Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes

Background/ Aims: Little is known about the effect of P450 oxidoreductase (POR) gene polymorphisms on the activities of CYPs with multiple genotypes. Methods: We genotyped 102 human livers for 18 known POR single nucleotide polymorphisms (SNPs) with allelic frequencies greater than 1% as well as for 27 known SNPs in 10 CYPs. CYP enzyme activities in microsomes prepared from these livers were determined by measuring probe substrate metabolism by high performance liquid chromatograph. Results: We found that the effects of the 18 POR SNPs on 10 CYP activities were CYP genotype-dependent. The POR mutations were significantly associated with decreased overall Km for CYP2B6 and 2E1, and specific genotypes within CYP1A2, 2A6, 2B6, 2C8, 2D6 and 2E1 were identified as being affected by these POR SNPs. Notably, the effect of a specific POR mutation on the activity of a CYP genotype could not be predicted from other CYP genotypes of even the same CYP. When combining one POR SNP with other POR SNPs, a hitherto unrecognized effect of multiple-site POR gene polymorphisms (MSGP) on CYP activity was uncovered, which was not necessarily consistent with the effect of either single POR SNP. Conclusions: The effects of POR SNPs on CYP activities were not only CYP-dependent, but more importantly, CYP genotype-dependent. Moreover, the effect of a POR SNP alone and in combination with other POR SNPs (MSGP) was not always consistent, nor predictable. Understanding the impact of POR gene polymorphisms on drug metabolism necessitates knowing the complete SNP complement of POR and the genotype of the relevant CYPs.

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Pharmacokinetics of Gemcitabine in Japanese Cancer Patients: The Impact of a Cytidine Deaminase Polymorphism

Journal of Clinical Oncology ◽

10.1200/jco.2006.06.7405 ◽

2007 ◽

Vol 26 (1) ◽

pp. 32-42 ◽

Cited By ~ 129

Author(s):

Emiko Sugiyama ◽

Nahoko Kaniwa ◽

Su-Ryang Kim ◽

Ruri Kikura-Hanajiri ◽

Ryuichi Hasegawa ◽

...

Keyword(s):

Cancer Patients ◽

High Performance ◽

Cytidine Deaminase ◽

Direct Sequencing ◽

Pharmacokinetic Parameters ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Inactive Metabolite ◽

Grade 3 ◽

The Impact

PurposeGemcitabine is rapidly metabolized to its inactive metabolite, 2′,2′-difluorodeoxyuridine (dFdU), by cytidine deaminase (CDA). We previously reported that a patient with homozygous 208A alleles of CDA showed severe adverse reactions with an increase in gemcitabine plasma level. This study extended the investigation of the effects of CDA genetic polymorphisms on gemcitabine pharmacokinetics and toxicities.Patients and MethodsGenotyping of CDA was performed by a direct sequencing of DNA obtained from the peripheral blood of Japanese gemcitabine-naïve cancer patients (n = 256). The patients recruited to the association study received a 30-minute intravenous infusion of gemcitabine at a dose of either 800 or 1,000 mg/m2, and eight blood samples were periodically collected (n = 250). Plasma levels of gemcitabine and dFdU were measured by high-performance liquid chromatography. Plasma CDA activities toward cytidine and gemcitabine were also measured (n = 121).ResultsTwenty-six genetic variations, including 14 novel ones and two known nonsynonymous single nucleotide polymorphisms (SNPs), were detected. Haplotypes harboring the nonsynonymous SNPs 79A>C (Lys27Gln) and 208G>A (Ala70Thr) were designated *2 and *3, respectively. The allelic frequencies of the two SNPs were 0.207 and 0.037, respectively. Pharmacokinetic parameters of gemcitabine and plasma CDA activities significantly depended on the number of haplotype *3. Haplotype *3 was also associated with increased incidences of grade 3 or higher neutropenia in the patients who were coadministered fluorouracil, cisplatin, or carboplatin. Haplotype *2 showed no significant effect on gemcitabine pharmacokinetics.ConclusionHaplotype *3 harboring a nonsynonymous SNP, 208G>A (Ala70Thr), decreased clearance of gemcitabine, and increased incidences of neutropenia when patients were coadministered platinum-containing drugs or fluorouracil.

