A major international study that involved mining the genomes of more than 250,000 individuals has uncovered previously unknown genetic risk factors for type 2 diabetes (T2D) and for coronary heart disease (CHD), and identified gene variants that link the two diseases. The new research, involving nearly 100 researchers from across the U.S., Canada, Europe, Japan, India, Pakistan, Taiwan, and Singapore, is published this week in Nature Genetics (“Identification of New Susceptibility Loci for Type 2 Diabetes and Shared Etiological Pathways with Coronary Heart Disease”) and could springboard the development of new T2D treatments that work to reduce CHD risk, the authors claim.
“I think we expected that there would be genetic results that were shared between diabetes and heart disease,” commented co-corresponding author Benjamin Voight, Ph.D., associate professor, systems pharmacology and translational therapeutics, and associate professor, genetics, at the University of Pennsylvania, Perelman School of Medicine, speaking with GEN. “But I think I was surprised as to the extent of that sharing across the genome.”
T2Dis a growing global health problem, and the number of people with the disorder is projected to reach about 592 million by 2035. T2D is also a major risk factor for CHD. CHD is the world’s leading cause of death, and patients with T2D are at a twofold higher risk of mortality due to CHD compared with individuals who do not have T2D.
Unknown Mechanisms
Despite the observed co-morbidity between these two diseases, the mechanisms that link them have not yet been fully elucidated. Prior genome-wide association studies (GWAS) have reported dozens of genetic risk factors for T2D and CHD, and research has indicated a genetic correlation between the two diseases; but no study has compared individual variants at any depth, or examined pathways shared by the two diseases, the Nature Genetics authors acknowledge.
“We know that CHD is a complication of T2D, yet the basis for this heightened risk is not completely understood,” Dr. Voight explained to GEN. “Existing, large-scale genetic efforts to understand the genetic basis of T2D and CHD have operated in parallel, but separately. We have an opportunity today to integrate large amounts of data from phenotypic scans to try to deduce genetic clues on this shared etiology, which may return yield insights to the underlying causes.”
The latest research was designed to enable a better understanding of the T2D–CHD relationship through genetics. But coordinating such a large group of researchers was no easy feat, commented Danish Salaheen, Ph.D. co-corresponding senior author, who is assistant professor of biostatistics and epidemiology at the University of Pennsylvania’s Perelman School of Medicine. “It took us two years just to bring all the researchers to agree and deposit their data,” he told GEN.
The team carried out a genome-wide, multiancestry analysis of genetic data from more than 250,000 individuals of South Asian, East Asian, or European descent, initially to identify risk loci for either T2D or CHD. Their results confirmed most of the known diabetes risk loci, but also identified 16 new diabetes genetic risk factors, including a new T2D association at a missense variant in HLA-DRB5, and one new CHD risk factor.
Eight Variants Linked with T2D and CHD
Further analysis indicated that a large fraction of genetic loci that are known to be associated with T2D were also linked with higher risk of CHD. Within these joint risk loci, the researchers focused in on eight specific variants, including two coding genes, that were associated with risk for both diseases. “The good news is that at least eight loci seemed to demonstrate a shared, genetic risk,” Prof. Voight noted. “However, in many cases, the gene target is not immediately obvious. That's also good news, because it means we've still got work to do—and that genetics can help point out core networks that are integral to this joint risk.”
The eight loci included those with known associations with T2D (nearby genes include TCF7L2, HNF1A, and CTRB1/2) as well as previously unreported T2D loci reported for the first time (MIR17HG and CCDC92) or that had previously been associated with CHD (MRAS and ZC3HC1). Seven of the eight loci increased the risk of both diseases. Two of these seven loci spanned regions harboring variants in the transcription factor genes HNF1A and ZC3HC1.
APOE Gene
In contrast, one of the eight loci, which spans a variant of the APOE gene, was associated with a higher risk of T2D but a lower risk of CHD. Although this might seem surprising, it turns out that variation in this region is also linked with lower cholesterol levels. The authors suggest that the finding is perhaps consistent with data from drug trials demonstrating that pharmacologically lowering low-density lipoprotein cholesterol (LDL-C) can modestly increase diabetes risk.
The “dual-impact” gene variants also demonstrated differing degrees of influence on CHD risk. Variants associated with increased likelihood of obesity or high blood pressure, for example, were more strongly linked than CHD risk than variants impacting on insulin or glucose levels.
Icosapent Gene Target
The researchers next looked carefully at associations beyond these highlighted eight loci, looking for additional, biologically compelling dual-impact candidates, Prof. Voight explained. One example included a gene target of an existing fish oil–derived cholesterol-lowering omega-3 fatty acid drug, icosapent, which is a FFAR1 and PPARG agonist and a COX1/COX2 inhibitor.
A second potential dual-impact locus spans a region that encompasses FABP4, a gene that is already being investigated as a potential diabetes and heart disease drug target. A final example highlighted another gene of previous interest, adipocyte fatty-acid-binding protein (aP2). Studies of this gene in mice have indicated that small-molecule inhibitors or antibodies to block the gene’s protein can reduce atherosclerosis as well as level of glucose and triglycerides.
“One message that I think I took back from the findings was that a better understanding (genetically) of diabetes—and ways to treat the growing health threat—will be a very important strategy to continuing to curb and further reduce risk of heart disease,” Voight noted to GEN.
Adipose Defects
“A key idea that emerges from this work is that genetic risk factors for T2D may play an important role in risk of CHD, thus emphasizing the need to understand the molecular basis for these factors,” Voight stressed. “A second idea is that joint risk factors perhaps point to biological pathways and mechanisms that we do not yet recognize or fully understand. CCDC92, for example, suggests the possibility of a new role of defects in adipose for the risk for both diseases, manifest through insulin resistance pathways—a possibility also supported by other work recently published while our paper was in revision. Other pathways involving other joint risk factors remain to be explained, but certainly are worth looking at more closely with focused, labor-intensive molecular studies.”
The team is now continuing to assemble and analyze new cohorts of genetic data for both diseases. “Our broad aim was to understand this relationship better through genetics; a great result for us would have been decisive genetic factors directly related to both traits, e.g., CCDC92,” Voight indicated. “This type of finding—and others like it—would be great from the point of view of scientific study, but also have some potential energy for clinical translation. We're engaged in follow-up work around the CCDC92 locus, in order to try to identify conclusively the molecular details, tissue of action, and underlying genetic mechanism.”
Opportunities for Drug Development
“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,” Prof. Saleheen stressed. “From a drug development perspective, it would make sense to focus on those pathways that are most strongly linked to both diseases.”
Using evidence from human genetics, it should be possible to design drugs for T2D that have either beneficial or neutral effects on CHD risk, he added. “However, it is important to identify and further deprioritize pathways that decrease the risk of T2D but increase the risk of CHD.”
The researchers are also applying the statistical approach utilized to jointly analyze T2D and CHD association data to other pairs of traits that are potentially (causally) related to each other. “For example, cholesterol levels with heart disease, adiposity with diabetes, etc., to identify new risk factors and also understand physiologically shared pathways for other traits and disease endpoints,” Voight told GEN.
