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Study Examines Interaction of Genetic, Lifestyle Type 2 Diabetes Risk Factors

NEW YORK (GenomeWeb) — Both genetic and lifestyle factors influence a person's risk of developing type 2 diabetes, but a new study appearing in PLOS Medicine suggests that the absolute risk of developing diabetes is highest in obese people, no matter their genetic risk.

Drawing on a large cohort of Europeans enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study, the international team of researchers calculated each individual's genetic risk of developing type 2 diabetes and then examined how that genetic risk influenced disease risk in the context of other risk factors like age, waist circumference, diet, and more.

From this, they found that the relative effect of a high T2D genetic risk score is greater in younger, leaner participants, but that that group has a low absolute risk. Instead, the researchers found that obese people had a high absolute T2D risk at any genetic risk level.

"This is the largest study to date examining the impact of genetic susceptibility and lifestyle factors on the risk of developing type 2 diabetes," said Nicholas Wareham from the University of Cambridge and the EPIC-InterAct study in a statement. "The high absolute risk associated with obesity at any level of genetic risk highlights the importance of population-wide, rather than genetically targeted, approaches to promoting healthy lifestyles that minimize excess weight."

Some 380 million people worldwide are estimated to have diabetes, a number that is projected to grow to upward of 590 million by 2035.

The EPIC study, which is examining the relationship between diet, lifestyle, and other factors and cancer and a number of chronic diseases, has followed more than 340,000 people of European descent for a mean 11.7 years. During that time, 12,403 individuals developed T2D — an overall incidence of 3.8 cases of T2D in per 1,000 person-years of follow up, the researchers noted.

To examine the interaction of lifestyle and diabetes risk, the researchers focused on a sub-cohort of 16,154 individuals for further analyses.

For each participant, the researchers gathered height, weight, waist circumference, and information regarding diet, including whether the participants followed a Mediterranean-style diet, and physical activity data. Additionally, a further subset of patients was genotyped using the Illumina 660W-Quad BeadChip.

Using this genotype data, Wareham and his colleagues developed a genetic risk score based on a set of 49 variants linked to T2D culled from the recent DIAGRAM meta-analysis. That set includes two known obesity loci, FTO and MC4R.

With statistical tools, they examined interactions between that risk score and other T2D risk factors like age, sex, family history of diabetes, physical activity, and diet on incidence of disease.

The effect of the genetic risk score, the researchers said, was greater in people who developed T2D at a younger age, as compared to those who developed it later in life. Additionally, they found that the relative genetic risk was greater for participants who were leaner, as determined by BMI and waist circumference — they noted a hazard ratio of 1.62 for normal weight, 1.46 for overweight, and 1.27 for obese participants.

They found no significant interactions between the genetic risk score and sex, family history of diabetes, physical activity, or diet, a finding that did not change with the addition of BMI as a covariate.

But by stratifying the cumulative incidence of T2D by the various lifestyle risk factors and quartiles of genetic risk, the researchers found that lifestyle factors had a stronger effect than genetic factors on absolute T2D risk.

For instance, the cumulative incidence of normal-weight individuals developing T2D over 10 years rose from 0.25 percent to 0.44 percent to 0.53 percent to 0.89 percent across the quintiles of genetic risk scores. Meanwhile obese individuals in the lowest quintile of genetic risk had a 10-year cumulative incidence of T2D of 4.22 percent, which rose to 5.78 percent, 5.83 percent, and 7.99 percent across the remainder of the genetic risk quintiles.

"The high absolute risk associated with obesity at any level of genetic risk highlights the importance of lifestyle interventions focusing on excess weight, and suggests that universal approaches regardless of genetic susceptibility based on established T2D loci are appropriate and are urgently warranted in the light of the current obesity epidemic," Wareham and his colleagues said.

"The observation of a higher relative risk among younger and thinner individuals would not be a logical basis for targeting genetic testing to this population sub-group, since the low absolute risk in this group would mean that the number needed to screen to identify a population for targeted prevention would be huge," they added.