Associations of circulating dimethylarginines with the metabolic syndrome in the Framingham Offspring study

Abstract

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.