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The impact of vascular endothelial growth factor single nucleotide polymorphisms in the development and severity of endometriosis: A systematic review of the literature

Journal of Gynecology Obstetrics and Human Reproduction ◽

10.1016/j.jogoh.2020.101732 ◽

2020 ◽

Vol 49 (10) ◽

pp. 101732

Author(s):

Vasilios Pergialiotis ◽

Maria Fanaki ◽

Ioannis Bellos ◽

Konstantinos Stefanidis ◽

Dimitrios Loutradis ◽

...

Keyword(s):

Systematic Review ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Single Nucleotide Polymorphisms ◽

Vascular Endothelial ◽

Nucleotide Polymorphisms ◽

Review Of The Literature ◽

Single Nucleotide ◽

Endothelial Growth Factor ◽

The Impact

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Impact of PD-1 gene polymorphism and its interaction with tea drinking on susceptibility to tuberculosis

Epidemiology and Infection ◽

10.1017/s0950268821000042 ◽

2021 ◽

Vol 149 ◽

Author(s):

Jing Wang ◽

Mian Wang ◽

Zihao Li ◽

Xinyin Wu ◽

Xian Zhang ◽

...

Keyword(s):

Case Control Study ◽

Preventive Measures ◽

Nucleotide Polymorphisms ◽

Unconditional Logistic Regression ◽

Negative Interaction ◽

Single Nucleotide ◽

High Risk Populations ◽

Tea Drinking ◽

The Impact ◽

Control Study

Abstract The aim of this study was to explore the impact of polymorphism of PD-1 gene and its interaction with tea drinking on susceptibility to tuberculosis (TB). A total of 503 patients with TB and 494 controls were enrolled in this case–control study. Three single-nucleotide polymorphisms of PD-1 (rs7568402, rs2227982 and rs36084323) were genotyped and unconditional logistic regression analysis was used to identify the association between PD-1 polymorphism and TB, while marginal structural linear odds models were used to estimate the interactions. Genotypes GA (OR 1.434), AA (OR 1.891) and GA + AA (OR 1.493) at rs7568402 were more prevalent in the TB patients than in the controls (P < 0.05). The relative excess risk of interaction (RERI) between rs7568402 of PD-1 genes and tea drinking was −0.3856 (95% confidence interval −0.7920 to −0.0209, P < 0.05), which showed a negative interaction. However, the RERIs between tea drinking and both rs2227982 and rs36084323 of PD-1 genes were not statistically significant. Our data demonstrate that rs7568402 of PD-1 genes was associated with susceptibility to TB, and there was a significant negative interaction between rs7568402 and tea drinking. Therefore, preventive measures through promoting the consumption of tea should be emphasised in the high-risk populations.

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Gene polymorphisms associated with an increased risk of exudative age-related macular degeneration in a Spanish population

European Journal of Ophthalmology ◽

10.1177/11206721211002698 ◽

2021 ◽

pp. 112067212110026

Author(s):

Pablo Gili ◽

Leyre Lloreda Martín ◽

José-Carlos Martín-Rodrigo ◽

Naon Kim-Yeon ◽

Laura Modamio-Gardeta ◽

...

Keyword(s):

Macular Degeneration ◽

Gene Polymorphisms ◽

Age Related Macular Degeneration ◽

Spanish Population ◽

Healthy Controls ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Exudative Amd ◽

