Advances in the genetics of diabetes

What is the role for genetic testing in our clinic patients?

In the past five years, large advances have been made in the field of diabetes genetics. We have seen a massive effort to identify genes associated with type 2 diabetes using genome-wide association studies performed by multi-institutional and international consortiums.

On a smaller, but even more meaningful scale, we have seen a direct translation from identifying the genes responsible for neonatal diabetes to the physiologically based transition of these patients from lifelong insulin therapy to sulfonylureas. The new developments in this field are exciting, open new opportunities for understanding this complex disease process and offer our patients the chance at individually directed therapeutic interventions. However, as caregivers for patients with diabetes, we must strive to remain educated about these new developments and proceed with caution because of the various ethical issues that surround genetic testing.

Dawn Belt Davis

First advances

The first major advances in the genetics of diabetes were the identification of the various genes that cause Maturity Onset Diabetes of the Young. Genetic testing for the various genes involved is commercially available, and in the most common form of MODY (mutations in the HNF1a transcription factor) pharmacogenetics has identified sulfonylureas as an effective therapy. Predictions about risk of progression and development of complications can also be made based on a MODY diagnosis.

More recently, the genes responsible for permanent neonatal diabetes have been identified. Mutations in the components of the K_ATP channel lead to a failure to close this channel and depolarize the b-cell membrane allowing insulin release. Understanding the pathophysiology of this disease by identifying the mutation has allowed clinicians to make the leap to directed therapy with sulfonylureas, which close the affected channel and allow insulin release to occur. Amazing stories have emerged of children and young adults on insulin since infancy, many of whom have been able to completely discontinue insulin therapy and have improved glycemic control. This is a striking example of the power of genetics to influence patient care.

However, before any of these scientific advances can impact our patients, the appropriate patients must be recognized and screened in our diabetes clinics. The vast majority of these patients are misdiagnosed as having type 1 diabetes and without careful review of their personal and family histories may never be identified as candidates for genetic testing. MODY should be considered in patients with a strong family history of diabetes, onset in early adult life, negative autoantibodies and associated conditions such as renal cysts. Neonatal diabetes is defined as diabetes diagnosed before the age of 6 months and can be transient (with recurrence later in life) or permanent. (More information can be found at www.diabetesgenes.org and www.genetests.org.)

Link to genes

Big headlines were made in the diabetes research world when researchers identified initially 10 and now 17 genes linked to susceptibility to type 2 diabetes. These genes were identified by finding specific regions of the genome that were associated with type 2 diabetes in large populations. Several important caveats about this research exist, and it is important to discuss them as we move toward interpretation and utilization of these results.

These studies were done in a white/European population, so applicability to other ethnic and racial groups is unclear. Patients were lean or overweight and had type 2 diabetes, so an argument can be made that genes involved in insulin resistance may have been missed without inclusion of an obese population. In many cases, the actual gene that leads to the increased risk of type 2 diabetes has not been clearly identified. Rather, a candidate gene within the associated region of the genome is proposed as the risk allele. Future work will be needed to link this specific gene to the disease risk. There is a wealth of research opportunity emerging from this data, and in the future, novel pathways involved in diabetes pathogenesis are likely to emerge.

Genetic testing

Currently, genetic testing is commercially available for $370 for a panel of these type 2 risk alleles that purports to allow patients to assess their risk for type 2 diabetes (www.dnadirect.com). Patients may begin consulting their endocrinologists or diabetes educators about whether to obtain this testing or how to interpret the results. Primarily, it is important to understand that these genetic tests are designed to identify risk of developing type 2 diabetes. Therefore, they are of no real benefit to the patient who already has a diagnosis of diabetes or even prediabetes. These alleles each individually contribute a very small proportion of risk and are present at high frequency in the general population, so interpretation of the results can be difficult. For example, the gene TCF7L2 has the highest association with a per-allele odds ratio of 1.4. Having two copies of the TCF7L2 risk allele would increase risk from a 10% baseline lifetime risk to 14.5%. However, 45% of Europeans carry at least one copy of the risk allele and 15% carry two copies. Therefore, there is a high likelihood of a white patient having a “positive” test.

We already know that patients with a family history of type 2 diabetes have a significantly increased risk of developing type 2 diabetes. Therefore, the additional information obtained from this genetic testing is minimal. There is also concern that a negative result could provide a false sense of security, as this testing only examines a small subset of the genes that determine risk for type 2 diabetes.

Potential for genetic discrimination based on the results of any of the above genetic tests is a real concern for both patients and their family members who may also be tested in follow-up. Given the complexity of type 2 diabetes risk assessment testing, there is a real concern for misinterpretation of these results by insurance providers.

On May 21, 2008, President Bush signed into law the Genetic Information Nondiscrimination Act, which protects individuals from discrimination by health insurance providers or employers based on genetic information about future disease risk. This law will go into effect in mid- to late-2009, so currently these protections do not exist on a national level. A few important exceptions to this law include life insurance, disability insurance and long-term care insurance providers. Genetic information about predisposition to disease may still be used by these entities to raise premiums or deny coverage to individuals. Members of the military are also excluded from this law. When counseling patients and their families about genetic testing, it is important to know the facts about their potential for discrimination and to weigh these risks against the benefits of the knowledge obtained before proceeding with testing. Individual clinicians should strongly consider referring patients to a certified genetic counselor for further discussion of these issues. However, this is not always a practical option, and the burden of this necessary discussion will fall on the endocrinologist.

The future holds a lot of promise in this field, and one can envision a time when genetic testing for type 2 diabetes could yield clinically useful pharmacogenetic information similar to that already available for MODY and neonatal diabetes. Translating these advances from the benchside to the bedside so that they may be utilized appropriately and effectively in clinical care will be one of the largest challenges.

Dawn Belt Davis, MD, PhD, is a Clinical Instructor in the Section of Endocrinology, Diabetes and Metabolism, at the University of Wisconsin-Madison and is a member of the Endocrine Today Editorial Board.

For more information:

• McCarthy MI, Hattersley AT. Learning from molecular genetics: novel insights arising from the definition of genes for monogenic and type 2 diabetes. Diabetes. 2008;57:2889-2898.
• Stoy J, Greeley SA, Paz VP, et al. Diagnosis and treatment of neonatal diabetes: a United States experience. Pediatr Diabetes. 2008; 9:450-459.