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Metabolic phenotyping for discovery of urinary biomarkers of diet, xenobiotics and blood pressure in the INTERMAP Study: an overview.

ABSTRACT: The etiopathogenesis of cardiovascular diseases (CVDs) is multifactorial. Adverse blood pressure (BP) is a major independent risk factor for epidemic CVD affecting ~40% of the adult population worldwide and resulting in significant morbidity and mortality. Metabolic phenotyping of biological fluids has proven its application in characterizing low-molecular-weight metabolites providing novel insights into gene-environmental-gut microbiome interaction in relation to a disease state. In this review, we synthesize key results from the INTERnational study of MAcro/micronutrients and blood Pressure (INTERMAP) Study, a cross-sectional epidemiologic study of 4680 men and women aged 40-59 years from Japan, the People's Republic of China, the United Kingdom and the United States. We describe the advancements we have made regarding the following: (1) analytical techniques for high-throughput metabolic phenotyping; (2) statistical analyses for biomarker identification; (3) discovery of unique food-specific biomarkers; and (4) application of metabolome-wide association studies to gain a better understanding into the molecular mechanisms of cross-cultural and regional BP differences.

SUBMITTER: Chan Q

PROVIDER: S-EPMC6278595 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Metabolic phenotyping for discovery of urinary biomarkers of diet, xenobiotics and blood pressure in the INTERMAP Study: an overview.

Chan Queenie Q Loo Ruey Leng RL Ebbels Timothy M D TM Van Horn Linda L Daviglus Martha L ML Stamler Jeremiah J Nicholson Jeremy K JK Holmes Elaine E Elliott Paul P

Hypertension research : official journal of the Japanese Society of Hypertension 20161222 4

The etiopathogenesis of cardiovascular diseases (CVDs) is multifactorial. Adverse blood pressure (BP) is a major independent risk factor for epidemic CVD affecting ~40% of the adult population worldwide and resulting in significant morbidity and mortality. Metabolic phenotyping of biological fluids has proven its application in characterizing low-molecular-weight metabolites providing novel insights into gene-environmental-gut microbiome interaction in relation to a disease state. In this review ...[more]

PMID: 28003647

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Project description:The prevalence of renal stone disease is increasing, although it remains higher in men than in women when matched for age. While still somewhat controversial, several studies have reported an association between renal stone disease and hypertension, but this may be confounded by a shared link with obesity. However, independent of obesity, hyperoxaluria has been shown to be associated with hypertension in stone-formers, and the most common type of renal stone is composed of calcium oxalate. The chloride-oxalate exchanger slc26a6 (also known as CFEX or PAT-1), located in the renal proximal tubule, was originally thought to have an important role in sodium homeostasis and thereby blood pressure control, but it has recently been shown to have a key function in oxalate balance by mediating oxalate secretion in the gut. We have applied two orthogonal analytical platforms (NMR spectroscopy and capillary electrophoresis with UV detection) in parallel to characterize the urinary metabolic signatures related to the loss of the renal chloride-oxalate exchanger in slc26a6 null mice. Clear metabolic differentiation between the urinary profiles of the slc26a6 null and the wild type mice were observed using both methods, with the combination of NMR and CE-UV providing extensive coverage of the urinary metabolome. Key discriminating metabolites included oxalate, m-hydroxyphenylpropionylsulfate (m-HPPS), trimethylamine-N-oxide, glycolate and scyllo-inositol (higher in slc26a6 null mice) and hippurate, taurine, trimethylamine, and citrate (lower in slc26a6 null mice). In addition to the reduced efficiency of anion transport, several of these metabolites (hippurate, m-HPPS, methylamines) reflect alteration in gut microbial cometabolic activities. Gender-related metabotypes were also observed in both wild type and slc26a6 null groups. Urinary metabolites that showed a sex-specific pattern included trimethylamine, trimethylamine-N-oxide, citrate, spermidine, guanidinoacetate, and 2-oxoisocaproate. The gender-dependent metabolic expression of the consequences of slc26a6 deletion might have relevance to the difference in prevalence of renal stone formation in men and women. The different composition of microbial metabolites in the slc26a6 null mice is consistent with the fact that the slc26a6 transporter is found in a range of tissues, including the kidney and intestine, and provides further evidence for the "long reach" of the microbiota in physiological and pathological processes.

Project description:BackgroundResults from observational studies regarding associations between fish (including shellfish) intake and cardiovascular disease risk factors, including blood pressure (BP) and BMI, are inconsistent.ObjectiveTo investigate associations of fish consumption and associated urinary metabolites with BP and BMI in free-living populations.MethodsWe used cross-sectional data from the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP), including 4680 men and women (40-59 y) from Japan, China, the United Kingdom, and United States. Dietary intakes were assessed by four 24-h dietary recalls and BP from 8 measurements. Urinary metabolites (2 timed 24-h urinary samples) associated with fish intake acquired from NMR spectroscopy were identified. Linear models were used to estimate BP and BMI differences across categories of intake and per 2 SD higher intake of fish and its biomarkers.ResultsNo significant associations were observed between fish intake and BP. There was a direct association with fish intake and BMI in the Japanese population sample (P trend = 0.03; fully adjusted model). In Japan, trimethylamine-N-oxide (TMAO) and taurine, respectively, demonstrated area under the receiver operating characteristic curve (AUC) values of 0.81 and 0.78 in discriminating high against low fish intake, whereas homarine (a metabolite found in shellfish muscle) demonstrated an AUC of 0.80 for high/nonshellfish intake. Direct associations were observed between urinary TMAO and BMI for all regions except Japan (P < 0.0001) and in Western populations between TMAO and BP (diastolic blood pressure: mean difference 1.28; 95% CI: 0.55, 2.02 mmHg; P = 0.0006, systolic blood pressure: mean difference 1.67; 95% CI: 0.60, 2.73 mmHg; P = 0.002).ConclusionsUrinary TMAO showed a stronger association with fish intake in the Japanese compared with the Western population sample. Urinary TMAO was directly associated with BP in the Western but not the Japanese population sample. Associations between fish intake and its biomarkers and downstream associations with BP/BMI appear to be context specific. INTERMAP is registered at www.clinicaltrials.gov as NCT00005271.

Dataset Information

Metabolic phenotyping for discovery of urinary biomarkers of diet, xenobiotics and blood pressure in the INTERMAP Study: an overview.

Publications

Metabolic phenotyping for discovery of urinary biomarkers of diet, xenobiotics and blood pressure in the INTERMAP Study: an overview.

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