Study Reveals Genetic Underpinnings of Type 2 Diabetes in Youth

By Marilynn Larkin

February 08, 2021

NEW YORK (Reuters Health) - The first genome-wide association study (GWAS) of type 2 diabetes in young people identified genes already known in adults as well as novel variants, researchers say.

"This suggests that type 2 diabetes in children has a robust genetic component," Dr. Jose Florez of Massachusetts General Hospital in Boston told Reuters Health by email. "In studies in adults, we have learned that healthy lifestyle is able to overcome a large proportion of the genetic predisposition. Whether this is the case in children and youth remains to be established."

As reported in Diabetes, to identify genetic variants predisposing to youth-onset type 2 diabetes, Dr. Florez and colleagues analyzed three multi-ethnic studies with data on 3,006 youth type 2 diabetes cases (mean age, 15.1) and 6,061 diabetes-free adult controls (mean age 54.2). About half of overall cases were female; 22%, non-Hispanic White; 36%, African American; and 59%, Hispanic.

After stratifying by principal component-clustered ethnicity, and after adjustment for sex, the team performed association analyses on about 10 million imputed genetic variants.

They identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (OR, 1.23).

Known loci included: rs7903146 in TCF7L2 (OR, 1.58); rs72982988 near MC4R (OR, 1.53); rs200893788 in CDC123 (OR, 1.32); rs2237892 in KCNQ1 (OR, 1.59); rs937589119 in IGF2BP2 (OR, 1.34); and rs113748381 in SLC16A11 (OR=1.04).

A secondary analysis including 856 diabetes-free youth controls uncovered an additional locus in CPEB2 (OR, 2.1) with a consistent direction of effect for diabetes risk.

Dr. Florez said, "In ongoing work, we are studying whether genetic variants, alone or aggregated in the form of polygenic scores, modify the response to metformin. Larger sample sizes in ethnically diverse cohorts are needed to fully characterize the genetic architecture of type 2 diabetes in youth."

Dr. Shailendra Patel, Director, Division of Endocrinology, Diabetes and Metabolism at the University of Cincinnati commented in an email to Reuters Health, "The study says that youth who are now developing diabetes have many of the same genetic risk factors as adults - not really a surprise - but there is a hint that perhaps factors not seen in adults may enhance the earlier manifestation."

"Seeing a genetic risk marker that is novel may be some support for this idea," he said. "However, one really must stress how preliminary these findings are, and that every risk locus identified needs verification, as we can see associations like this but they may not be causal."

"At present, these findings are strictly in the realm of research and clinical practice is not affected," he added. "We already know that lifestyle is the MAJOR driving force for the incidence and prevalence of diabetes and obesity. And we know from genetic studies that even when we may have strong genetic predisposition to such diseases, healthy lifestyle changes can really trump these risks."

SOURCE: Diabetes, online January 21, 2021.