Aug 29, 2012 - Methods: At our large regional academic medical center 65,950 patients ...... Le Chesnay, France; 2Hospital Andre Mignot, Le Chesnay, France.
Wednesday, 29 August 2012
Bench to practice: clues from the genes
BENCH TO PRACTICE: CLUES FROM THE GENES 5184 A blood pressure genetic risk score predicts incident cardiovascular events in 36,950 Finnish individuals V. Salomaa 1 , A.S. Havulinna 1 , J. Kettunen 1 , J. Eriksson 1 , A. Jula 2 , K. Kontula 3 , C. Newton-Cheh 4 . 1 National Institute for Health and Welfare, Helsinki, Finland; 2 National Institute for Health and Welfare, Turku, Finland; 3 University of Helsinki, Department of Medicine, Helsinki, Finland; 4 Massachusetts General Hospital, Center for Human Genetic Research and Cardiovascular Research Center, Boston, United States of America Background and purpose: Recent genome-wide association studies (GWAS) have identified several genetic variants associated with blood pressure (BP). We investigated whether genetic risk scores (GRS) constructed of these variants would be significant predictors for incident cardiovascular (CVD) events in the prospective, population-based setting. Methods: We genotyped 33 genome-wide significant variants in several Finnish cohorts (FINRISK 1992, 1997, 2002, 2007, Health 2000 and the Helsinki Birth Cohort), altogether in 36,950 individuals. Persons with prevalent CVD at baseline were excluded and the cohorts were followed for events through December 31, 2009. GRS were constructed for each individual by summing BP elevating alleles weighted by the beta coefficients from the earlier GWAS, separately for systolic and diastolic BP. We used Cox proportional hazards regression, adjusting for relevant covariates, for analyzing various complications of high BP, including incident coronary events (myocardial infarction, coronary death and revascularization), incident stroke, and their combination (incident CVD). The results were summarized with inverse variance weighted meta-analysis. Results: Cross-sectional analysis of baseline data confirmed associations of most GWAS hits for systolic and diastolic BP. GRS were strong predictors for systolic and diastolic BP and hypertension (all p10%), were included in pair-wise SNP-SNP exhaustive interaction analysis using two stage statistical approach employing logistic regression for additive allelic interaction models (PLINK and INTERSNP software packages). Results: None of the analysed SNP-SNP interactions was statistically significant after correction for multiple testing (P= 7.8 X 10-10). The most significant interaction identified in this analysis was between rs9840469 (FRMD4B) on chromosome 3 and rs10911935 (PLA2G4A) on chromosome 1 (P= 4.63 X 10-7). Analysis of subsets of SNPs pre-selected based on their nominal association with CAD (p1.2 Pa) ESS at baseline. The segments at followup were categorized in terciles of low, medium and high MHC-II and CD45 content. The expression of matrix-degrading proteases (MMP-2, MMP-9, MMP-12, Cathepsins K, L, S) and their inhibitors (TIMP-1, TIMP-2, Cystatin C) in the intima-media were measured by RT-PCR. Results: Thin-cap atheromas were evident in 79% of segments with high adventitial MHC-II but only in 46% of those with medium/low adventitial MHC-II (p
