Genome-Wide Association Study Identifies 3 Genomic Loci Significantly Associated With Serum Levels of Homoarginine: The AtheroRemo Consortium

Background—Low serum levels of the amino acid derivative, homoarginine, have been associated with increased risk of total and cardiovascular mortality. Homoarginine deficiency may be related to renal and heart diseases, but the pathophysiologic role of homoarginine and the genetic regulation of its serum levels are largely unknown. Methods and Results—In 3041 patients of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study referred for coronary angiography and 2102 participants of the Young Finns Study (YFS), we performed a genome-wide association study to identify genomic loci associated with homoarginine serum levels and tested for associations of identified single-nucleotide polymorphisms with mortality in LURIC. We found genome-wide significant associations with homoarginine serum levels on chromosome 2 at the carbamoyl phosphate synthetase I locus, on chromosome 5 at the alanine-glyoxylate aminotransferase 2 locus, and on chromosome 15 at the glycine amidinotransferase locus, as well as a suggestive association on chromosome 6 at the Homo sapiens mediator complex subunit 23 gene/arginase I locus. All loci harbor enzymes located in the mitochondrium are involved in arginine metabolism. The strongest association was observed for rs1153858 at the glycine amidinotransferase locus with a P value of 1.25E-45 in the combined analysis and has been replicated in both the Die Deutsche Diabetes Dialyse Studie (4D study) and the Graz Endocrine Causes of Hypertension (GECOH) study. Conclusions—In our genome-wide association study, we identified 3 chromosomal regions significantly associated with serum homoarginine and another region with suggestive association, providing novel insights into the genetic regulation of homoarginine.

[1]  James Tomlinson,et al.  Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[2]  H. Blom,et al.  Promiscuous activity of arginine:glycine amidinotransferase is responsible for the synthesis of the novel cardiovascular risk factor homoarginine , 2012, FEBS letters.

[3]  W. März,et al.  Homoarginine deficiency is associated with increased bone turnover , 2012, Osteoporosis International.

[4]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[5]  W. März,et al.  Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients , 2011, European journal of heart failure.

[6]  Christian Gieger,et al.  A genome-wide association study of metabolic traits in human urine , 2011, Nature Genetics.

[7]  O. Lichtarge,et al.  Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations , 2011, Human mutation.

[8]  W. März,et al.  Low homoarginine concentration is a novel risk factor for heart disease , 2011, Heart.

[9]  W. März,et al.  Low Serum Homoarginine Is a Novel Risk Factor for Fatal Strokes in Patients Undergoing Coronary Angiography , 2011, Stroke.

[10]  G. Abecasis,et al.  MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes , 2010, Genetic epidemiology.

[11]  W. März,et al.  Homoarginine, Cardiovascular Risk, and Mortality , 2010, Circulation.

[12]  Tsun-Po Yang,et al.  Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies , 2010, Bioinform..

[13]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[14]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[15]  R. Eils,et al.  Comparison of normalization methods for Illumina BeadChip HumanHT-12 v3 , 2010, BMC Genomics.

[16]  Uwe Völker,et al.  New loci associated with kidney function and chronic kidney disease , 2010, Nature Genetics.

[17]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[18]  Yurii S. Aulchenko,et al.  ProbABEL package for genome-wide association analysis of imputed data , 2010, BMC Bioinformatics.

[19]  D. Murry,et al.  Human Alanine-Glyoxylate Aminotransferase 2 Lowers Asymmetric Dimethylarginine and Protects from Inhibition of Nitric Oxide Production* , 2009, The Journal of Biological Chemistry.

[20]  T. Pieber,et al.  Graz Endocrine Causes of Hypertension (GECOH) study: a diagnostic accuracy study of aldosterone to active renin ratio in screening for primary aldosteronism , 2009, BMC endocrine disorders.

[21]  R. Collins,et al.  Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population: A Genome-Wide Evaluation of 13 974 Participants in the Women’s Genome Health Study , 2009, Circulation. Cardiovascular genetics.

[22]  M. Brosnan,et al.  Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. , 2009, American journal of physiology. Endocrinology and metabolism.

[23]  Risto Telama,et al.  Cohort profile: the cardiovascular risk in Young Finns Study. , 2008, International journal of epidemiology.

[24]  J. Calvin,et al.  Simultaneous determination of guanidinoacetate, creatine and creatinine in urine and plasma by un-derivatized liquid chromatography-tandem mass spectrometry , 2008, Annals of clinical biochemistry.

[25]  T. Laitinen,et al.  Serum L-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation. , 2008, Circulation journal : official journal of the Japanese Circulation Society.

[26]  J. Ribalta,et al.  Reference values for plasma concentrations of asymmetrical dimethylarginine (ADMA) and other arginine metabolites in men after validation of a chromatographic method. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[27]  M. Yacoub,et al.  Myocardial Expression of the Arginine:Glycine Amidinotransferase Gene Is Elevated in Heart Failure and Normalized After Recovery: Potential Implications for Local Creatine Synthesis , 2006, Circulation.

[28]  T. Lehtimäki,et al.  The Finnish Cardiovascular Study (FINCAVAS): characterising patients with high risk of cardiovascular morbidity and mortality , 2006, BMC cardiovascular disorders.

[29]  W. März,et al.  Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. , 2005, The New England journal of medicine.

[30]  W. März,et al.  Randomized Controlled Trial on the Efficacy and Safety of Atorvastatin in Patients with Type 2 Diabetes on Hemodialysis (4D Study): Demographic and Baseline Characteristics , 2004, Kidney and Blood Pressure Research.

[31]  A. Willis,et al.  Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. , 2004, Molecular genetics and metabolism.

[32]  D. Vaughan,et al.  Relationship Between Carbamoyl-Phosphate Synthetase Genotype and Systemic Vascular Function , 2004, Hypertension.

[33]  R. Nijveldt,et al.  Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. , 2002, Analytical biochemistry.

[34]  G Cioni,et al.  Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. , 2001, American journal of human genetics.

[35]  W F Walsh,et al.  Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. , 2001, The New England journal of medicine.

[36]  W. März,et al.  Rationale and design of the LURIC study--a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. , 2001, Pharmacogenomics.

[37]  A. Ooshima,et al.  Molecular cloning and sequencing of a cDNA encoding alanine-glyoxylate aminotransferase 2 from rat kidney. , 1995, Journal of biochemistry.

[38]  A. Hrabák,et al.  Comparison of substrate and inhibitor specificity of arginase and nitric oxide (NO) synthase for arginine analogues and related compounds in murine and rat macrophages. , 1994, Biochemical and biophysical research communications.

[39]  M. Kimoto,et al.  Purification and properties of a new enzyme, NG,NG-dimethylarginine dimethylaminohydrolase, from rat kidney. , 1989, The Journal of biological chemistry.

[40]  R. Johnson,et al.  Homoarginine synthesis by rat kidney. , 1969, Archives of biochemistry and biophysics.

[41]  I. Wells,et al.  Homocitrulline and Homoarginine Synthesis from Lysine , 1964, Science.

[42]  S. Moore,et al.  Automatic recording apparatus for use in the chromatography of amino acids. , 1958, Federation proceedings.

[43]  A. Heerschap,et al.  L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome. , 2013, Human molecular genetics.

[44]  W. März,et al.  Associations of homoarginine with bone metabolism and density, muscle strength and mortality: cross-sectional and prospective data from 506 female nursing home patients , 2012, Osteoporosis International.

[45]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[46]  S. Henikoff,et al.  Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm , 2009, Nature Protocols.

[47]  A. Schulze.  Creatine deficiency syndromes , 2003, Molecular and Cellular Biochemistry.