title: Reanalysis of mGWAS results and in vitro validation show that lactate dehydrogenase interacts with branched-chain amino acid metabolism.
abstract: The assignment of causative genes to noncoding variants identified in genome-wide association studies (GWASs) is challenging. We show how combination of knowledge from gene and pathway databases and chromatin interaction data leads to reinterpretation of published quantitative trait loci for blood metabolites. We describe a previously unidentified link between the rs2403254 locus, which is associated with the ratio of 3-methyl-2-oxobutanoate and alpha-hydroxyisovalerate levels, and the distal LDHA gene. We confirmed that lactate dehydrogenase can catalyze the conversion between these metabolites in vitro, suggesting that it has a role in branched-chain amino acid metabolism. Examining datasets from the ENCODE project we found evidence that the locus and LDHA promoter physically interact, showing that LDHA expression is likely under control of distal regulatory elements. Importantly, this discovery demonstrates that bioinformatic workflows for data integration can have a vital role in the interpretation of GWAS results.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Research, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mattijs M
authors.initials: MM
authors.lastname: Heemskerk
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Research, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vanessa J A
authors.initials: VJ
authors.lastname: van Harmelen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Research, Leiden University Medical Center, Leiden, The Netherlands.|Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ko Willems
authors.identifier: http://orcid.org/0000-0002-2172-7394
authors.initials: KW
authors.lastname: van Dijk
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Research, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan Bert
authors.initials: JB
authors.lastname: van Klinken
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D015870:Gene Expression; D055106:Genome-Wide Association Study; D045782:Hemiterpenes; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007651:Keto Acids / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D040641:Quantitative Trait Loci; D014631:Valerates / Q000378:metabolism*
chemical_list: D000597:Amino Acids, Branched-Chain; D045782:Hemiterpenes; D007527:Isoenzymes; D007651:Keto Acids; D014631:Valerates; C035864:2-hydroxyisovaleric acid; C001505:alpha-ketoisovalerate; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5