Pharmacogenetics and genomics
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Pharmacogenet. Genomics · Mar 2007
Polymorphisms predicted to alter function in prostaglandin E2 synthase and prostaglandin E2 receptors.
Prostaglandin synthesis is the primary target of aspirin and other nonsteroidal antiinflammatory drugs, and thus is a pathway of major interest to pharmacology, pharmacogenetics, and epidemiology. Several lines of evidence implicate prostaglandin E2 in carcinogenesis; this study aimed to identify genetic variants in genes related to prostaglandin E2 synthesis and signaling. ⋯ We identified 23 variants, 6 of which cause amino acid changes. The non-synonymous polymorphisms in PGES, EP1, and EP2 were present only among African-Americans; both populations carried non-synonymous polymorphisms in EP4. We used two sequence homology-based programs, SIFT and PolyPhen, to predict the impact of these polymorphisms. These programs predicted that the amino-acid changes p.Phe119Val in EP1, p.Ala44Glu in EP2, and possibly p.Val7Glu in PGES, p.Thr176Ile in EP4 and p.Gly420Asp in EP4 are likely to affect protein function. Thus, these variants may be relevant for inflammatory conditions, carcinogenesis, and pharmacogenetics.
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Pharmacogenet. Genomics · Nov 2006
Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence.
Opioid-induced hyperalgesia (OIH) is a state of paradoxically increased nociceptive sensitivity seen in both humans and rodents following the resolution of the acute opioid antinociceptive effects or during periods of chronic opioid administration. Using the power of genetic analysis, we hoped to discover novel mechanisms modulating this trait. ⋯ We conclude that the use of haplotypic mapping to identify novel mechanisms controlling complex traits is a viable approach. Variants of the Abcb1b gene may explain some portion of the interstrain differences in OIH and perhaps other consequences of chronic opioid administration.
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Pharmacogenet. Genomics · Nov 2006
Functional maternal catechol-O-methyltransferase polymorphism and fetal growth restriction.
The pathophysiologic processes that occur at the cellular and molecular levels in intrauterine fetal growth restriction are largely unknown. Catechol-O-methyltransferase (COMT) is a phase II enzyme that inactivates catechol estrogens by transfer of a methyl group. A functional Val158Met polymorphism in the COMT gene has been known as a susceptible marker for breast cancer. The aim of this study was to examine the association between this polymorphism and fetal growth. ⋯ Our findings suggest that the allele encoding low-activity COMT may be a susceptible marker for intrauterine fetal growth restriction.
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Pharmacogenet. Genomics · Sep 2006
Comparative Study Controlled Clinical TrialThe mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers.
To investigate whether OPRM1 118A>G polymorphism affects analgesic and respiratory depressive effects of alfentanil and assess its role for the therapeutic range of alfentanil. ⋯ OPRM1 118A>G polymorphism affects both analgesic and respiratory depressive effects of alfentanil. However, while the analgesic effects are already partly decreased in heterozygous carriers, depending on the pain model, the respiratory depressive effects are decreased in homozygous carriers of the variant 118G allele. The therapeutic range of alfentanil was only broadened in homozygous carriers.
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Pharmacogenet. Genomics · Jun 2006
Comparative StudyIntracisternal A-particle element in the 3' noncoding region of the mu-opioid receptor gene in CXBK mice: a new genetic mechanism underlying differences in opioid sensitivity.
CXBK mice, recombinant inbred mice derived from C57BL/6By and BALB/cBy progenitors, display reduced morphine-induced analgesia. Earlier we reported that CXBK mice expressed a reduced amount of the major transcript, MOR-1 mRNA, of the mu-opioid receptor gene. The CXBK MOR-1 mRNA contains a normal coding region and an abnormally long untranslated region. ⋯ Our data suggest that differences in the MOR-1 3' untranslated region appear to cause the CXBK phenotype. This genetic mechanism underlying the CXBK phenotype may provide good insight into the possible genetic mechanisms underlying individual differences in opioid sensitivity in humans.