ArticleAmerican journal of human genetics2016
A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 58 citations in OpenAlex.
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- Understanding the Genetic Architecture of Vitamin Status Biomarkers in the Genome-Wide Association Study Era: Biological Insights and Clinical Significance.Advances in nutrition (Bethesda, Md.) · 2024Review
- Vitamin BInternational journal of molecular sciences · 2024Review
- A Fatal Case of 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency in a Term Infant with Severe High Anion Gap Acidosis and Review of the Literature.Case reports in genetics · 2024Article
- Vitamin BBMJ (Clinical research ed.) · 2023Article
- Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study.BMC cancer · 2023Observational
- Vitamin BFood & nutrition research · 2023Article
- Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans.The Journal of nutrition · 2022Article
- 3-Hydroxyisobutyryl-CoA hydrolase deficiency in an infant with developmental delay and high anion gap acidosis.Clinical case reports · 2021Article
- N-Terminal Acetyltransferases Are Cancer-Essential Genes Prevalently Upregulated in Tumours.Cancers · 2020Article
- Associations of Circulating Methylmalonic Acid and Vitamin B-12 Biomarkers Are Modified by Vegan Dietary Pattern in Adult and Elderly Participants of the Adventist Health Study 2 Calibration Study.Current developments in nutrition · 2020Article
- Assessing the genetic association between vitamin B6 metabolism and genetic generalized epilepsy.Molecular genetics and metabolism reports · 2019Article
- Age-specific reference ranges are needed to interpret serum methylmalonic acid concentrations in the US population.The American journal of clinical nutrition · 2019Article
- The Many Faces of Cobalamin (Vitamin BMayo Clinic proceedings. Innovations, quality & outcomes · 2019Review
- Homocysteine Metabolism in Children and Adolescents: Influence of Age on Plasma Biomarkers and Correspondent Genotype Interactions.Nutrients · 2019Article
- 3-Hydroxyisobutyryl-CoA hydrolase deficiency in an Iranian child with novel HIBCH compound heterozygous mutations.Clinical case reports · 2019Article
- ComPaSS-GWAS: A method to reduce type I error in genome-wide association studies when replication data are not available.Genetic epidemiology · 2019Article
- Vitamin BJournal of nutritional science · 2019Article
- Article
- The 677C→T variant of MTHFR is the major genetic modifier of biomarkers of folate status in a young, healthy Irish population.The American journal of clinical nutrition · 2018Article
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Authors and funding
19 authors at 7 institutions in 4 countries.
Funding
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.
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