A Genetic Risk Variant for Myocardial Infarction on Chromosome 6p24 Is Associated With Impaired Central Hemodynamic Indexes

• Authors: Riyaz S. Patel, Emory University; Alanna Amyre Morris, Emory University; Yusuf Ahmed, Emory University; Nino Kavtaradze, Emory University; Salman Sher, Emory University; Shaoyong Su, Emory University; A. Maziar Zafari, Emory University; Rebecca Din-Dzietham, Morehouse School of Medicine; Salina P. Waddy, Emory University; Viola Vaccarino, Emory University; R Wayne Alexander, Emory University; Gary Gibbons, Morehouse School of Medicine; Arshed Ali Quyyumi, Emory University
• Journal Title: American Journal of Hypertension
• Volume: Volume 25, Number 7
• Publisher: Oxford University Press (OUP): Policy A - Oxford Open Option D | 2012-07, Pages 797-803
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/ajh.2012.41
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: 6p24; augmentation index; blood pressure; elasticity; genetic; genomic; GWAS; hypertension; myocardial infarction; SNP; stiffness

Abstract

Background 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. Methods 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). Results 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%. Conclusions 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.