Zee RY, Cook NR, Cheng S, Reynolds R, Erlich HA, Lindpaintner K, Ridker PMPolymorphism in the P-selectin and interleukin-4 genes as determinants of stroke: a population-based, prospective genetic analysis. Hum Molec Genet 13:389-396

Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Human Molecular Genetics (Impact Factor: 6.39). 03/2004; 13(4):389-96. DOI: 10.1093/hmg/ddh039
Source: PubMed


Candidate gene polymorphisms related to inflammation, thrombosis and lipid metabolism have been implicated in the development of ischemic stroke. Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we genotyped 92 polymorphisms from 56 candidate genes among 319 individuals who subsequently developed ischemic stroke and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years to prospectively determine whether candidate gene polymorphisms contribute to stroke risk. After adjustment for multiple comparisons and age, smoking, body mass index, hypertension, hyperlipidemia and diabetes, two related to inflammation [a val640leu polymorphism in the P-selectin gene (OR=1.63, 95% CI 1.22-2.17, P=0.001) and a C582T polymorphism in the interleukin-4 gene (OR=1.40, 95% CI 1.13-1.73, P=0.003)] were found to be independent predictors of thrombo-embolic stroke. In bootstrap replications, the inclusion of genetic information from these two polymorphisms improved prediction models for stroke based upon traditional risk factors alone (ROC 0.67 versus 0.64). Two polymorphisms related to thrombosis (an arg353gln polymorphism in the factor VII gene and a T11053G polymorphism in the plasminogen activator inhibitor type-1 gene) and one related to lipid metabolism [a C(-482)T polymorphism in the apolipoprotein CIII gene] achieved nominal significance, but were not found to be independent predictors after multiple comparison adjustment. Two inflammatory candidate gene polymorphisms were identified which were independently associated with incident stroke. These population-based data demonstrate the ability of prospective, epidemiological studies to test candidate gene associations for athero-thrombotic disease.

