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Genetics of Type 2 Diabetes: Concepts of Risk Rather Than Cause

Have you ever had a patient ask, how much do our genes contribute to our risk of developing diabetes? Or, “Diabetes seems to run in my family. Am I doomed to developing the disease too?” Phil Wood DVM, MS, PhD gives us a way to answer in his feature Genetics of Type 2 Diabetes: Concepts of Risk Rather Than Cause.

Genetics of Type 2 Diabetes:  Concepts of Risk Rather Than Cause
Philip A. Wood

As a geneticist I am often asked, “How much do our genes contribute to our risk of developing diabetes?”  Or, “Diabetes seems to run in my family. Am I doomed to developing the disease too?”  Those are tricky questions to answer because development of diabetes is complex.  That is, people with an affected first-degree relative (a parent or sibling) have a 3.5-fold risk of developing diabetes themselves compared to individuals with no affected family members. Collectively, development of diabetes involves our genetics (it’s really our alleles, or genetic variants), plus our nutrition, activity level, and even our mothers’ and our own nutritional status during gestation.

Roughly guessing, for most people, 50% of the effect comes from genetics and 50% comes from the environment, including nutrition at all stages of development and our activity level.  However, these contributions of risk will be different for different people or even groups of people.

Genetics has very clear and powerful roles in the development of some relatively rare forms of diabetes.  These forms include mutations of genes that encode for enzymes (glucokinase) or transcription factors that regulate sugar/fat metabolism and lead to types of diabetes known as MODY (Maturity Onset Diabetes of the Young).  These rare forms of diabetes are inherited in a Mendelian manner such that they are dominant (need one of two mutant alleles) or recessive (need two of two mutant alleles) in the development of diabetes.

In other words, people with mutations in these genes are highly likely to develop diabetes as an inherited disease, similar to the way people develop cystic fibrosis or sickle cell disease.  These forms of diabetes (e.g., MODY) are very rare, and the genetic concepts described here do not apply to the most common forms of type 2 diabetes, which do not have clear inheritance patterns.

I want you to understand the distinct differences between clear-cut inherited forms of diabetes and the genetically more complex forms such as type 2 diabetes. In the former, the alleles of perhaps a single gene have powerful effects on the development of rare forms of diabetes. In the latter, development of diabetes is thought to be due to alleles of many genes that, individually, have small to modest effects.  The collective effects can be thought of as “risk of” or “susceptibility for” diabetes rather than “cause of” diabetes.

What this means, in most cases, is that certain families are genetically prone to, at risk for, or susceptible to diabetes, but no one individual family member is “doomed” to have it.  Most of us can help keep ourselves from developing diabetes by remaining lean and physically active—in spite of the genes and other influences we happened to end up with.  We cannot do anything about the effects of our genetics or our maternal and neonatal environment, but we can choose to have a healthy diet and lifestyle.

At least in certain populations, variant alleles of a few genes impart risk or susceptibility for development of common forms of type 2 diabetes: calpain 10 (CALPN10), peroxisomal proliferator activated receptor-gamma (PPARG), potassium channel (KCNJ11) and others (1). Most of these have been associated with small risks for developing diabetes (odds ratio = 1.10-1.25) and have been difficult to replicate in multiple studies and populations (1).

A gene currently of much interest is a variant allele (known as “T” allele versus normal “C” allele) of the transcription factor-7–like 2 gene (TCF7L2) with an odds ratio of ~1.7 (1) for diabetes. Furthermore, in a very large study (2) of Finnish diabetes patients and normal glucose tolerant controls, the same gene variant (TCF7L2) was significantly associated with diabetes. The authors of that study made some important points based on their large and powerful data set. They wrote that their results argue against the idea of multiple, common, genetic variants that each have a large impact, and for the idea that there are multiple genetic variants, each of which has a modest impact (2). Both these studies indicate statistically significant associations of particular genotype variants with diabetes, but the effects are small to modest at best and can be modified by environmental variables.

For instance, in another recent study, people without diabetes were followed for about 3 years. Among people in that study who had the T-allele of the TCF7L2 gene, those who exercised showed a lower risk of developing diabetes than those who did not exercise (3). The utility of such genetic markers as screening tools will also be somewhat limited because these are not common Mendelian type genetic diseases (e.g., cystic fibrosis, sickle cell disease or familial hypercholesterolemia). Therefore, these genetic variants are not as clearly indicative of disease.

Many of the risks found with these genetic variants are barely above background environmental influences or risks. Furthermore, these genetic variants may point us toward pathways involved in disease mechanisms, but these individual genes and their functional products may not have the potent effects desired for drug development—as did, for example, what we learned from familial hypercholesterolemia and the LDL receptor leading to the use of HMG-CoA reductase inhibitors (statins) in cardiovascular disease.

What I want you to take away from this article is, first, that there are rare forms of diabetes in which variant alleles of a single gene could be thought to “cause” diabetes. These are the MODY forms of diabetes.  Second, in contrast, the most common forms of diabetes are associated with obesity and physical inactivity (acquired potent risks) along with genetic components consisting of variant alleles of several genes. Many of these components and alleles probably remain to be identified. Therefore, a combination of acquired risks and genetic risks collectively increase someone’s “total” risk for developing diabetes rather than “causing” the disease.  This means that in most cases, we have some room to work and reduce our risk by avoiding obesity and remaining physically active, despite our genetics.  This reduction will be especially important if diabetes runs in your family.

Family trends can be both genetic and behavioral; that is, how we eat and how active we are can also be family behaviors.  Risks add up, so reduce the ones that you can, whatever your genotype may be.

  1. Sladek R, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881-885, 2007.
  2. Scott LJ, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science published on-line 26 April 2007; 10.1126/science.1142382.

3.   Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PIW, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D for the Diabetes Prevention Program Research Group. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 355: 241-250, 2006.

Read more of Dr. Philip A. Wood’s articles