Age Related ◽

Increased Risk

Purpose: To identify the association between single-nucleotide polymorphisms (SNPs) in CFH, ARMS2, HTRA1, CFB, C2, and C3 genes and exudative age-related macular degeneration (AMD) in a Spanish population. Methods: In 187 exudative AMD patients and 196 healthy controls (61% women, mean age 75 years), 12 SNPs as risk factors for AMD in CFH (rs1410996, rs1061170, r380390), ARMS2 (rs10490924, rs10490923), HTRA1 (rs11200638), CFB (rs641153), C2 (rs547154, rs9332739), and C3 (rs147859257, rs2230199, rs1047286) genes were analyzed. Results: The G allele was the most frequent in CFH gene (rs1410996) with a 7-fold increased risk of AMD (OR 7.69, 95% CI 3.17–18.69), whereas carriers of C allele in CFH (rs1061170) showed a 3-fold increased risk for AMD (OR 3.22, 95% CI 1.93–5.40). In CFH (rs380390), the presence of G allele increased the risk for AMD by 2-fold (OR 2.52, 95% CI 1.47–4.30). In ARMS2 (rs10490924), the T-allele was associated with an almost 5-fold increased risk (OR 5.49, 95% CI 3.23–9.31). The A allele in HTRA1 (rs11200638) was more prevalent in AMD versus controls (OR 6.44, 95% CI 3.62–11.47). In C2 gene (rs9332739) the presence of C increased risk for AMD by 3-fold (OR 3.10, 95% CI 1.06–9.06). Conclusion: SNPs in CFH, ARMS2, HTRA1, and C2 genes were associated in our study with an increased risk for exudative AMD in Spanish patients.

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Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity

AJP Cell Physiology ◽

10.1152/ajpcell.00421.2014 ◽

2015 ◽

Vol 308 (9) ◽

pp. C758-C766 ◽

Cited By ~ 7

Author(s):

Xinjun Cindy Zhu ◽

Rafiquel Sarker ◽

John R. Horton ◽

Molee Chakraborty ◽

Tian-E Chen ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Large Fraction ◽

Regulatory Protein ◽

Nucleotide Polymorphisms ◽

Genetic Determinants ◽

Single Nucleotide ◽

Mutant Proteins ◽

Homologous Protein ◽

Genetic Abnormalities ◽

The Impact

Genetic determinants appear to play a role in susceptibility to chronic diarrhea, but the genetic abnormalities involved have only been identified in a few conditions. The Na+/H+ exchanger 3 (NHE3) accounts for a large fraction of physiologic intestinal Na+ absorption. It is highly regulated through effects on its intracellular COOH-terminal regulatory domain. The impact of genetic variation in the NHE3 gene, such as single nucleotide polymorphisms (SNPs), on transporter activity remains unexplored. From a total of 458 SNPs identified in the entire NHE3 gene, we identified three nonsynonymous mutations (R474Q, V567M, and R799C), which were all in the protein's intracellular COOH-terminal domain. Here we evaluated whether these SNPs affect NHE3 activity by expressing them in a mammalian cell line that is null for all plasma membrane NHEs. These variants significantly reduced basal NHE3 transporter activity through a reduction in intrinsic NHE3 function in variant R474Q, abnormal trafficking in variant V567M, or defects in both intrinsic NHE3 function and trafficking in variant R799C. In addition, variants NHE3 R474Q and R799C failed to respond to acute dexamethasone stimulation, suggesting cells with these mutant proteins might be defective in NHE3 function during postprandial stimulation and perhaps under stressful conditions. Finally, variant R474Q was shown to exhibit an aberrant interaction with calcineurin B homologous protein (CHP), an NHE3 regulatory protein required for basal NHE3 activity. Taken together, these results demonstrate decreased transport activity in three SNPs of NHE3 and provide mechanistic insight into how these SNPs impact NHE3 function.

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The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

Drug Metabolism and Disposition ◽

10.1124/dmd.111.043828 ◽

2012 ◽

Vol 40 (5) ◽

pp. 856-864 ◽

Cited By ~ 63

Author(s):

Tobias Hartmann ◽

Mineko Terao ◽

Enrico Garattini ◽

Christian Teutloff ◽

Joshua F. Alfaro ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Aldehyde Oxidase ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

The Impact

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Polymorphisms in the Chicken Growth Differentiation Factor 9 Gene Associated with Reproductive Traits

BioMed Research International ◽

10.1155/2018/9345473 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Lingbin Liu ◽

Zhifu Cui ◽

Qihai Xiao ◽

Haihan Zhang ◽

Xiaoling Zhao ◽

...

