Abstract
High L-homoarginine (hArg) levels are directly associated with several risk factors for cardiometabolic diseases whereas low levels predict increased mortality in prospective studies. The biomarker role of hArg in young adults remains unknown. To study the predictive value of hArg in the development of cardiometabolic risk factors and diseases, we utilized data on high-pressure liquid chromatography-measured hArg, cardiovascular risk factors, ultrasound markers of preclinical atherosclerosis and type 2 diabetes from the population-based Young Finns Study involving 2,106 young adults (54.6% females, aged 24–39). We used a Mendelian randomization approach involving tens to hundreds of thousands of individuals to test causal associations. In our 10-year follow-up analysis, hArg served as an independent predictor for future hyperglycaemia (OR 1.31, 95% CI 1.06–1.63) and abdominal obesity (OR 1.60, 95% 1.14–2.30) in men and type 2 diabetes in women (OR 1.55, 95% CI 1.02–2.41). The MR analysis revealed no evidence of causal associations between serum hArg and any of the studied cardiometabolic outcomes. In conclusion, lifetime exposure to higher levels of circulating hArg does not seem to alter cardiometabolic disease risk. Whether hArg could be used as a biomarker for identification of individuals at risk developing cardiometabolic abnormalities merits further investigation.
Highlights
Accumulating evidence indicates that low levels of serum non-proteinogenic amino acid L-homoarginine are associated with an increased risk of death from cardiovascular diseases, including heart failure, sudden cardiac death and fatal strokes, in various patient populations[1,2,3,4,5,6]
Consistent with the positive cross-sectional association of hArg with body mass index (BMI) in the present and several previous studies[1, 6, 8, 13], we showed that, in our 10-year follow-up analysis after adjustments with other cardiovascular risk factors, hArg served as a significant biomarker for future hyperglycaemia and for abdominal obesity in men and incident type 2 diabetes mellitus (T2DM) in women
The lack of a causal role of circulating hArg in body weight is supported by an experimental study on mice and a small clinical trial showing that several-fold elevations of plasma hArg by oral hArg supplementation for several weeks did not have any effect on body weight[14, 15]
Summary
Accumulating evidence indicates that low levels of serum non-proteinogenic amino acid L-homoarginine (hArg) are associated with an increased risk of death from cardiovascular diseases, including heart failure, sudden cardiac death and fatal strokes, in various patient populations[1,2,3,4,5,6]. Because common cardiometabolic diseases such as type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) develop over several decades during one’s lifespan before any symptoms or clinical manifestations, any clinical trials on the effects of the lifetime exposure to high hArg in primary prevention settings are not feasible in practice. As metabolic syndrome (Mets) or a high body mass index (BMI) are strong predictors of future T2DM and cardiovascular disease manifestations[11, 12], we investigated whether hArg levels could predict the incidence of Mets components or obesity (BMI >30 kg/ m2) and high insulin as well as incident T2DM and preclinical atherosclerosis in a population-based prospective cohort of young adults without clinical cardiovascular diseases. We have individual-level genome-wide genetic data available for the Cardiovascular Risk in Young Finns Study (YFS) participants, we used summary-level data from several large-scale meta-analyses of genome-wide association studies involving tens to hundreds of thousands of individuals available in the public domain to increase the statistical power to detect potentially causal associations between hArg and metabolites, cardiometabolic risk factors, T2DM and CAD
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