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26-06-2021 | Diabetes | News | Article

ADA 2021

Genetic influence stronger for youth- than adult-onset type 2 diabetes

Author:
Eleanor McDermid

medwireNews: The effect of common genetic variants on the risk for type 2 diabetes is markedly stronger for youth-onset than adult-onset disease, report researchers.

And the team also identified four rare variants with large individual effects on youth-onset diabetes risk, although this was still outweighed by the cumulative effects of multiple common variants, Soo Heon Kwak (Seoul National University, Republic of Korea) told attendees at the virtual ADA 81st Scientific Sessions.

The findings are based on whole-exome sequence analysis of 3005 people from the TODAY and SEARCH studies with type 2 diabetes diagnosed before the age of 20 years, as well as 9777 ancestry-matched adults without diabetes.

Two of the identified rare variants had genome-wide significance and both were associated with increased risk for youth-onset diabetes; the other two had exome-wide significance and one was associated with increased and the other with decreased risk.

Noting that the effect sizes of these variants were larger than usually observed in genetic studies of type 2 diabetes, the researchers went on to assess 16 common, previously identified variants that were also associated with youth-onset diabetes. They found that the effect size of these variants was an average of 11.8% stronger for youth- than adult-onset diabetes.

At the gene level, three genes were significantly associated with youth-onset diabetes. Two of these genes were HNF1A, defects in which can cause monogenic diabetes, and that encoding the melanocortin 4 receptor, disruption of which can lead to hyperphagia and severe obesity.

The third identified gene was ATXN2L, which Kwak said is a novel finding.

Looking at other diabetes-related genes, the researchers “were surprised to find large effect sizes for genes associated with obesity and beta-cell function,” he said.

Many of the associations involved genes with a recognized role in monogenic diabetes, such as GCK and RFX6, which Kwak said supports a model in which youth-onset diabetes “is enriched with variants in known monogenic diabetes genes.”

Indeed, the effect sizes of variants in almost all of these genes were larger for youth-onset than adult-onset diabetes. Notably, however, the association between variants in these genes and youth-onset diabetes remained significant even after the exclusion of variants that definitely caused or were likely to cause monogenic diabetes. For example, the odds ratio associated with GCK variants decreased from 7.7 to 2.8, but remained highly significant.

The presenter stressed that the cumulative contribution of rare gene variants to youth-onset diabetes risk was around 20–30% that of common single nucleotide variants; however, their contribution to youth-onset diabetes risk was 1.7-fold larger than their contribution to the risk for adult-onset diabetes.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

ADA Scientific Sessions; 25–29 June 2021

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