A diabetes‐associated genetic variant is associated with diastolic dysfunction and cardiovascular disease

AIMS: Although the epidemiological association between Type 2 diabetes and congestive heart failure (CHF) as well as cardiovascular disease (CVD) is well established, associations between diabetes‐related single‐nucleotide polymorphisms (SNPs), CHF, and CVD have been surprisingly inconclusive. Our aim is to examine if 43 diabetes‐related SNPs were associated with prevalent diastolic dysfunction assessed by echocardiography and incident CVD and/or CHF. METHODS AND RESULTS: We genotyped 43 SNPs that previously reported genome‐wide significant associations with Type 2 diabetes, in 1444 subjects from the population‐based Malmö Preventive Project‐Re‐examination Study (MPP‐RES) (mean age 68 years; 29% women, 36% prevalent diabetes) (discovery cohort) and in 996 subjects from the VARA cohort (mean age 51 years, 52% women, 7% prevalent diabetes) (replication cohort). Multivariable logistic regression was assessed. Genetic variants that reached significant association with diastolic dysfunction in both cohorts were then analysed for association with incident CVD/CHF in a larger sample of the MPP‐RES cohort (3,407 cases and 11,776 controls, median follow up >30 years) using Cox regression analysis. A common variant at the HNF1B [major allele (T) coded, also the risk allele for diabetes] was the only SNP associated with increased risk of prevalent diastolic dysfunction in both the discovery [MPP‐RES; odds ratio (OR) 1.21, P = 0.024), and the replication cohort (VARA; OR 1.38, P = 0.042]. Cox regression analysis showed that carriers of the T‐allele of rs757210 had an increased risk of future CVD (HR 1.05, P = 0.042). No significant association was seen for incident CHF. CONCLUSIONS: The diabetes susceptibility locus HNF1B is associated with prevalent diastolic dysfunction in two independent Swedish cohorts as well as incident cardiovascular disease.