Elsevier

Neurobiology of Aging

Volume 33, Issue 3, March 2012, Pages 629.e1-629.e3
Neurobiology of Aging

Genetic reports abstract
No association of ALOX5AP polymorphisms with risk of MRI-defined brain infarcts

https://doi.org/10.1016/j.neurobiolaging.2011.10.010Get rights and content

Abstract

The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene has been associated with stroke. The majority of the reported ALOX5AP associations have considered non-radiologically confirmed infarcts as the stroke phenotype. We assessed the association of genetic variants in ALOX5AP with stroke defined by the presence of infarcts on brain magnetic resonance imaging (MRI). We studied 202 persons with MRI-defined brain infarcts and 487 healthy individuals of Caribbean Hispanic ancestry. Another sample of European ancestry comprised 1823 persons with MRI-defined brain infarct and 7578 control subjects. Subjects were genotyped for the 4 single nucleotide polymorphisms (SNPs) that define ALOX5AP HapA haplotype. No association was found between SNPs and MRI-defined brain infarcts. Our data do not support the hypothesis that variants in ALOX5AP are associated with risk of MRI-defined brain infarcts.

Introduction

The genome-wide linkage scan published by deCODE (Helgadottir et al., 2004) implicated single nucleotide polymorphisms (SNPs) and haplotypes in the ALOX5AP and PDE4D genes in ischemic stroke (IS) in the Icelandic population. Their results identified a haplotype in the ALOX5AP gene, HapA, defined by the SNPs SG13S25 (rs17222814), SG13S114 (rs10507391), SG13S89 (rs4769874), and SG13S32 (rs9551963), which conferred an increased risk of myocardial infarction (haplotype frequency = 0.16, relative risk [RR] = 1.80) and stroke (haplotype frequency = 0.15, RR = 1.67). However, replication of these results in other populations has proven difficult (Zee et al., 2006).

Failure to replicate associations between ALOX5AP variants and stroke could have been due to the diagnosis of stroke on medical records only (Quarta et al., 2009). The sensitivity of self-reported history of clinical stroke has been questioned because it is likely that patients with ambiguous symptoms or silent strokes are underestimated, leading to a higher rate of false-negative results. Results using the Washington Heights Inwood Columbia Aging Project (WHICAP) cohort (Reitz et al., 2009) suggest that when using magnetic resonance imaging (MRI) scans as validation, the sensitivity and specificity of stroke self-report are low, validating the use of neuroimaging techniques to confirm a diagnosis of stroke based on the history.

The present study was designed to confirm or refute an association between MRI-defined brain infarcts (MRI infarcts) and SNPs in ALOX5AP using 2 different cohorts, i) a community-based predominantly Hispanic case-control sample from the WHICAP and ii) the published GWAS results from the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium meta-analysis.

Section snippets

Methods

The Caribbean Hispanic population consisted of 202 MRI infarct cases and 487 control subjects. The 4 SNPs that define the Hap A haplotype—SG13S25 (rs17222814), SG13S114 (rs10507391), SG13S89 (rs4769874), and SG13S32 (rs9551963)—were genotyped at the Illumina Genotyping Service Center (San Diego, CA). The CHARGE consortium includes 6 large, prospective, community-based cohort studies that have genome-wide variation data coupled with extensive data on multiple phenotypes. Clinical evaluation and

WHICAP cohort. Demographic and risk factor case-control differences

After comparing cases and controls for demographic variables, we found a significantly higher proportion of men than women among MRI stroke cases (p = 0.04). The cases differed from controls by having a higher frequency of hypertension and myocardial infarction. Only the presence of hypertension and previous myocardial infarction were associated with MRI infarct (Supplemental Table 1). No statistical differences were observed between cases and controls when comparing the distribution of SNP

Discussion

We found no association between ALOX5AP SNPs and MRI infarcts, suggesting that the SNP associations previously reported might not be risk factors for MRI infarcts. This is the first study that specifically examines the role of ALOX5AP SNPs using MRI-defined infarcts in both Hispanic and Caucasian community-based samples. Although the initial reports (Helgadottir et al., 2004) claimed an association between ALOX5AP and stroke, subsequent independent efforts failed to replicate the initial

Disclosure statement

The authors disclose no actual or potential conflicts of interest.

Acknowledgements

We acknowledge Dr. DeCarli and the Imaging of Dementia and Aging (IDeA) laboratory for their work in MRI infarct detection under subcontract to P01 AG0027232. We thank all the members of the CHARGE Neurology Working group: Aging Gene-Environment Susceptibility-Reykjavik Study, The Atherosclerosis Risk in Communities Study, The Austrian Stroke Prevention Study, Cardiovascular Health Study, Framingham Heart Study, and Rotterdam Study.

References (8)

  • A.M. Brickman et al.

    Brain morphology in older African Americans, Caribbean Hispanics, and whites from northern Manhattan

    Arch Neurol

    (2008)
  • S. Debette et al.

    Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium

    Stroke

    (2010)
  • W.J. Gauderman

    Sample size requirements for matched case-control studies of gene-environment interaction

    Stat Med

    (2002)
  • A. Helgadottir et al.

    The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

    Nat Genet

    (2004)
There are more references available in the full text version of this article.

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    In addition to the SNPs comprising the HapA and HapB risk haplotypes identified in the European studies, other ALOX5AP SNPs have been associated with ischemic stroke in various populations.25–27 Contrasting results reporting no association are equally abundant in the literature.28–30 Our results, like many others, show no evidence of a link between ALOX5AP SNP genotypes and risk of stroke in a southeastern Chinese population.

  • Mammalian lipoxygenases and their biological relevance

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    For example, the findings originally made in the Icelandic cohort were replicated in Scottish and Spanish [313], but not in a Swedish [314] population. One U.S.-based study did not confirm this connection [315], while another found an association for Americans of European, but not of African descent [316]. Similarly, studies of Chinese populations in some cases confirmed the original results, in others did not; but a recent meta-analysis concluded that the link could be confirmed in the Chinese population [317].

  • Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene rs4073259 polymorphism not associated with ischemic stroke in the Northeastern Chinese Han population

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    The same research group also found another haplotype, i.e., Hap B, was closely associated with the incidence of myocardial infarction in individuals from United Kingdom [22]. In contrast, another study found that ALOX5AP polymorphism had no association with MRI-defined brain infarcts [23]. However, there were only a few studies reporting the association of ALOX5AP rs4073259 with IS [24,25].

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