A Genetic Risk Variant for Myocardial Infarction on Chromosome 6p24 Is Associated With Impaired Central Hemodynamic Indexes
ABSTRACT Genome-wide association studies (GWAS) have identified novel variants associated with myocardial infarction (MI) in Caucasians. We hypothesized that those variants whose mechanism of risk is currently unknown, confer risk via pathways mediating arterial wave reflections which is an increasingly recognized risk factor for cardiovascular disease.
Single-nucleotide polymorphisms (SNPs) at eight MI risk loci were genotyped and correlated with noninvasively determined pulse wave analysis (PWA)-derived central hemodynamic indexes (augmentation index (AIx); augmented pressure (AP); time to reflected wave (TrW) and central systolic blood pressure (SBP) and diastolic BP (DBP)) in two independent Caucasian populations including (i) those free of measured cardiovascular risk factors (n = 133) and (ii) a community-based population (n = 270).
Of the eight SNPs examined in the healthy group, the variants at loci 6p24 (AIx and AP both P < 0.001, TrW P = 0.02) and 21q22 (AIx P = 0.002, TrW P = 0.037) were significantly associated with PWA indexes. In the replication group, only the 6p24 variant correlated with these phenotypes (AIx P = 0.005, AP P = 0.049, TrW P = 0.013). In the pooled population (n = 403), no new associations were identified but the association with 6p24 and AIx remained significant even after Bonferroni correction and adjustment for covariates including age, mean arterial pressure, height, gender, glucose, cholesterol, body mass index (BMI), and smoking (AIx (P = 0.03)). Each copy of the risk allele C increased the AIx by 3.5%.
The GWAS discovered MI risk variant at 6p24 in the protein phosphatase 1 regulator gene (PHACTR1) is associated with adverse arterial wave reflection indexes and may mediate MI risk through this pathway.
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ABSTRACT: Our aim was to examine the relative contributions of the first systolic shoulder (P1) and augmentation pressure (DeltaP(aug)) to central pulse pressure (cPP), their relation to central arterial stiffness (pulse wave velocity [PWV]) and arterial diameters, and their respective heritability estimates. cPP is augmented above P1 by DeltaP(aug) due to pressure waves reflected from the periphery of the circulation. Women (n = 496) from the Twins UK adult twin registry (112 monozygotic, 135 dizygotic pairs) age 21 to 81 years were studied. cPP, P1, and DeltaP(aug) were estimated using the SphygmoCor system (Atcor, West Ryde, Australia) from transformed radial waveforms. Carotid-femoral PWV was measured using the same system. Aortic and femoral artery diameters were measured by ultrasonography. Heritability was estimated using structural equation modeling. P1 and DeltaP(aug) accounted for 22% and 76%, respectively, of the variance in cPP. After adjustment for mean arterial pressure and heart rate, P1 strongly independently positively correlated with PWV (standardized regression coefficient, beta = 0.4, p < 0.0001), whereas DeltaP(aug) did not independently correlate with PWV but independently negatively correlated with the ratio of the diameter of the femoral to that of the abdominal aorta (beta = -0.12, p < 0.001). Estimates of heritability (h(2)) of cPP, PWV, P1, and DeltaP(aug) were 0.43, 0.34, 0.31, and 0.62, respectively, after adjustment for mean arterial pressure and heart rate. These results suggest that, in women, DeltaP(aug) is highly heritable, is associated with the ratio of distal to proximal arterial diameters, and, independent of PWV, is a major determinant of cPP.Journal of the American College of Cardiology 09/2009; 54(8):695-703. DOI:10.1016/j.jacc.2009.04.068 · 15.34 Impact Factor
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ABSTRACT: The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on chromosome 9p21. This study included a total of 4587 cases and 12,767 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated with the disease with high significance. Approximately 21% of individuals in the population are homozygous for this variant, and their estimated risk of suffering myocardial infarction is 1.64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases.Science 07/2007; 316(5830):1491-3. DOI:10.1126/science.1142842 · 31.48 Impact Factor
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ABSTRACT: Coronary heart disease (CHD) is a major cause of death in Western countries. We used genome-wide association scanning to identify a 58-kilobase interval on chromosome 9p21 that was consistently associated with CHD in six independent samples (more than 23,000 participants) from four Caucasian populations. This interval, which is located near the CDKN2A and CDKN2B genes, contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension, or diabetes. Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD.Science 07/2007; 316(5830):1488-91. DOI:10.1126/science.1142447 · 31.48 Impact Factor