Abstract P226: Exploring the Impact of Genetics for a General Cardiovascular Health Phenotype
A large number of genetic factors have recently been robustly associated with various individual cardiovascular traits, but less is known about genetic determinants of overall cardiovascular health; a trait that may reflect pleiotropic effects, as well as pathways involved in longevity. In order to find genetic factors responsible for maintaining general cardiovascular health, we performed meta-analyses of genome-wide association (GWA) data from two population-based cohorts. The TWINGENE cohort includes twins from Sweden born before 1958 (mean age, 64.9 years; 55% women), and the ULSAM cohort includes men born between 1920 and 1924 in Uppsala County, Sweden (mean age at DNA draw, 71.0 years). The present study was performed in 10,844 participants (9,740 and 1,104 from TWINGENE and ULSAM, respectively) with complete data on genotypes (Illumina OmniExpress in TWINGENE and Illumina CardioMetabochip in ULSAM) and phenotypes. Individuals without previously known coronary heart disease (CHD), heart failure, stroke, diabetes and hypertension, who had normal BMI (18.5-24.9 kg/m2), were normotensive (systolic blood pressure ≤140 mmHg), and had a preferable lipid profile (ratio of total cholesterol/high density lipoprotein ≤4.0) and HbA1c levels <6.5% were defined as cardiohealthy. We performed single marker association analyses with the cardiohealth phenotype as outcome using an additive genetic model adjusting for age, sex and smoking in PLINK (taking twinness into account for TWINGENE cohort). Summary statistics were subsequently meta-analyzed using inverse variance method in METAL. A total of 1,075 individuals (mean age, 61.5 years; 73% women) in TWINGENE and 54 individuals (mean age, 71.0 years) in the ULSAM cohort were identified as cardiohealthy. A non-synonymous variant (rs5880; Ala390Pro) in the CETP gene showed the strongest evidence for association (1.8*10-7). CETP encodes cholesteryl ester transfer protein, a key regulator of reverse cholesterol transport, and variants in this gene have been associated with several cardiovascular traits in recent GWA studies, such as CHD, metabolic syndrome and lipid fractions. Other genetic variants showing borderline significant association with the cardiohealthy phenotype included variants in or near ACCN1 that has been associated with factor VIII and von Willebrand factor, ATP6V04A that has been associated with F-cell level and SNX10 with smoking behavior. In the present meta-analysis comprising 10,844 individuals from the general population, we identified several genetic variants exhibiting suggestive association with cardiohealthy status. A few of these variants may exhibit pleiotropic effect modulating various risk factors involved simultaneously, thereby contributing towards cardiohealthy outcome. We are currently pursuing further replication and biological follow-up studies of these potential associations.
- © 2012 by American Heart Association, Inc.