Associations between plasma metabolite profiles and blood pressure: the HELIUS study

Background Blood pressure (BP) is regulated by plasma metabolites from different neurohumoral and cardiometabolic systems. Since there are established differences in hypertension pathogenesis and treatment response between ethnicities, we hypothesized that plasma metabolites may be differently associated with BP across ethnic groups. Purpose To investigate associations between plasma metabolite profiles and BP in a multi-ethnic population-based cohort. Methods From the Healthy Living In an Urban Setting (HELIUS) study, 369 subjects (mean age 52±11 years, 51%F) of African and non-African descent were included. Office systolic (136±21 mmHg) and diastolic (83±12 mmHg) BP levels were recorded. Plasma metabolites were measured semi-quantitively with LC-MS (Metabolon) from fasting plasma samples. Associations between metabolite profiles and BP were assessed with machine learning prediction models using the XGBoost algorithm with nested cross-validation. Associations between the resulting best predictors and BP were assessed with linear regression models while adjusting for age, sex, estimated glomerular filtration rate and diabetes. Results Plasma metabolite profiles explained 14.1% of systolic BP variance and 10.6% of diastolic BP variance. These were attenuated to 3.1% and 1.4% respectively, when using residuals of BP after adjusting for age and sex. Top predictors for both systolic and diastolic BP included N-formylmethionine, several acylcarnitines and polyunsaturated fatty acids such as hexadecadienoate. These metabolites were significantly associated with higher systolic BP with estimates ranging from 3.0 to 4.5 mmHg per 1 SD increase in the adjusted models. Associations with hexadecadienoate, dihomolinoleate and catecholamine metabolites, including vanillactate had significant interactions (p<0.05) with ethnicity, and were only significant in subjects of non-African descent. Conclusions Plasma metabolome composition explained a large proportion of BP variance, but this association was attenuated when adjusting for confounders. Polyunsaturated fatty acids and catecholamine metabolites were only associated with BP in the non-African descent subjects. N-formylmethionine was the most consistent predictor for systolic BP across all subgroups. Future studies could focus on translating these findings in vitro in order to decipher the role of N-formylmethionine in BP regulation. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Dutch Heart Foundation, the Netherlands Organization for Health Research and Development, the European Integration Fund and the European Union (Seventh Framework Programme) Explained variances of machine learning Linear regression models

The case of a patient with MIRAGE syndrome with familial dysautonomia-like symptoms

We describe a case of posthumously diagnosed MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital problems, and Enteropathy) in a girl with a new pathogenic SAMD9 variant (p.F437S), who was initially considered to have familial dysautonomia (FD)-like disease due to increased levels of catecholamine metabolites. Functional analyses of F437S-SAMD9 were performed, showing characteristics of disease-causing variants. This new SAMD9 variant (p.F437S) also causes MIRAGE syndrome.

Plasma metanephrines and prospective prediction of tumor location, size and mutation type in patients with pheochromocytoma and paraganglioma

ObjectivesPlasma free metanephrines are commonly used for diagnosis of pheochromocytoma and paraganglioma (PPGLs), but can also provide other information. This multicenter study prospectively examined whether tumor size, location, and mutations could be predicted by these metabolites.MethodsPredictions of tumor location, size, and mutation type, based on measurements of plasma normetanephrine, metanephrine, and methoxytyramine were made without knowledge of disease in 267 patients subsequently determined to have PPGLs.ResultsPredictions of adrenal vs. extra-adrenal locations according to increased plasma concentrations of metanephrine and methoxytyramine were correct in 93 and 97% of the respective 136 and 33 patients in who these predictions were possible. Predicted mean tumor diameters correlated positively (p<0.0001) with measured diameters; predictions agreed well for pheochromocytomas but were overestimated for paragangliomas. Considering only patients with mutations, 51 of the 54 (94%) patients with NF1 or RET mutations were correctly predicted with those mutations according to increased plasma metanephrine, whereas no or minimal increase in metanephrine correctly predicted all 71 patients with either VHL or SDHx mutations; furthermore, among the latter group increases in methoxytyramine correctly predicted SDHx mutations in 93% of the 29 cases for this specific prediction.ConclusionsExtents and patterns of increased plasma O-methylated catecholamine metabolites among patients with PPGLs allow predictions of tumor size, adrenal vs. extra-adrenal locations and general types of mutations. Predictions of tumor location are, however, only possible for patients with clearly increased plasma methoxytyramine or metanephrine. Where possible or clinically relevant the predictions are potentially useful for subsequent clinical decision-making.