Keyword(s):

Body Weight ◽

Single Nucleotide Polymorphisms ◽

Gene Polymorphisms ◽

Reproductive Traits ◽

Missense Mutations ◽

Nucleotide Polymorphisms ◽

Rt Pcr ◽

Single Nucleotide ◽

Egg Weight ◽

Growth Differentiation Factor 9

The aim of the study was to investigateGDF9gene polymorphisms and their association with reproductive traits in chicken using DNA sequencing. A total of 279 Dongxiang blue-shelled (DX) chickens and 232 Luhua (LH) chickens were used for validation. We detected 15 single nucleotide polymorphisms (SNPs): nine SNPs were previously unreported in chicken, two were missense mutations, and only three exhibited significant associations with reproductive traits. G.17156387C>T was significantly associated with age at first egg (AFE) and weight of first egg (WFE) in both breeds. Birds carrying the CC genotype exhibited higher AFE and WFE values than those with the TT genotype. The SNP g.17156427A>G exhibited an association with egg weight at 300 days of age (EWTA) in DX but not in LH chickens. The SNP g.17156703A>C affected the AFE and EN (total number of eggs at 300 days of age) in DX chickens. In addition, certain diplotypes significantly affected AFE, BWTA (body weight at 300 days of age), and EN in both breeds. RT-PCR results showed that theGDF9gene was highly expressed in stroma with cortical follicles (STR) and prehierarchal follicles. These results provided further evidence that theGDF9gene is involved in determining reproductive traits in chicken.

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Multicenter Study on Differential Human Neutrophil Antigen 2 Expression and Underlying Molecular Mechanisms

Transfusion Medicine and Hemotherapy ◽

10.1159/000505523 ◽

2020 ◽

Vol 47 (5) ◽

pp. 385-395

Author(s):

Brigitte K. Flesch ◽

Angelika Reil ◽

Núria Nogués ◽

Carme Canals ◽

Peter Bugert ◽

...

Keyword(s):

Expression Pattern ◽

Human Neutrophil ◽

Molecular Mechanisms ◽

Normal Population ◽

Regulatory Elements ◽

Population Exposure ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Immune Neutropenia ◽

The Impact

Background: The human neutrophil antigen 2 (HNA-2), which is expressed on CD177, is undetectable in 3–5% of the normal population. Exposure of these HNA-2null individuals to HNA-2-positive cells can cause immunization and production of HNA-2 antibodies, which can induce immune neutropenia and transfusion-related acute lung injury. In HNA-2-positive individuals, neutrophils are divided into a CD177pos. and a CD177neg. subpopulation. The molecular background of HNA-2 deficiency and the bimodal expression pattern, however, are not completely decoded. Study Design: An international collaboration was conducted on the genetic analysis of HNA-2-phenotyped blood samples, including HNA-2-deficient individuals, mothers, and the respective children with neonatal immune neutropenia and regular blood donors. Results: From a total of 54 HNA-2null individuals, 43 were homozygous for the CD177*787A>T substitution. Six carried the CD177*c.1291G>A single nucleotide polymorphism. All HNA-2-positive samples with >40% CD177pos. neutrophils carried the *787A wild-type allele, whereas a lower rate of CD177pos. neutrophils was preferentially associated with *c.787AT heterozygosity. Interestingly, only the *c.787A allele sequence was detected in complementary DNA (cDNA) sequence analysis carried out on all *c.787AT heterozygous individuals. However, cDNA analysis after sorting of CD177pos. and CD177neg. neutrophil subsets from HNA-2-positive individuals showed identical sequences, which makes regulatory elements within the promoter unlikely to affect CD177 gene transcription in different CD177 neutrophil subsets. Conclusion: This comprehensive study clearly demonstrates the impact of single nucleotide polymorphisms on the expression of HNA-2 on the neutrophil surface but challenges the hypothesis of regulatory epigenetic effects being implicated in the bimodal CD177 expression pattern.

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