Effects Of Several Single Nucleotide Polymorphisms Research Articles

CYP2C9*3 Increases the Ibuprofen Response of Hemodynamically Significant Patent Ductus Arteriosus in the Infants with Gestational Age of More Than 30 Weeks.

The online version contains supplementary material available at 10.1007/s43657-021-00028-9.

Causal effects of cardiovascular risk factors on onset of major age-related diseases: A time-to-event Mendelian randomization study

BackgroundsElucidating the causal effects of common intermediate risk factors on the onset of age-related diseases is indispensable for developing prevention and intervention procedures. MethodsWe conducted two-stage time-to-event Mendelian randomization meta-analyses combining five large-scale longitudinal cohorts to investigate dynamic causal effects of cardiovascular disease risk factors including body mass index (BMI), systolic blood pressure (SBP), and lipids on the age-at-onset of age-related diseases. We constructed weighted polygenic scores based on genetic markers from previously reported genome-wide association studies as instrumental variables to estimate the causal effects. To avoid false positive due to potential pleiotropic effects of the genetic markers, we performed a leave-one-out sensitivity analysis and an MR-Egger sensitivity analysis that we expanded in the survival context. ResultsOur results show that elevated BMI increases the absolute risk of type 2 diabetes (T2D) (p=7.68e−04), heart failure (p=9.03e−03), and cardiovascular diseases (CVD) (p=1.69e−03) and the causal effects start at different ages. A significant association between BMI and the risk of stroke is observed; however, the sensitivity analyses suggest that the association is attributed to the potential pleiotropic effects of rs2867125 and rs1558902. Raised SBP levels are significantly associated with the development of atrial fibrillation (p=6.42e−03). Low-density lipoprotein cholesterol (LDL-C) levels are inversely associated with the age-at-onset of T2D (p=1.05e−02). In addition, LDL-C and triglycerides are inversely associated with the risks of cancer and T2D, respectively. Nevertheless, the sensitivity analyses suggest that these associations are probably due to pleiotropic effects of several single-nucleotide polymorphisms including rs4970834 and rs1260326. ConclusionsOur results highlight the involvement of BMI in the development of multiple age-related diseases. Some observed causal associations can attribute to pleiotropic effects of some genetic variations. These findings have important implications in unraveling causal effects of common risk factors on age-related diseases and guiding effective intervention strategies to reduce the incidence of these diseases.

Abstract A61: Prognostic relevance of genome-wide association studies-identified single nucleotide polymorphisms in primary breast cancer

Abstract Purpose: Several single nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies (GWAS). We investigated whether eight risk SNPs identified in GWAS were associated with breast cancer disease-free survival (DFS) and overall survival (OS). Methods: A cohort of 739 white women with early-stage breast carcinoma was genotyped for eight GWAS-identified SNPs (rs2981582, rs1219648, rs3803662, rs12443621, rs8051542, rs999737, rs6504950, rs4973768), using Illumina GoldenGate platform. The relationships between SNPs and breast cancer outcomes were evaluated using univariate and multivariate Cox proportional hazard regression models. The cumulative effects of SNPs were assessed by computing the number of at-risk-alleles based on the results from the univariate analyses. In addition, we explored higher-order interactions between clinical variables and SNPs using classification and regression tree (CART) analysis. Results: Four SNPs (rs2981582, rs1219648, rs12443621 and rs6504950) were significantly associated with OS using univariate Cox proportional hazard regression analysis (P≤0.1) and there was no association with DFS. In multivariate model adjusted for age, hormonal status, clinical stage, and treatment, rs12443621 (16q12) and rs6504950 (17q23) polymorphisms remained as independent prognostic markers for OS. Compared with the GG/AG reference group, homozygous carriers of minor A allele for rs12443621 and rs6504950 had an increased risk for death (HR:1.38, 95% CI:1.01 to 1.86; P=0.04, and HR:1.80, 95% CI:1.18 to 2.77; P=0.007, respectively). In multivariate analysis, a higher risk for death was found in the sub-cohort of patients harboring 3–4 at-risk-alleles of the GWAS SNPs compared to patients carrying ≤2 at-risk-alleles (HR:1.5, 95% CI:1.14 to 1.85; P=0.002). In CART modeling, women with stage 2 breast cancer who did not receive chemotherapy and were carries of the AA genotype for rs6504950 had the highest risk for death (HR:10.0, 95% CI:3.47 to 28.78). Conclusion: SNPs in previously identified breast cancer risk susceptibility loci, rs12443621 (16q12) and rs6504950 (17q23), were also found to be independent prognostic markers for OS in breast cancer patients. The precise molecular mechanisms through which these SNPs influence clinical outcomes remain to be determined. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A61.

