A genetic risk score for fasting plasma glucose is independently associated with arterial stiffness: a Mendelian randomization study

BACKGROUND: Arterial stiffness is known to be associated with a number of clinical conditions including hypertension, diabetes and dyslipidemia, and may predict cardiovascular events and mortality. However, causal links are hard to establish. Results from genome-wide association studies have identified only a few single nucleotide polymorphisms associated with arterial stiffness, the results have been inconsistent between studies and overlap with other clinical conditions is lacking. Our aim was to investigate a potential shared set of risk single nucleotide polymorphisms between relevant cardiometabolic traits and arterial stiffness. METHOD: The study population consisted of 2853 individuals (mean age 72 years, 40% men) from the population-based Malmö Diet and Cancer study, Sweden. Carotid–femoral pulse wave velocity, a marker of arterial stiffness, was measured with Sphygmocor. Mendelian randomization analyses were performed using the two-stage least square regression and multivariate inverse-variance weighted methods. RESULTS: There were positive associations between arterial stiffness and genetic risk scores for type 2 diabetes (β = 0.03, P = 0.04) and fasting plasma glucose (β = 0.03, P = 0.03), but not for systolic blood pressure, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides. Multivariate inverse-variance weighted methods confirmed the significant positive association for fasting plasma glucose β coefficients (P = 0.006), but not for type 2 diabetes β coefficients (P = 0.88). CONCLUSION: Genetically elevated fasting plasma glucose, but not genetically elevated risk of type 2 diabetes, was associated with arterial stiffness suggesting a causal stiffening effect of glycemia on the arterial wall, independently of type 2 diabetes.