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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #140: The Genetics of Type 2 Diabetes Part 2

Aug 28, 2018
 

Heritability of T2DM

It has long been clear that T2DM clusters in families and it is well established that the risk of developing T2DM depends on both genetic and environmental factors. However, the exact proportion of the two, that is, the heritability, is difficult to determine and heritability estimates therefore vary in the range of 25–80% between studies. Twin-studies have estimated the genetic component by comparing disease concordance in dizygotic twins with concordance in monozygotic twins. In these studies probandwise concordance rates (number of affected twins having a diabetic co-twin) for monozygotic twins vary between 34 and 100% [3–6].

 

The relative risk for first-degree relatives, that is, the risk of developing T2DM if you have an affected parent or sibling compared to the general population, is approximately 3, and ∼6 if both parents are affected [7]. However, this statistic also varies depending on the cohort and population studied.

There are also large differences between ethnic groups that seem to depend on genetic factors. The prevalence of T2DM varies widely among populations, from a few percent among

Caucasians in Europe to as high as 50% among Pima Indians in Arizona [8].While part of the observed ethnic variability could be attributed to environmental and cultural factors some of the variation seems to depend on genetic differences.

One limitation of both twin and family studies is that they have a risk of overestimating heritability due to sampling and ascertainment errors. Concordant twins are more likely to participate in a study and the proportion of individuals with undiagnosed diabetes may differ compared to the general population. Also, the families recruited to genetic studies may represent a subset of highly heritable T2DM whereas an outbred population could have more sporadic or environmentally induced cases. Another limitation is that family studies often cannot distinguish between the effect of genetic inheritance and the effects of a shared environment and the gene–environment correlation that comes from nongenetic inheritance.This problem could be especially large in T2DM since poor eating and exercise habits are often part of the social inheritance and strongly affect diabetes risk.

Another interesting fact is that the risk of T2DM is higher in individuals who have an affected mother, compared to an affected father [9]. There are many possible explanations for this including a role for the intrauterine environment in programming events later in life. Intrauterine effects can also affect heritability estimates because monozygotic twins are often monochorionic, which results in growth retardation compared to dizygotic twins, and low birth weight is associated with increased risk of T2DM later in life.

In spite of these reservations, there is no doubt that the risk of T2DM is partly determined by genetic factors, many of which have already been identified, and while each identified variant explains only a very small proportion of the risk of T2DM in the human population they all contribute to our understanding of disease pathogenesis. One should also keep in mind that the variance explained by a risk allele in a population is not necessarily an indicator of its importance in specific patients, nor is it proportional to the affected pathway’s importance or potential as a therapeutic target.

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