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Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.

ABSTRACT: Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.

SUBMITTER: Burkhardt R

PROVIDER: S-EPMC4581711 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.

Burkhardt Ralph R Kirsten Holger H Beutner Frank F Holdt Lesca M LM Gross Arnd A Teren Andrej A Tönjes Anke A Becker Susen S Krohn Knut K Kovacs Peter P Stumvoll Michael M Teupser Daniel D Thiery Joachim J Ceglarek Uta U Scholz Markus M

PLoS genetics 20150924 9

Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based ...[more]

PMID: 26401656

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Project description:Background Identification of metabolomics profile in subjects with different blood pressure, including normal blood pressure, elevated blood pressure, stage 1 hypertension, and stage 2 hypertension, would be a promising strategy to understand the pathogenesis of hypertension. Thus, we conducted this study to investigate the association of plasma acylcarnitines and amino acids with hypertension in a large Iranian population. Methods 1200 randomly selected subjects from the national survey on the Surveillance of Risk Factors of Non-Communicable Diseases in Iran (STEPs 2016) were divided into four groups based on the ACC/AHA hypertension criteria: normal blood pressure (n = 293), elevated blood pressure (n = 135), stage 1 hypertension (n = 325), and stage 2 hypertension (n = 447). Plasma concentrations of 30 acylcarnitines and 20 amino acids were measured using a targeted approach with flow-injection tandem mass spectrometry. Univariate and multivariate logistic regression analysis was applied to estimate the association between metabolites level and the risk of hypertension. Age, sex, BMI, total cholesterol, triglyceride, HDL cholesterol, fasting plasma glucose, use of oral glucose-lowering drugs, statins, and antihypertensive drugs were adjusted in regression analysis. Results Of 50 metabolites, 34 were associated with an increased likelihood of stage 2 hypertension and 5 with a decreased likelihood of stage 2 hypertension. After full adjustment for potential confounders, 5 metabolites were still significant risk markers for stage 2 hypertension including C0 (OR = 0.75; 95%CI: 0.63, 0.90), C12 (OR = 1.18; 95%CI: 1.00, 1.40), C14:1 (OR = 1.20; 95%CI: 1.01, 1.42), C14:2 (OR = 1.19; 95%CI: 1.01, 1.41), and glycine (OR = 0.81; 95%CI: 0.68, 0.96). An index that included glycine and serine also showed significant predictive value for stage 2 hypertension after full adjustment (OR = 0.86; 95%CI: 0.75, 0.98). Conclusions Five metabolites were identified as potentially valuable predictors of stage 2 hypertension.

Dataset Information

Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.

Publications

Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.

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