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.
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.
Entities:
Keywords:
amino acids; arteriosclerosis; cardiovascular diseases; genome-wide association study
Authors: Thomas S Scerri; Anna Quaglieri; Carolyn Cai; Jana Zernant; Nori Matsunami; Lisa Baird; Lea Scheppke; Roberto Bonelli; Lawrence A Yannuzzi; Martin Friedlander; Catherine A Egan; Marcus Fruttiger; Mark Leppert; Rando Allikmets; Melanie Bahlo Journal: Nat Genet Date: 2017-02-27 Impact factor: 38.330
Authors: Johannes Raffler; Nele Friedrich; Matthias Arnold; Tim Kacprowski; Rico Rueedi; Elisabeth Altmaier; Sven Bergmann; Kathrin Budde; Christian Gieger; Georg Homuth; Maik Pietzner; Werner Römisch-Margl; Konstantin Strauch; Henry Völzke; Melanie Waldenberger; Henri Wallaschofski; Matthias Nauck; Uwe Völker; Gabi Kastenmüller; Karsten Suhre Journal: PLoS Genet Date: 2015-09-09 Impact factor: 5.917
Authors: Anja Kittel; Fabian Müller; Jörg König; Maren Mieth; Heinrich Sticht; Oliver Zolk; Ana Kralj; Markus R Heinrich; Martin F Fromm; Renke Maas Journal: PLoS One Date: 2014-02-24 Impact factor: 3.240
Authors: Jaana A Hartiala; W H Wilson Tang; Zeneng Wang; Amanda L Crow; Alexandre F R Stewart; Robert Roberts; Ruth McPherson; Jeanette Erdmann; Christina Willenborg; Stanley L Hazen; Hooman Allayee Journal: Nat Commun Date: 2016-01-29 Impact factor: 14.919