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Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.

Publication ,  Journal Article
Nackley, AG; Shabalina, SA; Lambert, JE; Conrad, MS; Gibson, DG; Spiridonov, AN; Satterfield, SK; Diatchenko, L
Published in: PLoS One
2009

Catechol-O-methyltransferase (COMT) is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val(158)met) position, designated as low (LPS), average (APS), and high pain sensitive (HPS), are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs), accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224) is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488) are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2009

Volume

4

Issue

4

Start / End Page

e5237

Location

United States

Related Subject Headings

  • RNA, Messenger
  • Polymorphism, Single Nucleotide
  • Pain Threshold
  • Nucleic Acid Conformation
  • Humans
  • Haplotypes
  • Genotype
  • Genetic Markers
  • General Science & Technology
  • Expressed Sequence Tags
 

Citation

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Nackley, A. G., Shabalina, S. A., Lambert, J. E., Conrad, M. S., Gibson, D. G., Spiridonov, A. N., … Diatchenko, L. (2009). Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs. PLoS One, 4(4), e5237. https://doi.org/10.1371/journal.pone.0005237
Nackley, Andrea G., Svetlana A. Shabalina, Jason E. Lambert, Mathew S. Conrad, Dustin G. Gibson, Alexey N. Spiridonov, Sarah K. Satterfield, and Luda Diatchenko. “Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.PLoS One 4, no. 4 (2009): e5237. https://doi.org/10.1371/journal.pone.0005237.
Nackley AG, Shabalina SA, Lambert JE, Conrad MS, Gibson DG, Spiridonov AN, et al. Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs. PLoS One. 2009;4(4):e5237.
Nackley, Andrea G., et al. “Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.PLoS One, vol. 4, no. 4, 2009, p. e5237. Pubmed, doi:10.1371/journal.pone.0005237.
Nackley AG, Shabalina SA, Lambert JE, Conrad MS, Gibson DG, Spiridonov AN, Satterfield SK, Diatchenko L. Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs. PLoS One. 2009;4(4):e5237.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2009

Volume

4

Issue

4

Start / End Page

e5237

Location

United States

Related Subject Headings

  • RNA, Messenger
  • Polymorphism, Single Nucleotide
  • Pain Threshold
  • Nucleic Acid Conformation
  • Humans
  • Haplotypes
  • Genotype
  • Genetic Markers
  • General Science & Technology
  • Expressed Sequence Tags