A high level of circulating triglycerides is a risk factor for type 2 diabetes, myocardial infarction, ischemic heart disease, and all-cause mortality (1-4). A recent Mendelian randomization study supports a causal effect of triglycerides on coronary heart disease risk (5). Regulation of blood levels of triglycerides involves a complex interplay implicating both the liver and pancreas. Some of the important players in this regard are body adiposity, insulin resistance, and glucose homeostasis (6). In addition, circulating triglyceride levels are heritable, as shown in a recent population-based study of twins (H 2 = 0.59; h 2 = 0.33) (7). Genetic association studies have identified more than 40 SNPs Abstract Blood concentrations of triglycerides are influenced by genetic factors as well as a number of environmental factors, including adiposity and glucose homeostasis. The aim was to investigate the association between a serum triglyceride weighted genetic risk score (wGRS) and changes in fasting serum triglyceride level over 5 years and to test whether the effect of the wGRS was modified by 5 year changes of adiposity, insulin resistance, and lifestyle factors. A total of 3,474 nondiabetic individuals from the Danish Inter99 cohort participated in both the baseline and 5 year follow-up physical examinations and had information on the wGRS comprising 39 genetic variants. In a linear regression model adjusted for age, sex, and baseline serum triglyceride, the wGRS was associated with increased serum triglyceride levels over 5 years [per allele effect = 1.3% (1.0-1.6%); P = 1.0 × 10 17 ]. This triglyceride-increasing effect of the wGRS interacted with changes in insulin resistance (P interaction = 1.5 × 10
6). This interaction indicated that the effect of the wGRS was stronger in individuals who became more insulin resistant over 5 years. In conclusion, our findings suggest that increased genetic risk load is associated with a larger