Effect of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Calcineurin Inhibitors: Part II

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes - in particular, CYP3A4 and CYP3A5 - and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacodynamics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed and all relevant primary research articles were critiqued and summarized. There is no evidence that the CYP3A4 -392A>G SNP has an effect on the pharmacodynamics of either ciclosporin or tacrolimus; however, studies have been limited. For patients prescribed ciclosporin, the CYP3A5 6986A>G SNP may influence long-term survival, possibly because of a different metabolite pattern over time. This SNP has no clear association with acute rejection during ciclosporin therapy. Despite a strong association between the CYP3A5 6986A>G SNP and tacrolimus pharmacokinetics, there is no consistent evidence of organ rejection as a result of genotype-related under-immunosuppression. This is likely to be explained by the practice of performing tacrolimus dose adjustments in the early phase after transplantation. The effect of the CYP3A5 6986A>G SNP on ciclosporin- and tacrolimus-related nephrotoxicity and development of hypertension is unclear. Similarly, the ABCB1 SNPs exert no clear influence on either ciclosporin or tacrolimus pharmacodynamics, with studies showing conflicting results in regard to the main parameters of acute rejection and nephrotoxicity. In kidney transplant patients, consideration of the donor kidney genotype rather than the recipient genotype may be more important when assessing development of nephrotoxicity. Studies with low patient numbers may account for many inconsistent results to date. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful, particularly ones that consider both donor and recipient genotype. The effects of polymorphisms associated with the pregnane X receptor, organic anion transporting polypeptides, calcineurin inhibitor target sites and immune response pathways need to be further investigated. A large standardized clinical trial is now required to evaluate the relationship between the pharmacokinetics and pharmacodynamics of CYP3A5-mediated tacrolimus metabolism, particularly in regard to the outcomes of acute rejection and nephrotoxicity. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.

Effect of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Calcineurin Inhibitors: Part I

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes--in particular, CYP3A4 and CYP3A5--and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacokinetics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed, and all relevant primary research articles were critiqued and summarized. Influence of the CYP3A4 -392A>G SNP on the pharmacokinetics of either ciclosporin or tacrolimus appears limited. Variability in CYP3A4 expression due to environmental factors is likely to be more important than patient genotype. Influence of the CYP3A5 6986A>G SNP on the pharmacokinetics of ciclosporin is also uncertain and likely to be small. CYP3A4 may play a more dominant role than CYP3A5 in the metabolism of ciclosporin. The CYP3A5 6986A>G SNP has a well established influence on the pharmacokinetics of tacrolimus. Several studies in kidney, heart and liver transplant recipients have reported an approximate halving of tacrolimus dose-adjusted trough concentrations and doubling of tacrolimus dose requirements in heterozygous or homozygous carriers of a CYP3A5*1 wild-type allele compared with homozygous carriers of a CYP3A5*3 variant allele. Carriers of a CYP3A5*1 allele take a longer time to reach target blood tacrolimus concentrations. Influence of ABCB1 3435C>T, 1236C>T and 2677G>T/A SNPs on the pharmacokinetics of ciclosporin and tacrolimus remains uncertain, with inconsistent results. Genetic linkage between the three variant genotypes suggests that the pharmacokinetic effects are complex and not related to any one ABCB1 SNP. It is likely that these polymorphisms exert a small but combined effect, which is additive to the effects of the CYP3A5 6986A>G SNP. In liver transplant patients, recipient and donor liver genotypes may act together in determining overall drug disposition, hence the importance of assessing both. Studies with low patient numbers may account for many inconsistent results to date. Meta-analyses of the current data should help resolve some discrepancies. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.

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Functional Analysis of Genetic Variation in Catechol-O-Methyltransferase ( COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain

Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.