medwireNews: People with type 2 diabetes have a high prevalence of pathogenic mutations in genes typically associated with monogenic diabetes, shows research presented at the 79th ADA Scientific Sessions in San Francisco, California, USA.
Amelie Bonneford (French National Centre for Scientific Research, Lille) told conference delegates that the findings “could lead to precision diabetic medicine, and to significant savings in health expenditure via systematic molecular diagnosis of newly diagnosed patients.”
She explained that “[i]n contrast to monogenic diabetes, the genetic investigations of common forms of type 2 diabetes […] have led to modest advances in precision medicine.”
To address this, Bonneford and team sequenced 33 genes known to cause monogenic diabetes in 2178 people with type 2 diabetes and 4170 controls.
In total, they identified 1408 rare coding variants of potential interest, of these 200 were considered pathogenic or likely pathogenic.
After adjustment for age, sex, BMI, and ethnicity the researchers observed “a strong association between the cluster of pathogenic variants across the 33 genes and increased risk for type 2 diabetes.” Specifically, 6.8% of people with diabetes carried a pathogenic variant compared with 3.5% of controls.
Further analysis at the individual gene level showed that pathogenic variants in HNF1A and GCK were associated with increased type 2 diabetes risk, and Bonneford pointed out that these are “the most frequently mutated genes in monogenic diabetes.”
Conversely, GATA6 variants were associated with decreased risk.
Of note, the majority (81.8%) of people with a pathogenic or likely pathogenic variant in GCK were taking oral diabetes medication with or without insulin, while two-thirds (66.7%) of those with a HNF1A variant were treated with insulin.
Bonneford said that some of these patients might have been treated unnecessarily and that the findings open “a gateway for precision medicine in these patients.”
Secondary analyses among the people with diabetes showed that pathogenic mutation carriers had a mean BMI that was a significant 1.4 kg/m² lower than the mean for the whole cohort (27.1 vs 28.5 kg/m2). Mutation carriers also had a higher tendency to develop type diabetes earlier (mean 1.5 years) than the whole cohort but were not significantly more likely to use antidiabetic drugs.
In spite of this, the patients with type 2 diabetes “were far from the definition” of a person with maturity onset diabetes of the young because none of the variant carriers developed diabetes before age 25 years and there was no significant difference between carriers and noncarriers in family history of diabetes, Bonneford remarked.
By Laura Cowen
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Diabetes 2019; doi:10.2337/db19-29-OR
79th ADA Scientific Sessions; San Francisco, California, USA: 7–11 June 2019