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: Anne M Molloy, Faith Pangilinan, James L Mills, Barry Shane, Mary B O'Neill, David M McGaughey, Aneliya Velkova, Hatice Ozel Abaan, Per M Ueland, Helene McNulty, Mary Ward, J J Strain, Conal Cunningham, Miriam Casey, Cheryl D Cropp, Yoonhee Kim, Joan E Bailey-Wilson, Alexander F Wilson, Lawrence C Brody
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 98 Issue 5 Pg. 869-882 (May 05 2016) ISSN: 1537-6605 [Electronic] United States
• PMID: 27132595 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Methylmalonic Acid
• Thiolester Hydrolases
• 3-hydroxyisobutyryl-CoA hydrolase
• Vitamin B 12

Topics

• Abnormalities, Multiple (blood, genetics)
• Adolescent
• Adult
• Aged
• Amino Acid Metabolism, Inborn Errors (blood, genetics)
• Case-Control Studies
• Female
• Homozygote
• Humans
• Infant, Newborn
• Longitudinal Studies
• Male
• Methylmalonic Acid (blood)
• Middle Aged
• Polymorphism, Genetic (genetics)
• Pregnancy
• Thiolester Hydrolases (blood, deficiency, genetics)
• Vitamin B 12 (blood)
• White People
• Young Adult