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.