Genotypic screening of the main opiate‐related polymorphisms in a cohort of 139 sickle cell disease patients

Abstract

10. Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Much of sickle cell disease (SCD) morbidity is due to recurrent painful crises mainly treated by codeine and morphine. However, surprisingly, there are no genotypic data that relate to the frequency of the main opiate-related SNPs in SCD populations [4]. One may argue that the allelic frequencies for African-Americans (AA) are known and that, since SCD patients are mostly of AA origins, their allelic frequencies should be the same. Obviously, this remark is true but we thought it was important to consider the particular subgroup of SCD patients to ensure that some SNPs were not under-or over-represented because of a founder effect. We, thus, decided to perform, in a cohort of 139 SCD patients, a quite extensive genotyping of these SNPs (Table I) with a haplotypic interpretation for those located on the same locus (Table II).Codeine is a pro-drug inactive by itself until it is metabolized into morphine by the CYP2D6 pathway. After oral or parenteral administration, morphine is partially metabolized by the CYP3A pathway (CYP3A4 and CYP3A5 genes) and by the UGT2B7 enzyme. Independently, an increased ABCB1 activity (a well-known drug efflux protein) is also expected to decrease the bioavailability of both morphine (brain efflux) and codeine (gut efflux) [10]. Very logically, the most frequent polymorphisms that modify the enzymatic activity were chosen for each pathway. For the CYP3A pathway, we genotyped two SNPs associated with a lower CYP3A activity: rs2740574 (A-392G 5 *1B allele) on the CYP3A4 gene (wild-type *1A) and rs776746 (A6986G 5 *3 allele) on the CYP3A5 gene (wild-type *1) [11]. For the UGT2B7 gene, we genotyped two SNPs associated with a lower glucuronidation of morphine and codeine: rs7438135 (A-840G) and rs73823859 (G-79A) [12,13]. For the CYP2D6 gene, we searched: (i) two polymorphisms associated with a null activity: rs892097 (G1846A 5 *4 allele) and the whole gene deletion (*5 allele), (ii) a SNP associated with an intermediate activity and very prevalent in the African population: rs28371706 (C1023T 5 *17 allele), and (iii) a gene duplication associated with an enhanced activity [8,14]. For the ABCB1 gene, we genotyped three SNPs associated with a variation (decrease or increase) of the efflux activity for many drugs: rs1128503 (C1236T) on exon 12, rs2032582 (G2677T) on exon 21 and rs1045642 (C3435T) on exon 26 [15]. Interestingly, the mutant T nucleotide for rs1045642 has been associated with a better morphine pain relief in two independent studies [16,17]. By taking these three SNPs together, some authors have defined the three main ABCB1 haplotypes [6,7]: (i) the *1 allele (C/G/C) which is the wild-type allele, (ii) the *2 allele (T/T/T), and (iii) the *2Kr allele (C/G/T).Two SNPs are mainly responsible for a lower analgesic effect of opioids. The most important one is A118G (Asn40Asp-rs1799971) on the OPRM1 gene [1,18], and the second one is G322A (Val158Met-rs4680) on the C...

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

“…With respect to the percentages of poor metabolizers and ultrarapid metabolizers, our findings are consistent with other CYP2D6 genotype analyses in African American patients with or without SCD and differ from the distribution of CYP2D6 phenotypes in individuals of European ancestry. [45][46][47][48] African American patients are more likely to be ultra-rapid metabolizers and less likely to be poor metabolizers compared with individuals of European ancestry. In our cohort, 53 patients with SCD (9% of patients with a known CYP2D6 genotype) have a high-risk CYP2D6 result (44 ultra-rapid metabolizers or possible ultra-rapid metabolizers and 9 poor metabolizers).…”

Prevalence of Pain-Related Single Nucleotide Polymorphisms in Patients of African Origin with Sickle Cell Disease

“…The survey includes genotype and allele frequency data for genes including OPRM1 (rs1799971) and ABCB1 (rs1045642) in an SCD cohort [24]. We found no differences between our study population and their two cohorts for these two SNPs for either genotype or allele frequencies.…”

“…A previous study reported major opiate-related polymorphisms in an SCD cohort [24]. The survey includes genotype and allele frequency data for genes including OPRM1 (rs1799971) and ABCB1 (rs1045642) in an SCD cohort [24].…”

“…Transient receptor potential (TRP) channels, which show therapeutic promise in pain relief [35] and inflammation in SCD also play, a prominent role [6]. There also has been a study reporting frequency data on major opiate-related polymorphisms in genes including OPRM1, COMT, CYP2D6, CYP3A, UGT2B7 and ABCB1 in an SCD cohort [24]. The survey includes genotype and allele frequency data for genes including OPRM1 (rs1799971) and ABCB1 (rs1045642).…”

Polymorphisms and Haplotypes of the UDP-Glucuronosyltransferase 2B7 Gene Promoter

“…Previous studies reported a similar higher promoter activity of haplotype II over haplotype I in the context of much shorter promoter regions; however, the functionality of this SNP was not verified by mutagenesis in these studies (Duguay et al, 2004;Nakamura et al, 2008). To further support the importance of this SNP, recent studies have shown that the production of acylmycophenolic acid-glucuronide was significantly higher in AA-and GA-human liver microsomes compared with GG-human liver microsomes (Djebli et al, 2007) and that GG and GA genotypes were associated with lower morphine glucuronide/morphine AUC (area under the concentration-time curve) ratios compared with the ratios of AA genotypes in patients with sickle cell disease treated with morphine (Darbari et al, 2008;Joly et al, 2012). Nakamura et al (2008) showed binding of transcription factors to the UGT2B7 promoter region covering SNP -900A.G by electrophoretic mobility shift assays; however, the identity of the transcription factor(s) involved was not defined in this study.…”