A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin

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, H McNulty, M Ward, JJ Strain, Conal Cunningham, Miriam Casey, Cheryl D. Cropp, Yoonhee Kim, Joan E. Bailey-Wilson, Alexander F. Wilson, Lawrence C. Brody

Research output: Contribution to journalArticle

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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 [25th–75th 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.
LanguageEnglish
Pages869-882
Number of pages13
JournalAmerican Journal of Human Genetics
Volume98
Issue number5
Early online date28 Apr 2016
DOIs
Publication statusPublished - 5 May 2016

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Methylmalonic Acid
Vitamin B 12
Single Nucleotide Polymorphism
3-hydroxyisobutyryl-CoA hydrolase
Homozygote
Valine
Methionine
Young Adult
Methylmalonyl-CoA Mutase
Newborn Infant
Coenzyme A Ligases
Inborn Errors Metabolism
Initiator Codon
Threonine
Gene Frequency
Longitudinal Studies
Pregnant Women
Genome

Cite this

Molloy, A. M., Pangilinan, F., Mills, J. L., Shane, B., O’Neill, M. B., McGaughey, D. M., ... Brody, L. C. (2016). A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin. American Journal of Human Genetics, 98(5), 869-882. https://doi.org/10.1016/j.ajhg.2016.03.005
Molloy, Anne M. ; Pangilinan, Faith ; Mills, James L. ; Shane, Barry ; O’Neill, Mary B. ; McGaughey, David M. ; Velkova, Aneliya ; Abaan, Hatice Ozel ; Ueland, Per M. ; McNulty, H ; Ward, M ; Strain, JJ ; Cunningham, Conal ; Casey, Miriam ; Cropp, Cheryl D. ; Kim, Yoonhee ; Bailey-Wilson, Joan E. ; Wilson, Alexander F. ; Brody, Lawrence C. / A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 5. pp. 869-882.
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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 [25th–75th 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.",
author = "Molloy, {Anne M.} and Faith Pangilinan and Mills, {James L.} and Barry Shane and O’Neill, {Mary B.} and McGaughey, {David M.} and Aneliya Velkova and Abaan, {Hatice Ozel} and Ueland, {Per M.} and H McNulty and M Ward and JJ Strain and Conal Cunningham and Miriam Casey and Cropp, {Cheryl D.} and Yoonhee Kim and Bailey-Wilson, {Joan E.} and Wilson, {Alexander F.} and Brody, {Lawrence C.}",
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Molloy, AM, Pangilinan, F, Mills, JL, Shane, B, O’Neill, MB, McGaughey, DM, Velkova, A, Abaan, HO, Ueland, PM, McNulty, H, Ward, M, Strain, JJ, Cunningham, C, Casey, M, Cropp, CD, Kim, Y, Bailey-Wilson, JE, Wilson, AF & Brody, LC 2016, 'A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin', American Journal of Human Genetics, vol. 98, no. 5, pp. 869-882. https://doi.org/10.1016/j.ajhg.2016.03.005

A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin. / Molloy, Anne M.; Pangilinan, Faith; Mills, James L.; Shane, Barry; O’Neill, Mary B.; McGaughey, David M.; Velkova, Aneliya; Abaan, Hatice Ozel; Ueland, Per M.; McNulty, H; Ward, M; Strain, JJ; Cunningham, Conal; Casey, Miriam; Cropp, Cheryl D.; Kim, Yoonhee; Bailey-Wilson, Joan E.; Wilson, Alexander F.; Brody, Lawrence C.

In: American Journal of Human Genetics, Vol. 98, No. 5, 05.05.2016, p. 869-882.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin

AU - Molloy, Anne M.

AU - Pangilinan, Faith

AU - Mills, James L.

AU - Shane, Barry

AU - O’Neill, Mary B.

AU - McGaughey, David M.

AU - Velkova, Aneliya

AU - Abaan, Hatice Ozel

AU - Ueland, Per M.

AU - McNulty, H

AU - Ward, M

AU - Strain, JJ

AU - Cunningham, Conal

AU - Casey, Miriam

AU - Cropp, Cheryl D.

AU - Kim, Yoonhee

AU - Bailey-Wilson, Joan E.

AU - Wilson, Alexander F.

AU - Brody, Lawrence C.

PY - 2016/5/5

Y1 - 2016/5/5

N2 - 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 [25th–75th 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.

AB - 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 [25th–75th 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.

U2 - 10.1016/j.ajhg.2016.03.005

DO - 10.1016/j.ajhg.2016.03.005

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