BACKGROUND: Circulating levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are positively associated with the prevalence of metabolic syndrome (MetS) in cross-sectional investigations. It is unclear if circulating ADMA and other methylarginines are associated with incident MetS prospectively.
METHODS: We related circulating ADMA, symmetric dimethylarginine (SDMA), L-arginine (ARG) concentrations (measured with a validated tandem mass spectrometry assay) and the ARG/ADMA ratio to MetS and its components in 2914 (cross-sectional analysis, logistic regression; mean age 58 years, 55% women) and 1656 (prospective analysis, Cox regression; mean age 56 years, 59% women) individuals from the Framingham Offspring Study who attended a routine examination.
RESULTS: Adjusting for age, sex, smoking, and eGFR, we observed significant associations of ADMA (direct) and ARG/ADMA (inverse) with odds of MetS (N = 1461 prevalent cases; Odds Ratio [OR] per SD increment 1.13, 95%CI 1.04-1.22; and 0.89, 95%CI 0.82-0.97 for ADMA and ARG/ADMA, respectively). Upon further adjustment for waist circumference, systolic and diastolic blood pressure, glucose, high-density lipoprotein cholesterol, and triglycerides, we observed a positive relation between SDMA and MetS (OR per SD increment 1.15, 95% CI 1.01-1.30) but the other associations were rendered statistically non-significant. We did not observe statistically significant associations between any of the methylarginines and the risk of new-onset MetS (752 incident events) over a median follow-up of 11 years.
CONCLUSION: It is unclear whether dimethylarginines play an important role in the incidence of cardiometabolic risk in the community, notwithstanding cross-sectional associations. Further studies of larger samples are needed to replicate our findings.
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This study was partially supported by a research grant Bo1431/4-1 (Dr. Böger) by the Deutsche Forschungsgemeinschaft, by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contracts N01-HC-25195, HHSN268201500001I and 75N92019D00031) and by NHLBI 5T32HL125232 (T32 Multidisciplinary Training Program in Cardiovascular Epidemiology). Dr. Vasan is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine.
All data can be found here: https://biolincc.nhlbi.nih.gov/studies/framoffspring/.
Yola, Ibrahim Musa; Moser, Carlee; Duncan, Meredith S.; Schwedhelm, Edzard; Atzler, Dorothee; Maas, Renke; Hannemann, Juliane; Böger, Rainer H.; Vasan, Ramachandran S.; and Xanthakis, Vanessa, "Associations of Circulating Dimethylarginines with the Metabolic Syndrome in the Framingham Offspring Study" (2021). Biostatistics Faculty Publications. 55.
Association between biomarkers and prevalent metabolic syndrome: Restricted cubic spline plots. https://doi.org/10.1371/journal.pone.0254577.s001
pone.0254577.s002.docx (109 kB)
Association between biomarkers and incident metabolic syndrome: Restricted cubic spline plots. https://doi.org/10.1371/journal.pone.0254577.s002