Association between the Gene Encoding 5-Lipoxygenase–Activating Protein and Stroke Replicated in a Scottish Population

deCODE Genetics, Reykjavik, Iceland.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2005; 76(3):505-9. DOI: 10.1086/428066
Source: PubMed

ABSTRACT Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase-activating protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP in cardiovascular diseases.

Download full-text


Available from: Mary Joan Macleod, Sep 26, 2015
19 Reads
  • Source
    • "More specifically HapA, defined by four SNPs (SG13S25, SG13S114-rs 10507391, SG13S89-rs4769874, and SG13S32) in the first four exons, had been recognized as the most strongly associated with stroke and myocardial infarction (Helgadottir et al., 2004). The association between HapA and stroke was later replicated in a Scottish population from Aberdeenshire (Helgadottir et al., 2005). More recently an association between two SNPs (SG13S106-rs9579646 and SG13S89- rs4769874) in white stroke patients (Kaushal et al., 2007) was reported. "
    [Show abstract] [Hide abstract]
    ABSTRACT: ALOX5AP (5-lipoxygenase) has been recognized as a susceptibility gene for stroke. Using a case-control design, the whole coding and adjoining intronic regions of ALOX5AP was sequenced to study the role of SNPs and their interplay with other risk factors in Greek patients with stroke. Patients (n=213) were classified by the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Their mean age of was 58.9±14.64, comprising 145 males. The control group consisted of 210 subjects, ethnicity, sex and age matched, with no stroke history. Risk factors (hyperlipidemia, hypertension, atrial fibrillation, migraine, CAD, diabetes, smoking and alcohol consumption) were assessed as confounding factors and comparisons were done using logistic regression analysis. SNPs rs4769055, rs202068154 and rs3803277 located in intronic regions of the gene and according to in silico programs EX_SKIP and HSF possibly affecting splicing of exons 1 and 2 of ALOX5AP, showed significantly different frequencies between patients and controls. The genotype frequencies of rs4769055: AA, of rs202068154: AC and of rs3803277: CA were significantly higher (p<0.001, 0.058) in controls than in patients. The results were indicative of a protective role of the three SNPs either in homozygosity or heterozygosity for MAF and more specifically rs3803277: CA/AA genotypes were protective against SVO stroke subtype.
    Gene 07/2014; 548(1). DOI:10.1016/j.gene.2014.07.007 · 2.14 Impact Factor
  • Source
    • "ALOX5AP genetic variants have been linked to heightened inflammation, an undisputed cause of MI/CAD. Subsequently, these investigators reported that ALOX5AP was associated with CAD in British and stroke in Icelandic and Scottish populations (Helgadottir et al., 2005). We also found an association between an at-risk allele of the ALOX5AP gene and in a small sample of patients with acute coronary syndrome in the United States (Wung & Aouizerat, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: This article provides an update on cardiovascular genomics using three clinically relevant exemplars, including myocardial infarction (MI) and coronary artery disease (CAD), stroke, and sudden cardiac death (SCD). Organizational Construct: Recent advances in cardiovascular genomic research, testing, and clinical implications are presented. Methods: Genomic nurse experts reviewed and summarized recent salient literature to provide updates on three selected cardiovascular genomic conditions. Findings: Research is ongoing to discover comprehensive genetic markers contributing to many common forms of cardiovascular disease (CVD), including MI and stroke. However, genomic technologies are increasingly being used clinically, particularly in patients with long QT syndrome (LQTS) or hypertrophic cardiomyopathy (HCM) who are at risk for SCD. Conclusions: Currently, there are no clinically recommended genetic tests for many common forms of CVD even though direct-to-consumer genetic tests are being marketed to healthcare providers and the general public. On the other hand, genetic testing for patients with certain single gene conditions, including channelopathies (e.g., LQTS) and cardiomyopathies (e.g., HCM), is recommended clinically. Clinical Relevance: Nurses play a pivotal role in cardiogenetics and are actively engaged in direct clinical care of patients and families with a wide variety of heritable conditions. It is important for nurses to understand current development of cardiovascular genomics and be prepared to translate the new genomic knowledge into practice.
    Journal of Nursing Scholarship 01/2013; 45(1). DOI:10.1111/jnu.12002 · 1.64 Impact Factor
  • Source
    • "ALOX5 activity has been implicated in plaque formation (Spanbroek et al., 2003) and plaque instability (Qiu et al., 2006), and a promoter region variation has been associated with carotid intima-media thickness (Dwyer et al., 2004). Results from two populationbased studies show a six SNP haplotype in the ALOX5AP gene predicts risk of myocardial infarction (MI; Helgadottir et al., 2004, 2005). Nicotinamide adenine dinucleotide phosphate oxidase is a major source of superoxide in the vasculature, and the p22phox subunit of NAD(P)H oxidase has been spatially associated with oxidized LDL and reactive oxygen species production in atherosclerotic plaques (Azumi et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress has been implicated in all stages of atherosclerosis, but how inherited variations in oxidative stress genes influence the severity of cardiovascular disease is not known. We tested associations between polymorphisms in candidate oxidative stress genes, plasma oxidative stress biomarkers, and cardiovascular mortality in an angiography cohort. Single nucleotide polymorphisms (SNPs) across 15 genes were selected by linkage disequilibrium tagging. Genotyping was performed using customized arrayed primer extension micro-arrays, with automated genotype calling methods. Effects of SNPs and haplotypes on plasma oxidative stress and coronary artery disease (CAD) were estimated using a stochastic estimation maximization algorithm. Proportionate hazards analyses were used to determine effects of single and combined genetic markers on cardiovascular mortality risk, and on the following oxidative stress biomarkers: myeloperoxidase (MPO), nitrotyrosine, oxidized low-density lipoprotein, and antioxidant capacity. Oxidative stress gene SNPs associated with CAD were combined into an oxidative stress risk allele score, which predicted disease presence (1.5-fold risk increase per allele, P < 0.001). Combined risk alleles were also associated with elevated plasma MPO (P < 0.003), an oxidative stress biomarker that predicts cardiovascular mortality. Genetic markers that represent lifetime oxidative stress burden may implicate specific oxidative stress pathways in the pathogenesis of atherosclerosis, and offer therapeutic opportunities.
    Annals of Human Genetics 11/2012; 76(6):435-447. DOI:10.1111/j.1469-1809.2012.00731.x · 2.21 Impact Factor
Show more