they influence cell biology, are linked.
For their study, the team examined GWAS data from more than 250,000 people of South Asian, East Asian, and European descent and confirmed many of the known risk loci for diabetes. They also found 16 new risk loci for type 2 diabetes and one new one for coronary heart disease.
Further analysis revealed that most of the loci on the genome that are known to be linked with raised risk for type 2 diabetes are also linked to higher risk for coronary heart disease.
In the case of eight of the loci, the team was able to identify a specific variant – or spelling of the letters in their genetic code – that altered risk for both diseases.
The shared variants “implicate several new pathways,” note the authors. The pathways affect immunity, cardiovascular development, and cell proliferation.
Joint senior study author Danish Saleheen, an assistant professor of biostatistics and epidemiology at the University of Pennsylvania, suggests, “Identifying these gene variants linked to both type 2 diabetes and CHD [coronary heart disease] risk in principle opens up opportunities to lower the risk of both outcomes with a single drug.”
Seven of the eight new variants appear to increase risk for both type 2 diabetes and coronary heart disease.
However, the eighth variant – in a gene that codes for the cholesterol-transport protein ApoE – differed in a way that puzzled the team. While it was tied to higher risk for type 2 diabetes, it appeared to lower the risk of coronary heart disease.
This may explain, says Prof. Saleheen, why evidence from statin trials shows that using drugs to lower low-density lipoprotein cholesterol might “modestly” raise the risk of developing type 2 diabetes.
Overall, the team found that the genetic links that they identified between the two diseases appear “to work in one direction” – that is, the risk loci for type 2 diabetes are significantly more likely to be linked to higher risk for coronary heart disease than the other way around.
They also suggest that there might be pathways through which drugs that lower the risk of one disease may increase the risk of another.
“Using evidence from human genetics, it should be possible to design drugs for type 2 diabetes that have either beneficial or neutral effects on CHD risk; however, it is important to identify and further deprioritize pathways that decrease the risk of type 2 diabetes but increase the risk of CHD.”
Prof. Danish Saleheen
The team also found that some of the shared variants that raise risk for type 2 diabetes appear to have different effects on risk for coronary heart disease, depending on which pathway they influenced.
For example, variants that appear to exert influence through obesity and high blood pressure appear to have a stronger effect on coronary heart disease risk than variants that influence levels of blood sugar and insulin.
The team is hoping to take the investigation further by studying people who have mutations in the shared risk loci.