CYP2C19*17 Gain-of-Function Polymorphism Is Associated With Peptic Ulcer Disease

1] Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK [2] Department of Gastroenterology, University of Liverpool, Liverpool, UK [3] The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 10/2012; 93(2). DOI: 10.1038/clpt.2012.215
Source: PubMed


Single-nucleotide polymorphisms (SNPs) in the CYP2C gene cluster have been extensively investigated as predisposing factors for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer disease (PUD) or upper gastrointestinal bleeding (UGIB). However, results have been inconclusive owing to different study designs, limited genotyping strategies, and small sample sizes. We investigated whether eight functional SNPs in the CYP2C family of genes-CYP2C8*3 (rs11572080 and rs10509681), CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17-are associated with PUD in 1,239 Caucasian patients. Logistic regression analysis showed that only CYP2C19*17 was associated with PUD (odds ratio additive model: 1.47 (95% confidence interval (CI) 1.12 to 1.92); P = 0.005; R(2) 16%), but not UGIB, independent of NSAID use or Helicobacter pylori infection. PUD distribution varied (P = 0.024) according to CYP2C19*17 genotype: *1/*1, 490 (64.3%); *1/*17, 304 (71.7%); and *17/*17, 31 (73.8%). CYP2C19*17, a gain-of-function polymorphism, is associated with PUD irrespective of etiology.Clinical Pharmacology & Therapeutics (2012); advance online publication 26 December 2012. doi:10.1038/clpt.2012.215.

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    • "A recent study has linked CYP2C19*2 rs4244285 with the regulation of blood pressure [47]. CYP2C19 may also influence arachidonic acid metabolism predisposing to peptic ulcer disease [48,49] and vascular disease [50]. These functions might also influence the interaction with environmental pathogens although the mechanism by which the resulting selective force might operate and the strength of the selective pressure that would result is not clear. "
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    ABSTRACT: Cytochrome P450 CYP2C19 metabolises a wide range of pharmacologically active substances and a relatively small number of naturally occurring environmental toxins. Poor activity alleles of CYP2C19 are very frequent worldwide, particularly in Asia, raising the possibility that reduced metabolism could be advantageous in some circumstances. The evolutionary selective forces acting on this gene have not previously been investigated.We analyzed CYP2C19 genetic markers from 127 Gambians and on 120 chromosomes from Yoruba, Europeans and Asians (Japanese + Han Chinese) in the Hapmap database. Haplotype breakdown was explored using bifurcation plots and relative extended haplotype homozygosity (REHH). Allele frequency differentiation across populations was estimated using the fixation index (FST) and haplotype diversity with coalescent models. Bifurcation plots suggested conservation of alleles conferring slow metabolism (CYP2C19*2 and *3). REHH was high around CYP2C19*2 in Yoruba (REHH 8.3, at 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at -29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19*3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity < = 0.037, p <0.001. We found some evidence that the slow metabolising allele CYP2C19*2 is subject to positive selective forces worldwide. Similar evidence was also found for CYP2C19*3 which is frequent only in Asia. FST is low at the CYP2C19 locus, suggesting balancing selection overall. The biological factors responsible for these selective pressures are currently unknown. One possible explanation is that early humans were exposed to a ubiquitous novel toxin activated by CYP2C19. The genetic adaptation took place within the last 10,000 years which coincides with the development of systematic agricultural practices.
    BMC Evolutionary Biology 04/2014; 14(1):71. DOI:10.1186/1471-2148-14-71 · 3.37 Impact Factor
  • 10/2014; 28(9):488.
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    ABSTRACT: Background Polymorphism of CYP2C19 gene is one of the important factors in pharmacokinetics of CYP2C19 substrates. Omeprazole is a proton pump inhibitor which is mainly metabolized by cytochrome P450 2C19 (CYP2C19). The aim of present study was to assess omeprazole hydroxylation index as a measure of CYP2C19 activity considering new variant allele (CYP2C19*17) in Iranian population and also to see if this activity is sex dependent.Methods One hundred and eighty healthy unrelated Iranian individuals attended in this study. Blood samples for genotyping and phenotyping were collected 3 hours after administration of 20 mg omeprazole orally. Genotyping of 2C19 variant alleles *2, *3 and *17 was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and semi-nested PCR methods. Plasma concentrations of omeprazole and hydroxyomeprazole were determined by high performance liquid chromatography (HPLC) technique and hydxroxylation index (HI) (omeprazole/ hydroxyomeprazole) was calculated.ResultsThe CYP2C19*17 was the most common variant allele in the studied population (21.6%). Genotype frequencies of CYP2C19*17*17, *1*17, and *2*17 were 5.5%, 28.8% and 3.3% respectively. The lowest and the highest median omeprazole HI was observed in *17*17 and *2*2 genotypes respectively (0.36 vs. 13.09). The median HI of omeprazole in subjects homozygous for CYP2C19*1 was 2.16-fold higher than individuals homozygous for CYP2C19*17 (P¿<¿0.001) and the median HI of CYP2C19*1*17 genotype was 1.98-fold higher than CYP2C19 *17*17 subjects (P¿<¿0.001). However, subjects with CYP2C19*2*17 (median HI: 1.74) and CYP2C19*1*2 (median HI: 1.98) genotypes and also CYP2C19*1*17 (median HI: 0.71) and CYP2C19*1*1 (mean HI: 0.78) did not show any significantly different enzyme activity. In addition, no statistically significant difference was found between women and men in distribution of CYP2C19 genotypes. Furthermore, the hydroxylation index of Omeprazole was not different between women and men in the studied population.Conclusion Our data point out the importance of CYP2C19*2 and CYP2C19*17 variant alleles in metabolism of omeprazole and therefore CYP2C19 activity. Regarding the high frequency of CYP2C19*17 in Iranian population, the importance of this new variant allele in metabolism of CYP2C19 substrates shall be considered.
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