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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.

SUBMITTER: Patel RS

PROVIDER: S-EPMC4127881 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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A genetic risk variant for myocardial infarction on chromosome 6p24 is associated with impaired central hemodynamic indexes.

Patel Riyaz S RS Morris Alanna A AA Ahmed Yusuf Y Kavtaradze Nino N Sher Salman S Su Shaoyong S Zafari A Maziar AM Din-Dzietham Rebecca R Waddy Salina P SP Vaccarino Viola V Alexander R Wayne RW Gibbons Gary G Quyyumi Arshed A AA

American journal of hypertension 20120419 7

<h4>Background</h4>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.<h4>Methods</h4>Single-nucleotide polymorphisms (SNPs) at eight MI risk loci were genotyped and correlated with noninvasively determine ...[more]

PMID: 22513829

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Project description:BACKGROUND: Genetic variation at 1p13 modulates serum lipid levels and the risk of coronary heart disease through the regulation of serum lipid levels. Here we investigate if the interaction between genetic variants at 1p13 and serum lipid levels affects the risk of non-fatal myocardial infarction (MI) in the Stockholm Heart Epidemiology Program (SHEEP), a large population based case control study. METHODS: In the present study only non fatal MI cases (n?=?1213, men/women: 852/361) and controls (n?=?1516, men/women =1054/507) matched by age, sex and residential area, were included. Three SNPs 12740374?G/T, rs599839A/G and rs646776T/C mapping at 1p13 were analysed for association with serum lipid levels and the risk of MI by a weighted least square regression and logistic regression analyses, respectively. To analyse the effect of the interaction between genetic variants and serum lipid levels on the risk of MI, we applied the biological model of interaction that estimates the difference in risk, expressed as OR (95%CI), observed in the presence and in the absence of both exposures. One derived measure is the Synergy index (S) and 95%CI, where S?>?1 indicates synergy and S?<?1 antagonism between the two interaction terms. RESULTS: Rs12740374G/T and rs646776T/C were in strong linkage disequilibrium (LD) (r2?=?0.99), therefore only rs599839A/G and rs646776 were included in the analysis. Consistently with published data, presence of the rare genotypes was associated with reduced total-, LDL-cholesterol and ApoB serum levels (all p?<?0.05) as compared to the reference genotype, but was not associated with the risk of MI.However, the increased risk of MI observed in individual exposed to high (?75th percentile) serum lipid levels was offset in subjects carrying the rare alleles G and C. In particular, the risk of MI associated with high ApoB serum levels OR (95%CI) 2.27 (1.86-2.77) was reduced to 1.76 (1.33-2.34) in the presence of the G allele at rs599839 with an S of 0.47 (0.20-0.90). CONCLUSIONS: These results indicate that an antagonism between ApoB serum levels and genetic variants at 1p13 contributes to reduce the risk of non-fatal MI in the presence of high ApoB serum levels.

Dataset Information

A genetic risk variant for myocardial infarction on chromosome 6p24 is associated with impaired central hemodynamic indexes.

Publications

A genetic risk variant for myocardial infarction on chromosome 6p24 is associated with impaired central hemodynamic indexes.

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