Elsevier

Atherosclerosis

Volume 177, Issue 2, December 2004, Pages 375-381
Atherosclerosis

Homocysteine as a risk factor for coronary heart diseases and its association with inflammatory biomarkers, lipids and dietary factors

https://doi.org/10.1016/j.atherosclerosis.2004.07.020Get rights and content

Abstract

The causal relation of total Homocysteine (tHcy) to coronary heart diseases (CHD) is unclear. In vitro studies suggest a proinflammatory effect. Among 32,826 women from the Nurses’ Health Study who provided blood samples in 1989–1990, 237 CHD events were documented during 8 years of follow-up. The cases (1:2) were matched to controls on age, smoking, and month of blood draw. Plasma tHcy was inversely associated with blood levels of folate (partial r = −0.3, P < 0.0001) and B12 (r = −0.2, P < 0.0001) and with dietary intake of folate (r = −0.1, P < 0.01) and B2 vitamin (r = −0.1, P = 0.01). tHcy was positively associated with soluble tumor necrosis receptor (sTNF-R) 1 and 2 (partial r = 0.2, P < 0.0001). In a multivariate model adjusted for age, smoking, BMI, parental history, hypertension, diabetes, postmenopausal hormone use, physical activity and alcohol intake, the relative risk of CHD between the extreme quartiles of tHcy was 1.66 (95% CI; 1.05–2.64, P trend = 0.02). The association was not appreciably attenuated after further adjustments for sTNF-R1, sTNF-R2, CRP, or Total Cholesterol:/HDL-c ratio. tHcy is an independent risk predictor of CHD and modestly associated with TNF-receptors. However, the inflammatory biomarkers measured could not explain its role in CHD.

Section snippets

Background

tHcy, a highly reactive sulfur-containing amino acid, is an intermediary product of methionine metabolism which can be either remethylated to methionine or metabolized to cysteine. tHcy is a modest independent predictor of CHD [1], [2], but the pathophysiologic mechanism is unclear. tHcy might induce atherosclerosis by impairing coronary microvascular dilator function [3], by smooth muscle proliferation [4], platelet activation, thrombogenesis [5], endothelial dysfunction, and collagen

The Nurses’ Health Study (NHS) cohort population and blood collection

The NHS was initiated in 1976, with the enrollment of 121,700 female nurses aged 30–55. Since then, follow-up questionnaires have been mailed to the cohort every 2 years to update information on exposures and the occurrence of major illnesses. Between 1989 and 1990, blood samples were collected from 32,826 women. Within 24 h of collection 97% of the samples were returned. They were immediately centrifuged, aliquoted into plasma, red blood cell, and buffy-coat fractions, and stored in liquid

Population characteristics and MTHFRC677T polymorphism

After excluding 24 subjects who were taking cholesterol-lowering drugs at time of blood collection and 9 whose tHcy data were missing, we documented 237 incident MI cases (202 nonfatal MI and 35 fatal CHD) during 8 years of follow-up. Compared with 458 controls, case subjects had higher plasma tHcy levels (P = 0.02) were more likely to have diabetes, hypertension, higher BMI and a parental history of MI. In our population, the prevalence of heterozygosity and homozygosity of the thermolabile

Discussion

In a nested prospective case-control assessment including 202 nonfatal MI and 35 fatal CHD events during 8 years of follow-up, we found a positive association between tHcy levels and CHD risk. We observed a linear trend, but the elevated risk was significant only in the top quartile. This association persisted after controlling for other established CHD factors. tHcy levels were independently inversely correlated with elevated blood levels and dietary intake of folate, and modestly associated

Acknowledgments

This study was supported by NIH research grants CA42182, CA18293 and from Merck Research Laboratories. We thank Dr. Frank Speizer, the founding principal investigator and Dr. Graham Colditz, the current principal investigator of the Nurses’ Health Study, for their invaluable contributions and the participants of the Nurses’ Health Study for their continued cooperation and participation. We are indebted to the S. Daniel Abraham International Center for Health and Nutrition, Ben-Gurion University

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