title: A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin.
abstract: Methylmalonic acid (MMA) is a by-product of propionic acid metabolism through the vitamin B12 (cobalamin)-dependent enzyme methylmalonyl CoA mutase. Elevated MMA concentrations are a hallmark of several inborn errors of metabolism and indicators of cobalamin deficiency in older persons. In a genome-wide analysis of 2,210 healthy young Irish adults (median age 22 years) we identified a strong association of plasma MMA with SNPs in 3-hydroxyisobutyryl-CoA hydrolase (HIBCH, p = 8.42 × 10(-89)) and acyl-CoA synthetase family member 3 (ACSF3, p = 3.48 × 10(-19)). These loci accounted for 12% of the variance in MMA concentration. The most strongly associated SNP (HIBCH rs291466; c:2T>C) causes a missense change of the initiator methionine codon (minor-allele frequency = 0.43) to threonine. Surprisingly, the resulting variant, p.Met1?, is associated with increased expression of HIBCH mRNA and encoded protein. These homozygotes had, on average, 46% higher MMA concentrations than methionine-encoding homozygotes in young adults with generally low MMA concentrations (0.17 [0.14-0.21] μmol/L; median [25(th)-75(th) quartile]). The association between MMA levels and HIBCH rs291466 was highly significant in a replication cohort of 1,481 older individuals (median age 79 years) with elevated plasma MMA concentrations (0.34 [0.24-0.51] μmol/L; p = 4.0 × 10(-26)). In a longitudinal study of 185 pregnant women and their newborns, the association of this SNP remained significant across the gestational trimesters and in newborns. HIBCH is unique to valine catabolism. Studies evaluating flux through the valine catabolic pathway in humans should account for these variants. Furthermore, this SNP could help resolve equivocal clinical tests where plasma MMA values have been used to diagnose cobalamin deficiency.
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland. Electronic address: amolloy@tcd.ie.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Faith
authors.initials: F
authors.lastname: Pangilinan
authors.affiliation: Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Shane
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: O'Neill
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: McGaughey
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Aneliya
authors.initials: A
authors.lastname: Velkova
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Hatice Ozel
authors.initials: HO
authors.lastname: Abaan
authors.affiliation: Section of Pharmacology, Institute of Medicine, University of Bergen and Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
authors.affiliation: Northern Ireland Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, Northern Ireland.
authors.forename: Helene
authors.initials: H
authors.lastname: McNulty
authors.affiliation: Northern Ireland Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, Northern Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: Ward
authors.affiliation: Northern Ireland Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, Northern Ireland.
authors.forename: J J
authors.initials: JJ
authors.lastname: Strain
authors.affiliation: St. James's Hospital, Dublin 8, Ireland.
authors.forename: Conal
authors.initials: C
authors.lastname: Cunningham
authors.affiliation: St. James's Hospital, Dublin 8, Ireland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Casey
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Cropp
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Wilson
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA. Electronic address: lbrody@mail.nih.gov.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
mesh_terms: D000015:Abnormalities, Multiple / Q000097:blood / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D008764:Methylmalonic Acid / Q000097:blood*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011247:Pregnancy; D013869:Thiolester Hydrolases / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D014805:Vitamin B 12 / Q000097:blood*; D044465:White People; D055815:Young Adult
chemical_list: D008764:Methylmalonic Acid; D013869:Thiolester Hydrolases; C035908:3-hydroxyisobutyryl-CoA hydrolase; D014805:Vitamin B 12