Whole genome analyses suggest ischemic stroke and heart disease share an association with polymorphisms on chromosome 9p21

Stroke (Impact Factor: 6.02). 05/2008; 39(5):1586-9. DOI: 10.1161/STROKEAHA.107.502963
Source: PubMed

ABSTRACT 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 01/2015; 2015:1-9. DOI:10.1155/2015/164652 · 1.52 Impact Factor
  • Source
    • "The study of the 9p21 region with risk to CAD and MI has been replicated in most populations (Hiura et al., 2008; Meng et al., 2008; Shen et al., 2008b, Zhou et al., 2008; Chen et al., 2009; Lemmens et al., 2009; Wahlstrand et al., 2009; Zhang et al., 2009). In addition to CAD and MI, the locus 9p21 was also found to be associated with abdominal aortic aneurysm, rs10757278 (Bown et al., 2008; Helgadottir et al., 2008; Thompson et al., 2009), and stroke, rs1333040 and rs2383207 (Matarin et al., 2008), and rs2383207 and rs10757278 (Wahlstrand et al., 2009). Recently, the C allele (rs1333049) at the locus 9p21 has been associated with an "
    [Show abstract] [Hide abstract]
    ABSTRACT: The chromosomal region 9p21 has been reported to be associated with myocardial infarction, coronary artery disease (CAD), diabetes, and many other related multifactorial diseases in humans. Although the genome-wide association studies have identified a limited number of single-nucleotide polymorphisms (SNPs) at 9p21 for CAD risk, the role of flanking SNPs has not been studied so far. Therefore, in the present work, we studied the role of flanking SNPs with respect to that of the previously identified SNPs rs10757278 and rs2383207 at 9p21 among the Indian subjects found to have CAD (n = 414) along with age- and sex-matched control subjects (n = 408). Our study replicated the association of genome-wide association studies that had identified SNPs rs2383207 (p = 4.7 × 10(-5)) and rs10757278 (p = 5.5 × 10(-5)) among Indians with CAD. Further, we evaluated nine additional SNPs, of which two SNPs flanking rs2383207 (rs1537375 [p = 2.4 × 10(-5)] and rs1537374 [p = 5.6 × 10(-5)]) were also strongly associated with CAD. The haplotypes constructed using four risk SNPs revealed that the haplotypes with combinations of rs10757278 showed CAD risks, whereas the minor alleles of rs2383207, rs1537375, and rs1537374 in combinations reduce the CAD risks substantially. Our study demonstrates that the variation in the chromosomal region 9p21 is involved in modifying progression toward CAD among Indians and the risk may be variable, contributed by the SNPs that are flanking previously identified SNPs.
    DNA and cell biology 02/2011; 30(2):105-10. DOI:10.1089/dna.2010.1046 · 1.99 Impact Factor
  • Source
    • "These findings link for the first time a locus previously implicated in the pathogenesis of atherothrombotic events (9p21.3 locus) (Helgadottir et al., 2007, 2008; Shen et al., 2008a,b; Matarin et al., 2008; Chen et al., 2009; Abdullah et al., 2008; Tousoulis Table 2 Distribution of rs1333049 genotype and allele frequency for the three study groups. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vascular risk factors have been implicated in the pathogenesis of vascular dementia and Alzheimer's disease. The identification of a novel vascular disease susceptibility locus at 9p21.3 has recently generated great interest. In the present study, we sought to determine whether a common genetic variant (tagged by rs1333049, G/C) in the 9p21.3 locus-that has been previously linked to an increased vascular risk-might influence the susceptibility to vascular dementia (VaD) and late-onset Alzheimer's disease (LOAD). A cohort of 200 VaD patients, 407 LOAD patients and 405 cognitively healthy controls were genotyped for rs1333049 using a fluorogenic 5' nuclease assay. The frequency of the C allele of rs1333049 was significantly higher in VaD (62.2%, P=0.005) and LOAD (60.7%, P=0.004) patients than in controls (53.6%). After adjustment for the APOE ε4 carrier status and other vascular risk factors, the C allele of rs1333049 remained significantly associated with both VaD (OR 1.31, 95% CI 1.07-1.77, P<0.01) and LOAD (OR 1.28, 95% CI 1.04-1.55, P<0.01). Altogether, our data indicate for the first time that the C allele of rs1333049 in the vascular disease susceptibility locus is associated with VaD and LOAD, independent of traditional risk factors and the APOE ε4 genotype.
    Neurobiology of aging 09/2009; 32(7):1231-5. DOI:10.1016/j.neurobiolaging.2009.07.003 · 4.85 Impact Factor
Show more