Whole Genome Analyses Suggest Ischemic Stroke and Heart Disease Share an Association With Polymorphisms on Chromosome 9p21

Stroke (Impact Factor: 5.72). 05/2008; 39(5):1586-9. DOI: 10.1161/STROKEAHA.107.502963
Source: PubMed


Recently independent studies reported an association between coronary heart disease and single-nucleotide polymorphisms (SNPs) located at chromosome 9p21, near CDKN2A and CDKN2B genes. Given that stroke is a common complication after myocardial infarction, we investigated if the same SNPs were associated with ischemic stroke in our population.
We recently initiated a whole genome analysis of ischemic stroke and published the first stage of a case control study using >400,000 SNPs from Illumina Infinium Human-1 and HumanHap300 assays. We focused on SNPs recently associated with heart disease by Helgadottir and colleagues and SNPs from the same haplotype block.
In analyses both unadjusted and adjusted for stroke risk factors, significant associations with ischemic stroke were observed for SNPs from the same haplotype block previously associated with myocardial infarction. Significant association was also seen between disease and haplotypes involving these SNPs, both with and without adjustment for stroke risk factors (odd ratios: 1.01 to 2.65).
These data are important for 3 reasons: first, they suggest a genetic association for stroke; second, they suggest that this association shares pathogenic mechanisms with heart disease and diabetes; and third, they illustrate, that public release of data can facilitate rapid risk locus discovery.

Download full-text


Available from: Mar Matarin, Jul 03, 2014
  • Source
    • "The 9p21 region also contains two adjacent, but separate, T2D signals; a strong signal mapped to a 2 kb LD-block (represented by rs10811661 and rs10757282) and a putatively independent second signal (rs564398) located ∼100 kb from the T2D interval [9] [10] [11]. After the initial genome-wide association studies (GWASs), several investigations confirmed the association with the 9p21 candidate SNPs in T2D [12] [13] [14] [15] [16] [17] and CVD [18– 24] and extended the number of CVD phenotypes associated with the region [25] [26] [27] [28] [29] [30]. A shared mechanistic link might "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background. Two adjacent regions upstream CDKN2B on chromosome 9p21 have been associated with type 2 diabetes (T2D) and progression of cardiovascular disease (CVD). The precise location and number of risk variants have not been completely delineated and a possible synergistic relationship between the adjacent regions is not fully addressed. By a population based cross-sectional case-control design, we genotyped 18 SNPs upstream of CDKN2B tagging 138 kb in and around two LD-blocks associated with CVD and T2D and investigated associations with T2D, angina pectoris (AP), myocardial infarction (MI), coronary heart disease (CHD; AP or AMI), and stroke using 5,564 subjects from HUNT2. Results. Single point and haplotype analysis showed evidence for only one common T2D risk haplotype (rs10757282∣rs10811661: OR = 1.19, ) in the region. We confirmed the strong association between SNPs in the 60 kb CVD region with AP, MI, and CHD . Conditioning on the lead SNPs in the region, we observed two suggestive independent single SNP association signals for MI, rs2065501 and rs3217986 . Conclusions. We confirmed the association of known variants within the 9p21 interval with T2D and CHD. Our results further suggest that additional CHD susceptibility variants exist in this region.
    International Journal of Endocrinology 06/2015; 2015:1-9. DOI:10.1155/2015/164652 · 1.95 Impact Factor
  • Source
    • "They are helpful for structuring classification and identifying the changes that took place in genes over the course of time. Recently genetic (Floßmann et al., 2004; Jerrard-Dunne et al., 2003) and genomic (Matarin et al., 2008) studies are greatly contributing to the study of brain and genetically transmitted diseases. Advanced studies have shown that certain genes can be mutated or deactivated (Li et al., 2008) to reduce the risks of these diseases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: One of the most communal causes of death in the world and the foremost cause of severe, long-standing disability is Ischemic Stroke. There is an imperative need for automated techniques and mechanisms to pre diagnose people at high risk of ischemic stroke. Genetics as well as phenotypes of the visible symptoms contribute highly to the risk of stroke. There is a compelling need of post analysis and follow up checkups to prevent further strokes. A lot of research is being carried out on computer based automated techniques and mechanisms for estimation of Ischemic Stroke risk evaluation. A comparative study of different Carotid Imaging Techniques is being reported in this paper. Also the Work done by different researchers to estimate the Ischemic Stroke risk by using different feature sets is also reviewed. In depth knowledge of the preprocessing involved before actual analysis to achieve the results is also covered. Carotid Artery morphology, noise and artifacts in the Carotid images can lead to false classification. Historical patterns can facilitate improvement and accuracy of the risk evaluation. Genes trees can help take into account the genetic risk factors and gene mutations. The historical patterns can be extracted using these trees from the sampled group of data. Keeping these facts in view, we have also proposed an improved classification model for estimation of Ischemic Stroke risk. This model considers the Carotid Image Features and the Genetic Features.
  • Source
    • "At the same time, genetic variants around the same genes were associated with an increased risk of type 2 diabetes mellitus [14-16] atherothrombosis [17] and ischemic stroke [18]. All these data suggest that there may be common pathogenic mechanisms involved in these apparently disparate diseases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated whether 9p21 polymorphisms are associated with cardiovascular events in a group of 611 patients enrolled in the Medical, Angioplasty or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease (CAD) and preserved left ventricular function. The participants of the MASS II were genotyped for 9p21 polymorphisms (rs10757274, rs2383206, rs10757278 and rs1333049). Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, death from cardiac causes and myocardial infarction using a Cox proportional hazards survival model. We observed significant differences between patients within each polymorphism genotype group for baseline characteristics. The frequency of diabetes was lower in patients carrying GG genotype for rs10757274, rs2383206 and rs10757278 (29.4%, 32.8%, 32.0%) compared to patients carrying AA or AG genotypes (49.1% and 39.2%, p = 0.01; 52.4% and 40.1%, p = 0.01; 47.8% and 37.9%, p = 0.04; respectively).Significant differences in genotype frequencies between double and triple vessel disease patients were observed for the rs10757274, rs10757278 and rs1333049. Finally, there was a higher incidence of overall mortality in patients with the GG genotype for rs2383206 compared to patients with AA and AG genotypes (19.5%, 11.9%, 11.0%, respectively; p = 0.04). Moreover, the rs2383206 was still significantly associated with a 1.75-fold increased risk of overall mortality (p = 0.02) even after adjustment of a Cox multivariate model for age, previous myocardial infarction, diabetes, smoking and type of coronary anatomy. Our data are in accordance to previous evidence that chromosome 9p21 genetic variation may constitute a genetic modulator in the cardiovascular system in different scenarios. In patients with established CAD, we observed an association between the rs2383206 and higher incidence of overall mortality and death from cardiac causes in patients with multi-vessel CAD.
    BMC Cardiovascular Disorders 08/2012; 12(1):61. DOI:10.1186/1471-2261-12-61 · 1.88 Impact Factor
Show more