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    • "Previous studies that added candidate SNPs to conventional risk factors, using either genetic risk scores (a count of the number or risk alleles) or weighting of SNPs, have generally not significantly improved model discrimination as measured by C-index. They have however indicated through NRI [26] and/or increased hazard ratios that SNPs could improve risk prediction [27], [28], [29], [30], [31]; with significant associations reported between incident CHD and genetic risk scores [26], [27], [28]. Humphries et al. (2007) [32] found a significant improvement in C-index in the Northwick Park Heart Study II (P<0.001), which was further improved after inclusion of an interaction with smoking (P = 0.01). "
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    ABSTRACT: We examined whether a panel of SNPs, systematically selected from genome-wide association studies (GWAS), could improve risk prediction of coronary heart disease (CHD), over-and-above conventional risk factors. These SNPs have already demonstrated reproducible associations with CHD; here we examined their use in long-term risk prediction. SNPs identified from meta-analyses of GWAS of CHD were tested in 840 men and women aged 55-75 from the Edinburgh Artery Study, a prospective, population-based study with 15 years of follow-up. Cox proportional hazards models were used to evaluate the addition of SNPs to conventional risk factors in prediction of CHD risk. CHD was classified as myocardial infarction (MI), coronary intervention (angioplasty, or coronary artery bypass surgery), angina and/or unspecified ischaemic heart disease as a cause of death; additional analyses were limited to MI or coronary intervention. Model performance was assessed by changes in discrimination and net reclassification improvement (NRI). There were significant improvements with addition of 27 SNPs to conventional risk factors for prediction of CHD (NRI of 54%, <0.001; C-index 0.671 to 0.740, = 0.001), as well as MI or coronary intervention, (NRI of 44%, <0.001; C-index 0.717 to 0.750, = 0.256). ROC curves showed that addition of SNPs better improved discrimination when the sensitivity of conventional risk factors was low for prediction of MI or coronary intervention. There was significant improvement in risk prediction of CHD over 15 years when SNPs identified from GWAS were added to conventional risk factors. This effect may be particularly useful for identifying individuals with a low prognostic index who are in fact at increased risk of disease than indicated by conventional risk factors alone.
    PLoS ONE 02/2013; 8(2):e57310. DOI:10.1371/journal.pone.0057310 · 3.23 Impact Factor
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    • "Some these risk factors were localized to a region on the q-arm of chromosome one (1q24; Turner et al., 2005; Kochunov et al., 2010b). This region was also previously identified as harboring risk genes for development of cardiovascular disorders (Blann et al., 2003; Zee et al., 2004; Rutherford et al., 2007) and essential hypertension (Duggirala et al., 2000; Chang et al., 2007; Goring et al., 2007). Five genes within this region, including a constellation of selectin (SELP, SELL, and SELE) genes, ATP1B1 and the coagulation factor V (F5) genes, were confirmed to be involved in determining individual susceptibility for essential hypertension (Kochunov et al., 2009, 2010a). "
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    ABSTRACT: Background and Purpose: We hypothesized that the P-selectin (SELP) gene, localized to a region on chromosome 1q24, pleiotropically contributes to increased blood pressure and cerebral atrophy. We tested this hypothesis by performing genetic correlation analyses for 13 mRNA gene expression measures from P-selectin and 11 other genes located in 1q24 region and three magnetic resonance imaging derived indices of cerebral integrity. Methods: The subject pool consisted of 369 (219F; aged 28-85, average = 47.1 ± 12.7 years) normally aging, community-dwelling members of large extended Mexican-American families. Genetic correlation analysis decomposed phenotypic correlation coefficients into genetic and environmental components among 13 leukocyte-based mRNA gene expressions and three whole-brain and regional measurements of cerebral integrity: cortical gray matter thickness, fractional anisotropy of cerebral white matter, and the volume of hyperintensive WM lesions. Results: From the 13 gene expressions, significant phenotypic correlations were only found for the P- and L-selectin expression levels. Increases in P-selectin expression levels tracked with decline in cerebral integrity while the opposite trend was observed for L-selectin expression. The correlations for the P-selectin expression were driven by shared genetic factors, while the correlations with L-selectin expression were due to shared environmental effects. Conclusion: This study demonstrated that P-selectin expression shared a significant variance with measurements of cerebral integrity and posits elevated P-selectin expression levels as a potential risk factor of hypertension-related cerebral atrophy.
    Frontiers in Genetics 05/2012; 3:65. DOI:10.3389/fgene.2012.00065
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    • "APOE ε2/ε3/ε4 variants were genotyped according to a previously described multilocus assay [13], except for the use of a simplified PCR protocol to improve APOE genotyping, which was validated by RFLP and sequencing. Briefly, each sample was amplified by two 33-cycle multiplex polymerase chain reactions (PCR, 32 ng of genomic DNA each) and the PCR products were then hybridized to an array of immobilised, sequence-specific oligonucleotide probes. "
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    ABSTRACT: The R952Q variant in the low density lipoprotein receptor-related protein 8 (LRP8)/apolipoprotein E receptor 2 (ApoER2) gene has been recently associated with familial and premature myocardial infarction (MI) by means of genome-wide linkage scan/association studies. We were interested in the possible interaction of the R952Q variant with another established cardiovascular genetic risk factor belonging to the same pathway, namely apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 genotype, in modulating apolipoprotein E (ApoE) plasma levels and risk of MI. In the Italian cohort used to confirm the association of the R952Q variant with MI, we assessed lipid profile, apolipoprotein concentrations, and APOE epsilon2/epsilon3/epsilon4 genotype. Complete data were available for a total of 681 subjects in a case-control setting (287 controls and 394 patients with MI). Plasma ApoE levels decreased progressively across R952Q genotypes (mean levels +/- SD = RR: 0.045 +/- 0.020, RQ: 0.044 +/- 0.014, QQ: 0.040 +/- 0.008 g/l; P for trend = 0.047). Combination with APOE genotypes revealed an additive effect on ApoE levels, with the highest level observed in RR/non-carriers of the E4 allele (0.046 +/- 0.021 g/l), and the lowest level in QQ/E4 carriers (0.035 +/- 0.009 g/l; P for trend = 0.010). QQ/E4 was also the combined genotype with the most significant association with MI (OR 3.88 with 95%CI 1.08-13.9 as compared with RR/non-carriers E4). Our data suggest that LRP8 R952Q variant may have an additive effect to APOE epsilon2/epsilon3/epsilon4 genotype in determining ApoE concentrations and risk of MI in an Italian population.
    BMC Medical Genetics 06/2009; 10(1):41. DOI:10.1186/1471-2350-10-41 · 2.08 Impact Factor
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