Components of the choline oxidation pathway in relation to acute myocardial infarction, type 2 diabetes and mortality. Prospective observational studies among patients with suspected or verified coronary heart disease in Norway
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BACKGROUND. The choline oxidation pathway comprises the sequential metabolism of choline into betaine, dimethylglycine (DMG), and sarcosine. In addition, dietary choline and betaine can be turned into trimethylamine N-amino oxide (TMAO). Alterations in choline metabolism may relate to cardiovascular disease (CVD) and type 2 diabetes (T2D). Several investigations have focused on systemic concentrations of choline and betaine; however large-scale prospective data are scarce. There is therefore a need for more comprehensive assessments of choline metabolites in relation to incident CVD, T2D and mortality, in addition to investigating any potential benefit in risk prediction from such biomarkers.AIM. We carried out observational cohort studies of the prospective relationships between plasma DMG and incident acute myocardial infarction (AMI) and mortality, as well as the association between systemic and urinary choline metabolites with the risk of incident T2D. The biomarkers’ impact on model discrimination and reclassification of patients at risk was also assessed, as were their test-retest reliabilities and temporal trends according to B-vitamin treatment. MATERIALS AND METHODS. Analyses on the association between plasma DMG and incident AMI, as well as the relationships between choline metabolites and incident T2D were performed among patients evaluated for suspected stable angina pectoris (SAP). The risk assessment between plasma DMG and mortality included SAP patients and patients with AMI from an independent cohort. Clinical endpoint data were obtained from regional and national health registries. Endpoint analyses on incident AMI and mortality were carried out by Cox regression, whereas analyses on incident T2D were performed by logistic regression. Model discrimination and reclassification were explored by calculating the C-statistics, the integrated discrimination index (IDI), and the continuous net reclassification improvement (NRI>0), respectively. Mixed linear modelling was used for assessing temporal trends in metabolite concentrations. RESULTS. Higher plasma DMG was associated with several traditional risk factors for coronary heart disease (CHD). After about four and a half years of follow-up, plasma DMG showed linear relationships with incident AMI among 4154 patients with suspected SAP (age, gender and fasting adjusted hazard ratio (HR) for the fourth vs. first quartile (95% confidence intervals (CI)) 1.95 (1.42-2.68); P<0.001). The relationship between plasma DMG and incident AMI was particularly strong among non-smokers and patients with lower serum apoB and triglyceride levels (P for interaction≤0.03). Among essentially the same patients, as well as among 3733 patients with AMI who were followed for 7 years, higher plasma DMG was also associated with increased risk of all-cause mortality (age and gender adjusted HRs (95% CIs) for the fourth vs. the first quartile 1.72 (1.21–2.46) and 1.76 (1.42–2.18) among SAP and AMI patients, respectively) and CVD mortality (HRs (95% CIs) 1.94 (1.21–3.11) and 1.97 (1.50–2.59) among SAP and AMI patients, respectively). The associations were only slightly attenuated when adjusting for established CHD risk factors, to which adding plasma DMG also improved risk prediction for both AMI and all-cause mortality. Moreover, plasma DMG showed good to excellent within-person reproducibility throughout repeated measurements among patients not receiving supplementation with folic acid + vitamin B12. In general, higher plasma choline and lower plasma betaine and serum sarcosine levels were associated with an adverse risk profile of T2D. In urine, most choline metabolites were positively related to an adverse diabetes risk profile. After an average follow-up of 7.5 years, 233 (6.4%) out of 3621 non-diabetic patients were registered with new-onset T2D. Incident T2D was strongly inversely associated with plasma betaine and positively related to urine betaine, DMG and sarcosine (age, gender and fasting adjusted odds ratios (95% CIs) per 1 SD increment 0.72 (0.62-0.83), 1.25 (1.09-1.43), 1.22 (1.06-1.40), and 1.30 (1.13-1.49), respectively). We did not find any relationship between choline or TMAO and incident T2D. The estimates were not materially altered when adjusting for a range of traditional T2D risk factors and potential confounders, and were similar in sensitivity analyses. Among the choline metabolites associated with new-onset T2D in univariate analyses, plasma betaine and urine sarcosine were most strongly related to incident T2D, and both indices also enhanced risk prediction when added to the multivariate model. After 1 year, as compared to placebo treatment, supplementation with folic acid + vitamin B12 lowered plasma DMG and sarcosine, but increased plasma betaine and choline. No alterations in plasma TMAO were observed. In urine, we observed similar responses to supplementation as to those seen in blood. CONCLUSION AND IMPLICATIONS. Among patients with suspected or verified SAP, high plasma DMG was related to increased risk of AMI, as well as all-cause and CVD mortality, the latter endoints being validated among patients with AMI. Moreover, plasma DMG improved risk prediction of both AMI and mortality. Lower plasma betaine and higher urine betaine, DMG and sarcosine concentrations were related to incident T2D. Plasma betaine and urine sarcosine also improved reclassification of patients at risk. Plasma DMG and betaine, as well as urine sarcosine showed good to excellent within-subject reproducibility among patients not supplemented with folic acid + vitamin B12, justifying one-time assessment of biomarker status. Our observational findings suggest novel pathophysiological pathways involved in conditions heavily impacting the global burden of disease, warranting more research into the field of one-carbon and choline metabolism in relation to life-style related diseases.
PAPER I: Svingen GF, Ueland PM, Pedersen EK, Schartum-Hansen H, Seifert R, Ebbing M, Løland KH, Tell GS, Nygård O. Plasma dimethylglycine and risk of incident acute myocardial infarction in patients with stable angina pectoris. Arterioscler Thromb Vasc Biol. 2013; 33(8):2041-8. (Appendix I) This article is not available in BORA. The published version is available at: 10.1161/ATVBAHA.113.301714
PAPER II: Svingen GFT, Schartum-Hansen H, Ueland PM, Pedersen EP, Seifert R, Ebbing M, Bønaa KH, Mellgren G, Nilsen DWT, Nordrehaug JE, Øyen J, and Nygård O. Elevated plasma dimethylglycine is a risk marker of mortality in patients with coronary heart disease. Eur J Prev Cardiol 2015; 22(6):743-52. (Appendix II) This article is not available in BORA. The published version is available at: 10.1177/2047487314529351
PAPER III: Svingen GFT, Schartum-Hansen H, Pedersen EKR, Ueland PM, Tell GS, Mellgren G, Njølstad PR, Strand E, Karlsson T, Seifert R, Nygård O. Prospective associations of systemic and urinary choline metabolites with incident type 2 diabetes. Clinical Chemistry 2016; 62 (5):1-11 (Appendix III) This article is not available in BORA. The published version is available at: 10.1373/clinchem.2015.250761