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Diabetes Subtypes Stem From Distinct Genetic Contributors, Study Suggests

NEW YORK – A research team in Sweden, Finland, the UK, and the US has started deciphering some of the genetic differences underlying proposed diabetes subtypes, including several severe forms of disease and cases marked by insulin resistance.

"[T]he data provide strong evidence for distinct genetic backgrounds of the subtypes," senior and corresponding author Emma Ahlqvist, a researcher with the Lund University Diabetes Centre, and her colleagues wrote in Nature Genetics on Thursday.

Using genotyping data for thousands of participants with or without a family history of type 1 diabetes or T2D in the All New Diabetics in Scania study in Sweden, the researchers did genome-wide association analyses aimed at identifying contributors to several proposed diabetes sub-classifications: severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD).

Those clinical classifications were enhanced using information on a half a dozen clinical variables ranging from body mass index or age at diagnosis to autoantibody and insulin secretion estimates, they explained. Along with available risk SNP data from prior studies, these phenotypes also helped in coming up with GRS for type 1 diabetes (T1D), type 2 diabetes (T2D), and related traits and clinical features. They also shored up their results with validation testing on individuals from other large studies in Finland.

While almost 88 percent of participants with obesity-related diabetes and nearly 84 percent of SIDD patients had a first- or second-degree relative with T2D, for example, family history of T2D turned up in fewer than 78 percent of those with the SIRD, MARD, or SAID subtypes of diabetes.

The SAID subtype had the most pronounced ties to a family history of T1D, on the other hand. Those cases were significantly also linked to a GRS for T1D and showed associations with risk variants at the human leukocyte antigen locus, but showed only tenuous ties to T2D-associated variants.

On the other hand, the severe insulin-resistant form of the disease corresponded most closely with a fasting insulin-focused GRS, they noted, but not with a GRS linked to insulin secretion risk or with T2D-associated variants in TCF7L2.

When it came to the milder subtypes, the team tracked down a risk SNP near the LRMDA gene that was significantly associated with the relatively mild, early-onset, obesity-related form of the disease. The mild obesity- and age-related subtypes also associated with an insulin secretion risk score, as did severe insulin-deficient cases.

Based on these and other findings, the authors argued that it may eventually be possible to better tailor treatment for individuals with diabetes, depending on the distinct genetic and clinical features involved.

"These results suggest translational potential in terms of intervention stratification, which is backed up with our previously published clinical data showing different treatment responses in the subtypes," the authors concluded. "This is an important public health aspect as what we think of as T2D is 80-90 percent of all diabetes; better knowledge of its pathogenesis, early detection, and intervention in the face of heterogeneity is critical."

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