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      H-type hypertension and risk of stroke in chinese adults: A prospective, nested case–control study

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          Abstract

          Objectives

          To investigate the independent and joint associations of hyperhomocysteinemia and hypertension with incident stroke and stroke death in Chinese adults.

          Methods

          About 39,165 rural Chinese adults aged 35 years or older who had no history of stroke at the baseline study were prospectively followed to determine major cardiovascular events, with an average follow-up of 6.2 years. Using a nested case–control design, this report includes 179 incident stroke cases (121 stroke deaths) and 179 controls without vascular events from the original cohort matched by age, sex, community, and length of plasma storage. Baseline plasma total homocysteine (tHcy) measurements were obtained for all subjects. Logistic regression analysis was performed to investigate the independent and joint associations between H-type hypertension, defined as subjects with concomitant hypertension and elevated homocysteine (≥10 μmol/L), and risk of incident stroke and stroke death, after adjusting for important covariates.

          Results

          We analyzed each risk factor independently and jointly. For analysis, homocysteine was divided into three groups: low (tHcy <10 μmol/L), moderate (≥10 μmol/L tHcy <20 μmol/L), and high (tHcy≥20μmol/L). Compared to subjects in the low group, the odds ratios (95% CI) of incident stroke for those in the moderate group and the high group were 1.7 (0.8–3.7) and 3.1 (1.2–8.6), respectively. The odds ratios (95% CI) of stroke death for the moderate and high groups were 2.8 (1.1–7.4) and 5.1 (1.6–16.4), respectively. Hypertension was also independently associated with a higher risk of incident stroke and stroke death: 3.8 (2.3–6.4) and 3.2 (1.8–6.0), respectively, compared to those without hypertension. When analyzed jointly, the highest risk was found among patients with H-type hypertensive with both hyperhomocysteinemia and hypertension: 12.7 (2.8–58.0) for incident stroke and 11.7 (2.5–54.7) for stroke death.

          Conclusions

          This study provides strong evidence that hyperhomocysteinemia and hypertension are two independent, modifiable risk factors, which act additively to increase the risk of incident stroke and stroke death. The results strongly suggest that H-type hypertension is a major risk factor for vascular disease and mortality, and those with H-type hypertension may particularly benefit from homocysteine-lowering therapy along with anti-hypertension therapy in Chinese populations.

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          Most cited references33

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          'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?

          Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
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            Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.

            It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke. To assess the relationship of homocysteine concentrations with vascular disease risk. MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators. Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete. Data from 30 prospective or retrospective studies involving a total of 5073 IHD events and 1113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression. Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 micromol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk. This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.
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              Plasma homocysteine levels and mortality in patients with coronary artery disease.

              Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined. We prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease. At the time of angiography in 1991 or 1992, risk factors for coronary disease, including homocysteine levels, were evaluated. The majority of the patients subsequently underwent coronary-artery bypass grafting (318 patients) or percutaneous transluminal coronary angioplasty (120 patients); the remaining 149 were treated medically. After a median follow-up of 4.6 years, 64 patients (10.9 percent) had died. We found a strong, graded relation between plasma homocysteine levels and overall mortality. After four years, 3.8 percent of patients with homocysteine levels below 9 micromol per liter had died, as compared with 24.7 percent of those with homocysteine levels of 15 micromol per liter or higher. Homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infarction, the left ventricular ejection fraction, and the serum creatinine level. The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders. In an analysis in which the patients with homocysteine levels below 9 micromol per liter were used as the reference group, the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 micromol per liter, 2.8 for those with levels of 15.0 to 19.9 micromol per liter, and 4.5 for those with levels of 20.0 micromol per liter or higher (P for trend=0.02). When death due to cardiovascular disease (which occurred in 50 patients) was used as the end point in the analysis, the relation between homocysteine levels and mortality was slightly strengthened. Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease.
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                Author and article information

                Journal
                J Transl Int Med
                J Transl Int Med
                Journal of Translational Internal Medicine
                De Gruyter Open
                2450-131X
                2224-4018
                Oct-Dec 2015
                30 December 2015
                : 3
                : 4 , A special issue on chronic obstructive pulmonary disease
                : 171-178
                Affiliations
                [1 ]Department of Cardiology, Peking University First Hospital, Beijing, China
                [2 ]School of Life Sciences, Anhui University, Hefei, China
                [3 ]Institute of Biomedicine, Anhui Medical University, Hefei, China
                [4 ]National Clinical Research Study Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
                Author notes
                [* ] Address for Correspondence: Binyan Wang, M.D., Ph.D., National Clinical Research Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China, Email: binyanwang126@ 123456126.com , Yong Huo, MD, Department of Cardiology, Peking University First Hospital, Beijing, China, Email: huoyong@ 123456263.net.cn
                [§]

                These two authors contributed equally to this paper.

                Article
                jtim-2015-0027
                10.1515/jtim-2015-0027
                4936453
                27847909
                c5cdbef1-b89e-4b74-8969-f6b34148f008
                Copyright © International Society of Translational Sciences

                This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License (CC BY-NC-ND 3.0)

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                Original Article

                h-type hypertension,stroke,nested case-control study,synergistic effect

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