January 29, 2020
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New genetic discoveries help predict risk for type 1, type 2 diabetes

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Ruth Loos

Researchers continue to discover more each year about the genetic risk factors for type 1 and type 2 diabetes and how those risk factors interact with the environment. Scientists have linked several genetic mutations to diabetes risk, though not everyone with a genetic mutation will go on to develop the disease.

Healio spoke with Ruth Loos, PhD, professor at The Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai, about the differences in genetic susceptibility for type 1 vs. type 2 diabetes, which genes might confer greatest risk, and what endocrinologists should know about the growing interest in at-home genetic testing kits.

What role does genetics play, generally speaking, in the development of type 1 and type 2 diabetes? Do genes have a stronger influence on type 1 vs. type 2 diabetes?

Genes for ET weekender 11.2.2018 
Researchers continue to discover more each year about the genetic risk factors for type 1 and type 2 diabetes and how those risk factors interact with the environment. Scientists have linked several genetic mutations to diabetes risk, though not everyone with a genetic mutation will go on to develop the disease.
Source: Adobe Stock

Loos: It is important to make that distinction, because the genetics of type 1 vs. type 2 diabetes are very different. We know from twin studies, family studies and family history studies that diabetes is heritable. The lifetime risk for developing type 2 diabetes is almost 70% if both parents are affected. Type 2 diabetes is what we call a complex, polygenetic and multifactorial disease. When we say “polygenic,” a lot of genetic variants contribute to a person’s genetic susceptibility — some people may have a low genetic risk, whereas others may have a high genetic risk, but most of us have an average risk. While the heritability gives you an idea of how much genes contribute to variation in type 2 diabetes susceptibility in the overall population, a polygenetic risk score determines how many risk variants a person inherited from both parents. Thus, using this score, you can stratify the population by who is more genetically prone and who is less.

Type 1 diabetes is far less common; however, heritability is higher. In twin studies, what we have learned is that if one twin of an identical pair has type 1 diabetes, and one twin of a nonidentical pair also has type 1, the other sibling in the identical pair is far more likely to develop type 1 diabetes compared with the sibling in the nonidentical pair. That is not so much the case in type 2 diabetes. There is definitely a stronger genetic component to type 1 diabetes vs. type 2.

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Which genes confer the greatest risk for developing diabetes?

Loos: For type 2 diabetes, we know it's a large number. Today, we know there are over 400 genetic variants across the whole genome that each contribute a small increase in a person’s susceptibility to developing type 2 diabetes. TCF7L2 was identified more than 10 years ago and has the biggest effect on type 2 diabetes risk among all genes identified so far. We know that people who carry two risk alleles will develop type 2 diabetes at an earlier age.

For type 1 diabetes, about 80% of the genetic risk is due to variations in the HLA, a region in the genome that covers a series of genes that are important for a person’s immune system. Genes in HLA are reported to account for approximately 40% to 50% of the familial aggregation of type 1 diabetes, according to the NIH.

What role does the environment play in influencing genetic risk?

Loos: While genetics are important, we always need the environment. Genes are the loaded gun, and the environment is the trigger.

For type 2 diabetes, if the heritability is, say, 40% to 70%, this means that 40% to 70% of the variation we see in people’s susceptibility to develop type 2 diabetes is due to genetic variation, which means that the other 30% to 60% is due to non-genetic, environmental factors. Individual risk differs, not just because of genetic differences, but also because each person’s individual lifestyle is different, and each person’s exposures are different. Studies do suggest that people with risk alleles for type 2 diabetes who live a healthier lifestyle develop type 2 diabetes at a rate similar to people who do not have these risk alleles. That said, these people will always have to work harder to lower their risk for the disease.

For type 1 diabetes, there are also environmental triggers. Sometimes it is hard to distinguish whether it is indeed the actual environment that contributes to type 1 diabetes risk, or whether it is our increased knowledge or greater awareness of the disease. But, there's also an interaction between the two. Some studies, as an example, suggest an association between genetic susceptibility and exposure to infection in type 1 diabetes. Researchers have also observed that prevalence of type 1 diabetes is higher in Finland and other Nordic countries. All of this suggests that there are also likely environmental factors at play with respect to type 1 diabetes.

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There is now a huge public interest in at-home genetic testing. What should endocrinologists keep in mind when a patient comes to them and asks about their genetic risk for diabetes or obesity and perhaps how they can prevent it?

Loos: As far as I know, there are no companies that offer an at-home test that predicts type 1 diabetes, but yes, you can now purchase an at-home kit to test for your genetic risk for type 2 diabetes. I have taken these tests myself, but I have also conducted the studies that try to predict type 2 diabetes or obesity. From those studies we know that even though the associations that we see in research studies are very strong, the predictive ability of these genetic variations are very low. They are barely a little better than flipping a coin, so we cannot really rely on these genetic testing companies. In fact, according to 23andme, I am at “very high” risk for developing type 2 diabetes. I knew this already, because I had looked up my own alleles and I know that I carry that TCF7L2 variation. But when the testing company sent me this report, they didn’t take into account that I try to eat a healthy diet, that I am not overweight, and that I am physically active. It is single minded to base any information about disease risk solely on genetics.

What genetic research that relates to diabetes are you most excited about right now?

Loos: At Mount Sinai, we have a big biobank that includes more than 50,000 patients. BioMe is an electronic medical record-linked biobank that enables researchers to rapidly and efficiently conduct genetic, epidemiologic, molecular and genomic studies on large collections of research specimens linked with medical information. We currently have sequencing data for 30,000 individuals, which allows us to identify those who carry mutations. They are very rare, but it might be very informative toward causes of disease and maybe even the development of therapeutics. What we want to do is identify these individuals who carry these mutations and bring them back to the hospital to be further phenotyped — assess them in a metabolic room, give them a liquid meal, and look at how their hormones and proteins change over time, conduct microbiome analysis, conduct MRI and functional MRI, and learn even more. We’ve come full circle, from research where we studied large populations, millions of individuals, and we have come back to assessing individual patients to help develop better therapeutics and also to personalize their treatment. That is the definition of precision medicine. – by Regina Schaffer

Disclosures: Loos reports no relevant financial disclosures.