The observation that diabetes has a strong genetic component has been known for decades based on concordance data from monozygotic vs. fraternal twins. When Dr. Francis Collins was directing the human genome project beginning in 1990, his presentations at the ADA often included the fact that diabetes mellitus fell under the concept of a “complex” disorder in which genetic determinants of disease were confounded by such things as the fact that family history may have been inaccurate. Young people with a genetic predisposition to diabetes might not yet have manifested the phenotype, and the pathobiology of the diabetes syndrome was still evolving. In the nearly two decades since the completion of the initial human genome project in 2003, we have learned much about the genetics of Type 2 diabetes. Currently, there are greater than 40 genes associated with rare variants of diabetes (monogenic diabetes), more than 100 independent associations with signals for Type 1 diabetes, over 500 independent associations with signals for Type 2 diabetes, and beyond 200 independent associations for macrovascular or microvascular complications of diabetes. In 2021, the genetic story of diabetes is still complex.
At this year’s American Diabetes 81st Scientific Sessions, there were multiple sessions on the data from genetic studies of diabetes. This report can only provide a sample of these sessions and a limited number of references for each concept. However, this sampling of the presentations should be helpful to get a sense of the current level of understanding, especially for those of us who are clinicians involved in the treatment of many patients with diabetes mellitus.
The clearest association of genes, the defect causing hyperglycemia, and the appropriate glucose-lowering therapy is with the monogenic forms of diabetes included those that are sulfonylurea responsive or do not need glucose-lowering therapy. These clear associations were the starting point in many presentations. Genetic prediction for the risk to develop diabetes was discussed in several presentations, and clusters of genes are associated with the risk to develop diabetes in some, but not all, studies. Heterogeneity of type 2 diabetes can now also be characterized by genetic clusters of genes or a palette of genes. In turn, these genetic clusters may inform potential responses to glucose-lowering therapy. Genetic determinants of response to glucose-lowering medications were reported in many sessions, and data show that there are clear genetic predictors for responses to sulfonylureas, metformin, and GLP1 RA. Genetic variables may also inform medication side effects. Specific genes or gene clusters also are associated with increased risk for coronary heart disease or the microvascular complications of diabetes. These data suggest the potential that genetic profiles may be used to identify persons with diabetes at increased risk for complications and guide earlier intervention for risk mitigation of diabetes complications.
Currently, the actual clinical applicability of genetic markers of risk to develop diabetes, treatment of diabetes, and its complications is limited by several factors. Dr. Jose Florez, one of the investigators in many of these genetic studies, noted that the identified gene might not be the actual culprit to define the disease process; but more likely is associated with one or more causal variants. These causal variants are important both to understanding the medical trait of interest and identification of the specific target for medical treatment, including future drug development. Thus, genetic association with the disease extends beyond the actual gene that is identified by association. Second, identification of a genetic association in a cohort may not be easily applicable to the individual patient — with the notable exception of monogenic diabetes. Thus, routine clinical applications of risk prediction and therapeutic intervention are still aspirational.
The recent report on “Precision Medicine in Diabetes” from the ADA and EASD touches on many of these issues and includes many references related to the topics discussed above including thoughts about future research. The reader is referred to this document for an additional discussion of the role of genetics in approaches to understanding diabetes and its management.
Dr. Hoogwerf has investments with, and is formerly employed by, Eli Lilly, he has received consulting fees from MannKind Corp, and his spouse is a full-time employee of Bayer Corp