Homocysteine and its determinants in relation to cardiovascular risk factors and myocardial infarction

Sammanfattning: Background: Globally, cardiovascular diseases (CVD), including myocardial infarction (MI) and stroke, are the leading cause of illness and death and constitute a significant part of the disease burden in Sweden and Western Europe. Age, hypertension, smoking, obesity, dyslipoproteinemia, diabetes, and impaired renal function are considered established risk factors for CVD. However, these factors do not explain all MI cases, and much is still unknown. Homocysteine is a sulfur-containing amino acid used in clinical practice as a biomarker of functional vitamin B12 and folate status. Earlier observational studies have shown associations with higher plasma homocysteine concentrations (tHcy) and CVD. The causal relationship between tHcy and MI has been debated as homocysteine-lowering prevention studies have not shown a protective effect on MI, although there may be a protective effect on ischemic stroke. Still, tHcy is a prognostic biomarker or risk determinant of MI. There is a need for more knowledge on the pathophysiologic mechanisms of how homocysteine interacts with its determinants, and other risk factors, on the risk of MI.Aims: The overall aim of the thesis was to expand knowledge about how homocysteine, as a risk determinant, can have an impact on cardiovascular disease. Specifically, the purposes were to explore the associations between tHcy, determinants of homocysteine and risk factors of CVD, and the associated risk of prospectively developing a first-ever MI.Material and methods: In papers I, III, and IV, a prospective incident nested case-referent study design was used with 545 cases of MI and 1054 matched referents. In paper II the design was cross-sectional, comparing strictly defined smokers and snus users. All study subjects emanated from the Northern Sweden Health and Disease Study (NSHDS). Blood samples stored frozen at -80ºC were later thawed, and analyses of biomarkers for renal function, lipids, B-vitamins, tHcy, cotinine, and genetic polymorphisms related to homocysteine metabolism were performed. Results: In a prospective setting, folate, but not tHcy, was positively associated with apolipoprotein A1 (Apo A1). The association was seen among referents and not among those later developing an MI. Among strictly defined smokers and snus users, cotinine was positively associated with tHcy among smokers but not among snus users, despite higher cotinine concentrations in snus users. No association was observed between tHcy and the number of cigarettes/day.The CTH G1208T and MTHFR A1298C polymorphisms were, among women, associated with a higher risk of developing a first-ever MI with a fatal outcome. No such associations were seen among men or all MI patients. Further, no associations were seen between the MTHFR C677T polymorphism and the risk of having an MI, fatal or non-fatal. Mild impairment of renal glomerular function defined by eGFRcystatin C /eGFRcreatinine ratio and the associated risk of MI is previously not studied prospectively. In the present study, a lower eGFRcystatin C/eGFRcreatinine ratio was associated with a higher risk of later developing a first-ever MI among women, both when analyzed as a continuous variable and across the quartiles of the ratio. These associations did not appear among men.Conclusions: The independent association of folate but not tHcy with Apo A1 emphasizes the need to adjust for possible confounding effects in studies on homocysteine and endpoints or biomarkers. The results suggest a possible link between one-carbon metabolism and lipid metabolism. The independent association between cotinine and tHcy in smokers and not among snus users indicate that nicotine per se may not mediate higher tHcy concentrations. Cotinine concentrations in plasma appeared as a better predictor of tHcy than self-reported smoking data. Thus, whenever possible, self-reported smoking should be supplemented by biomarkers, such as cotinine, in epidemiological studies. After outcome stratification, fatal or non-fatal MI, the associated higher risk among women of a fatal MI and CTH G1208T and MTHFR A1298C polymorphisms, respectively, may indicate that women with the minor alleles risk having a more serious MI leading to death than women with the wild-type alleles. In a prospective setting, the eGFRcystatin C/eGFR creatinine ratio was associated with an increased risk of later developing a first-ever MI among women. The eGFRcystatin C/eGFRcreatinine ratio may be a tool, easily implemented at clinical laboratories, for evaluating the risk of having a future first-ever MI.