Diabetes risk according to family history – can we quantify the risk?

29th January 2020, Dr Chee L Khoo

If you have someone in the family with type 2 diabetes (T2D), then your risk of developing diabetes significantly increases. How much is “significant” though? Is it 2 times, 3 times or is it 10 times? Does it matter how many members in the family have diabetes? Is paternal diabetes important too? Do we know the numbers? Can we even measure those numbers? What about the environment? How much does it contribute to the risk? Let’s look at some attempts in answering those questions.

You can imagine how difficult it is to do studies of this sort. For one, you need large numbers of participants with a very long period of follow up. We also need to isolate the environmental component as well. The Framingham Offspring Study and The Danish Family Related and Unrelated Diabetes Study looked at the data differently but both give us meaningful data to ponder.

The Framingham Offspring Study

The original cohort of the Framingham Heart Study consisted of 5,209 men and women, including 1,404 couples, randomly selected from the community of Framingham, Massachusetts, aged 30–62 years at the study onset in 1949 (1). At the time of recruitment, this cohort was essentially all Caucasian and of mixed European ethnic descent. The prevalence rate for diabetes is low for this cohort. Subjects of the Framingham Offspring Study are the natural children of the original Framingham Heart Study cohort families, aged 12–58 years old at the first offspring examination in 1971–1975 (2). 2,629 children from 1,303 families completed 20 years of quadrennial follow-up through 1995. They looked for diabetes as well as abnormal glucose tolerance in the study.

The findings

  • Risk for type 2 diabetes among offspring with a single diabetic parent was 5-fold higher and for those with two diabetic parents was 6-fold higher compared with offspring without parental diabetes
  • Offspring with maternal diabetes age of onset <50 years had a 7- to almost 10-fold increased odds of meeting criteria for abnormal or diabetic glucose tolerance compared with individuals without parental diabetes, whereas individuals with older maternal diabetes age of onset had only a 2- to 3-fold increased odds.
  • Offsprings of young maternal diabetics are significantly younger at diagnosis themselves compared with older maternal diabetes or paternal diabetics
  • 43% of offspring with bilineal diabetes had fasting glucose levels ≥ 6.1 mmol/l compared with 29% with maternal diabetes, 16% with paternal diabetes, and 11% without parental diabetes.

The Danish family related and unrelated diabetes study

Out of an eligible population of 7.3 million identified from Danish registries between 1995-2018, 343, 237 (4.7%) were identified with diabetes (3). 92.0% had data on both parents, 0.6% only had data on father only and 7.4% had data on mother only.

The findings

  • If you have any member of the family with diabetes, you have a 2.02 relative risk of developing diabetes
  • If you have a diabetic mother, your relative risk of developing diabetes is 2.06
  • If you have a diabetic father, your relative risk of developing diabetes is 1.79
  • If you have both parents with diabetes, your relative risk of developing diabetes is 3.4
  • If you have a full sibling with diabetes, your relative risk of developing diabetes is 2.77
  • If you have a half sibling with diabetes, your relative risk of developing diabetes is 1.99 (common father) and 2.35 (common mother)
  • For twins, the relative risk of developing diabetes is 5.76. They were not able to distinguish between identical or non-identical twins.
  • Interestingly, if your husband has diabetes, your relative risk of developing diabetes of 1.4 whereas if you have diabetic wife, then the relative risk is 1.6. This gives us some idea of the environmental component in the development of diabetes.

Both studies (and many other studies) use prescription drugs for identifying subjects with diabetes. They assumed that overwhelming majority of those prescribed an anti-diabetic agent are diabetes although with the widespread use of metformin for diabetes prevention, this may affect the numbers.

High concordance rates in twins and high aggregation in families lend support to the genetic determinants of type 2 diabetes (T2D). There is no one single gene that causes T2D. Genome-wide association studies have identified more than 100 genetic loci, each tied to a small but increased susceptibility of developing T2D [4]. However, this polygenic understanding of type 2 diabetes captures only up to 10 percent of familial aggregation of the disease [5].

Both studies looked at one generation of offspring. WIth epigenetic influence, I wonder whether the numbers will be amplified in subsequent generations. Nonetheless, it’s important to take a good family history.

References:

  1. Wilson PWF, Kannel WB, Anderson KM: Lipids, glucose intolerance and vascular disease: the Framingham Study. Monogr Atheroscler 13:1–11, 1985
  2. James B. Meigs, L. Adrienne Cupples, and Peter W.F. Wilson. Parental Transmission of Type 2 Diabetes The Framingham Offspring Study. DIABETES, VOL. 49, DECEMBER 2000
  3. Aasbjerg, C. Holm Nørgaard, N. Vestergaard, P. Søgaard, L. Køber, P. Weeke, G. Gislason, C. Torp-Pedersen, Risk of diabetes among related and unrelated family members, Diabetes Research and Clinical Practice (2019), doi: https://doi.org/10.1016/j.diabres.2019.107997
  4. Merino J, Udler MS, Leong A, Meigs JB. A Decade of Genetic and Metabolomic Contributions to Type 2 Diabetes Risk Prediction. Curr Diab Rep 2017;17. https://doi.org/10.1007/s11892-017-0958-0.
  5. Morris A, Voight B, Teslovich T. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 2012;44:981–90. https://doi.org/10.1038/ng.2383.Largescale.