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      C-reactive protein polymorphisms and genetic susceptibility to ischemic stroke and hemorrhagic stroke in the Chinese Han population

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          Abstract

          Aim:

          The inflammatory marker C-reactive protein (CRP) has been strongly correlated with the risk of cardiovascular disease. Some single-nucleotide polymorphisms (SNPs) have been reported to be associated with serum CRP levels. In this study, we assessed the genetic association between SNPs within the CRP gene and ischemic and hemorrhagic stroke in the Han Chinese population.

          Methods:

          This study comprises 564 ischemic stroke patients, 220 hemorrhagic stroke patients and 564 controls from the ethnic Han Chinese population in Wuhan. Four CRP SNPs, −757A>G (rs3093059), −717A>G (rs2794521), −286C>T>A (rs3091244) and +2147C>T (rs1205), were genotyped from patients using TaqMan assays.

          Results:

          The A allele frequency for the −717A>G polymorphism was significant higher in controls than in ischemic stroke patients ( P=0.037), after adjustment for traditional risk factors (odds ratio 0.28; 95% CI 0.12–0.65; P=0.003), suggesting a protective effect for this allele against ischemic stroke. Haplotype analysis showed that the H3 (G-C-C) haplotype conferred a significantly increased risk of ischemic stroke (odds ratio 1.052, 95% CI 1.001–1.106: P=0.047). Neither CRP genotypes nor haplotypes showed an association with hemorrhagic stroke. However, the frequency for haplotype H5 (A-T-C) was significantly higher in ischemic stroke than hemorrhagic stroke patients ( P=0.0003).

          Conclusion:

          These data suggest that the CRP gene −717A allele confers a protective effect against ischemic stroke. Furthermore, the H3 haplotype (G-C-C) is an independent risk marker for ischemic stroke, whereas the H5 haplotype (A-T-C) can be used as a prognostic marker of hemorrhagic stroke.

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          Most cited references32

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          Diabetes and cardiovascular disease. The Framingham study.

          Based on 20 years of surveillance of the Framingham cohort relating subsequent cardiovascular events to prior evidence of diabetes, a twofold to threefold increased risk of clinical atherosclerotic disease was reported. The relative impact was greatest for intermittent claudication (IC) and congestive heart failure (CHF) and least for coronary heart disease (CHD), which was, nevertheless, on an absolute scale the chief sequela. The relative impact was substantially greater for women than for men. For each of the cardiovascular diseases (CVD), morbidity and mortality were higher for diabetic women than for nondiabetic men. After adjustment for other associated risk factors, the relative impact of diabetes on CHD, IC, or stroke incidence was the same for women as for men; for CVD death and CHF, it was greater for women. Cardiovascular mortality was actually about as great for diabetic women as for diabetic men.
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            Score tests for association between traits and haplotypes when linkage phase is ambiguous.

            A key step toward the discovery of a gene related to a trait is the finding of an association between the trait and one or more haplotypes. Haplotype analyses can also provide critical information regarding the function of a gene; however, when unrelated subjects are sampled, haplotypes are often ambiguous because of unknown linkage phase of the measured sites along a chromosome. A popular method of accounting for this ambiguity in case-control studies uses a likelihood that depends on haplotype frequencies, so that the haplotype frequencies can be compared between the cases and controls; however, this traditional method is limited to a binary trait (case vs. control), and it does not provide a method of testing the statistical significance of specific haplotypes. To address these limitations, we developed new methods of testing the statistical association between haplotypes and a wide variety of traits, including binary, ordinal, and quantitative traits. Our methods allow adjustment for nongenetic covariates, which may be critical when analyzing genetically complex traits. Furthermore, our methods provide several different global tests for association, as well as haplotype-specific tests, which give a meaningful advantage in attempts to understand the roles of many different haplotypes. The statistics can be computed rapidly, making it feasible to evaluate the associations between many haplotypes and a trait. To illustrate the use of our new methods, they are applied to a study of the association of haplotypes (composed of genes from the human-leukocyte-antigen complex) with humoral immune response to measles vaccination. Limited simulations are also presented to demonstrate the validity of our methods, as well as to provide guidelines on how our methods could be used.
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              Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.

              A large number of epidemiologic studies have reported on associations between various "inflammatory" factors and coronary heart disease (CHD). To assess the associations of blood levels of fibrinogen, C-reactive protein (CRP), and albumin and leukocyte count with the subsequent risk of CHD. Meta-analyses of any long-term prospective studies of CHD published before 1998 on any of these 4 factors. Studies were identified by MEDLINE searches, scanning of relevant reference lists, hand searching of cardiology, epidemiology, and other relevant journals, and discussions with authors of relevant reports. All relevant studies identified were included. The following information was abstracted from published reports (supplemented, in several cases, by the authors): size and type of cohort, mean age, mean duration of follow-up, assay methods, degree of adjustment for confounders, and relationship of CHD risk to the baseline assay results. For fibrinogen, with 4018 CHD cases in 18 studies, comparison of individuals in the top third with those in the bottom third of the baseline measurements yielded a combined risk ratio of 1.8 (95% confidence interval [CI], 1.6-2.0) associated with a difference in long-term usual mean fibrinogen levels of 2.9 pmol/L (0.1 g/dL) between the top and bottom thirds (10.3 vs 7.4 pmol/L [0.35 vs 0.25 g/dL]). For CRP, with 1053 CHD cases in 7 studies, the combined risk ratio of 1.7 (95% CI, 1.4-2.1) was associated with a difference of 1.4 mg/L (2.4 vs 1.0 mg/L). For albumin, with 3770 CHD cases in 8 studies, the combined risk ratio of 1.5 (95% CI, 1.3-1.7) was associated with a difference of 4 g/L (38 vs 42 g/L, ie, an inverse association). For leukocyte count, with 5337 CHD cases in the 7 largest studies, the combined risk ratio of 1.4 (95% CI, 1.3-1.5) was associated with a difference of 2.8 x 10(9)/L (8.4 vs 5.6 x 10(9)/L). Each of these overall results was highly significant (P<.0001). The published results from these prospective studies are remarkably consistent for each factor, indicating moderate but highly statistically significant associations with CHD. Hence, even though mechanisms that might account for these associations are not clear, further study of the relevance of these factors to the causation of CHD is warranted.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                March 2009
                05 March 2009
                : 30
                : 3
                : 291-298
                Affiliations
                [1 ]The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430030, China
                [2 ]Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100037, China
                [3 ]Center for Biotechnology and Genomic Medicine, Medical College of Georgia , 1120 15th Street, CA4098, Augusta, GA, USA
                Author notes
                [#]

                The first three authors contributed equally to this work.

                Article
                aps200914
                10.1038/aps.2009.14
                4002404
                19262552
                65144fc5-ebbf-44c9-b123-3dea0095f70d
                Copyright © 2009 CPS and SIMM
                History
                : 07 December 2008
                : 23 January 2009
                Categories
                Original Article

                Pharmacology & Pharmaceutical medicine
                c-reactive protein gene,stroke,genetic polymorphism
                Pharmacology & Pharmaceutical medicine
                c-reactive protein gene, stroke, genetic polymorphism

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