A higher genetic risk for type 2 diabetes was linked to a greater risk for all-cause mortality, independent of body mass index (BMI), lifestyle and metabolic risk factors, and whether a person had diabetes at baseline, researchers reported. For each type 2 diabetes (T2D) risk allele a person carried, their mortality risk increased by 4% over the 17-year study period, according to James Meigs, MD, of Harvard Medical School in Boston, and colleagues in Diabetes Care.

However, based on an analysis by ethnicity, the association held true for whites and blacks, but not Mexican Americans, the authors noted.

"Epidemiologic studies have shown that T2D is associated with increased all-cause mortality risk. Given that T2D is partly genetically determined, genetic factors that increase T2D susceptibility may also raise mortality risk through T2D or its related complications," they wrote. "Here, we tested the hypothesis that carrying a higher aggregate genetic burden of T2D risk ... predicted all-cause mortality."

The study included 6,501 participants from the Third National Health and Nutrition Examination Survey. They were 81.1% white, 12.7% black, and 6.2% Mexican American. The prevalence of type 2 diabetes was similar across the ethnic groups, ranging from 8%-11%. Over the 17-year study period, 1,556 participants, about 19%, died.

The study participants were genotyped, and genetic data was analyzed with a focus on 38 single nucleotide polymorphisms associated with type 2 diabetes risk. The investigators looked for an association between aggregate genetic risk for type 2 diabetes and all-cause mortality. They also sought to determine whether this association was modified by ethnicity or BMI.



After adjusting for age, sex, BMI, smoking, alcohol use, hypertension, and other risk factors, the investigators found that, for the group as a whole, mortality risk increased slightly for every type 2 diabetes risk allele a person had (odds ratio 1.04, 95% CI 1.00-1.08, P=0.05).

Further adjustment for type 2 diabetes at baseline yielded nearly identical results, with only a slight difference in the P-value (OR 1.04, 95% CI 1.00-1.08, P=0.04).

When they authors evaluated the results by ethnicity, the association remained significant for whites and blacks but not for Mexican Americans (OR 0.95, 95% CI 0.89-1.01, P=0.10).

In an analysis by ethnicity and BMI category (<25 kg/m2, 25–30 kg/m2, and ≥30 kg/m2), the results were only statistically significant for obese whites (OR 1.07, 95% CI 1.02-1.12).

In fact, Meigs and colleagues found that a higher genetic type 2 diabetes risk was negatively associated with mortality risk in Mexican Americans of normal weight (BMI <25 kg/m2, OR 0.91, 95% CI 0.82-1.00).

"The trend toward a mortality advantage among Mexican American participants of normal weight carrying more T2D-related risk alleles warrants replication in larger population-based cohorts consisting of persons of Mexican ancestry with thorough longitudinal follow-up for clinical end points," they wrote. "Future genetic-environment interaction studies may clarify the mechanisms underlying the heterogeneous effects of T2D-related genetic variants on mortality by ethnicity and BMI, and inform lifestyle intervention strategies directed at those with stronger genetic susceptibility to T2D-related mortality," they said.

Asked if the genetic risk impacted mortality even in people who did not develop type 2 diabetes, co-author Aaron Leong, MD, also from Harvard, told MedPage Today via email that "we unfortunately couldn't determine whether the excess mortality risk associated with a higher T2D genetic predisposition occurred only among those who did develop T2D within their lifetime, as we do not have data on new cases of T2D during follow-up."

"So it is possible that the higher genetic risk for T2D impacts mortality risk even if a person does not develop diabetes; however, we could not test this specific hypothesis," Leong said.

"In sum, in the U.S., carriers of more T2D risk-raising alleles have a higher mortality risk than non-carriers, suggesting that having a higher genetic burden for the development of T2D may increase the mortality risk. The underlying genetic basis of mortality likely involves complex interactions with non-genetic factors related to ethnicity, T2D, or body weight," the authors stated. "In the midst of a T2D and obesity co-epidemic from an increasingly obesogenic environment, maintaining a normal body weight may be especially important for lowering mortality risk in individuals with a high genetic predisposition to T2D."

The study had some limitations, namely the researchers were unable to distinguish type 1 diabetes from type 2 diabetes, and the study was underpowered to demonstrate an association between genetic risk score and specific causes of death.