Type 2 Diabetes Genetic Predisposition, Obesity, and All-Cause Mortality Risk in the U.S.: A Multiethnic Analysis

Type 2 diabetes (T2D) is associated with increased mortality in ethnically diverse populations, although the extent to which this association is genetically determined is unknown. We sought to determine whether T2D-related genetic variants predicted all-cause mortality, even after accounting for BMI, in the Third National Health and Nutrition Examination Survey.

We modeled mortality risk using a genetic risk score (GRS) from a weighted sum of risk alleles at 38 T2D-related single nucleotide polymorphisms. In age-, sex-, and BMI-adjusted logistic regression models, accounting for the complex survey design, we tested the association with mortality in 6,501 participants. We repeated the analysis within ethnicities (2,528 non-Hispanic white [NHW], 1,979 non-Hispanic black [NHB], and 1,994 Mexican American [MA]) and within BMI categories (<25, 25-30, and ≥30 kg/m(2)). Significance was set at P < 0.05.

Over 17 years, 1,556 participants died. GRS was associated with mortality risk (OR 1.04 [95% CI 1.00-1.07] per T2D-associated risk allele, P = 0.05). Within ethnicities, GRS was positively associated with mortality risk in NHW and NHB, but not in MA (0.95 [0.90-1.01], P = 0.07). The negative trend in MA was largely driven by those with BMI <25 kg/m(2) (0.91 [0.82-1.00]). In NHW, the positive association was strongest among those with BMI ≥30 kg/m(2) (1.07 [1.02-1.12]).

In the U.S., a higher T2D genetic risk was associated with increased mortality risk, especially among obese NHW. The underlying genetic basis for mortality likely involves complex interactions with factors related to ethnicity, T2D, and body weight.