CYP2D6 Gene Polymorphisms Research Articles

CYP1A2 and CYP2D6 Gene Polymorphisms in Schizophrenic Patients with Neuroleptic Drug-Induced Side Effects.

Polymorphic variants of CYP1A2 and CYP2D6 genes of the cytochrome P450 system were studied in patients with schizophrenia with drug-induced motor disorders and hyperprolactinemia against the background of long-term neuroleptic therapy. We revealed an association of polymorphic variant C-163A CYP1A2*1F of CYP1A2 gene with tardive dyskinesia and association of polymorphic variant 1846G>A CY2D6*4 and genotype A/A of CYP2D6 gene (responsible for debrisoquin-4-hydroxylase synthesis) with limbotruncal tardive dyskinesia in patients with schizophrenia receiving neuroleptics for a long time.

Design and synthesis of novel tamoxifen analogues that avoid CYP2D6 metabolism

Tamoxifen (TAM) is a widely used drug in the prophylaxis and treatment of breast cancer. TAM is metabolized to the more active 4-hydroxytamoxifen (4-OH-TAM) and endoxifen by cytochrome P450 (CYP) mainly CYP2D6 and CYP3A4 enzymes. Due to the genetic polymorphisms in CYP2D6 genes, high variation in the clinical outcomes of TAM treatment is observed among women of different populations. To address this issue, novel TAM analogues with possible altered activation pathways were synthesized. These analogues were tested for their antiproliferative action on MCF-7 breast cancer cell lines as well as their binding affinity for estrogen receptor (ER) ER-α and ER-β receptors. These entire novel compounds showed better antiproliferative activity than did TAM on the MCF-7 cells. Moreover, compound 10 exhibited a half maximal growth inhibition (GI50) that was 1000 times more potent than that of TAM (GI50 < 0.005 μM vs 1.58 μM, respectively). Along with a broad spectrum activity on various cancer cell lines, all the TAM analogues showed considerable activity on the ER-negative breast cancer cell line. For further study, compound 10 was incubated in human liver microsomes (HLM), human hepatocytes (hHEP) and CYP2D6 supersomes. The active hydroxyl metabolite was detected after incubation in HLM and hHEP, implicating the involvement of other enzymes in its metabolism. These results prove that this novel series of TAM analogues might provide improved clinical outcomes for poor 2D6 metabolizers.

Impact of CYP2D6 Polymorphism on Steady-State Plasma Levels of Risperidone and 9-Hydroxyrisperidone in Thai Children and Adolescents with Autism Spectrum Disorder.

The purpose of this study was to investigate the influence of CYP2D6 gene polymorphisms on plasma concentrations of risperidone and its metabolite in Thai children and adolescents with autism spectrum disorder (ASD). All 97 autism spectrum disorder patients included in this study had been receiving risperidone at least for 1 month. The CYP2D6 genotypes were determined by real-time polymerase chain reaction (PCR)-based allelic discrimination for CYP2D6*4, *10, and *41 alleles. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Among the 97 patients, the most important nonfunctional alleles (CYP2D6*4 and *5) were detected, whereas the most common allele was CYP2D6*10 (55.9%). CYP2D6 genotyping revealed 90 (92.78%) patients to be extensive metabolizers (EM) and 7 (7.22%) to be intermediate metabolizers (IM). Plasma levels of risperidone were significantly higher in individuals with CYP2D6*5/*10 (p = 0.02), CYP2D6*10/*10 (p = 0.04), and CYP2D6*10/*41 (p = 0.04). Additionally, the plasma concentration of risperidone/9-OH risperidone ratio in patients with a CYP2D6 activity score of 0.5 were significantly higher than those with a CYP2D6 activity score of 2 (p = 0.04). Conversely, no significant influence was found among CYP2D6 polymorphisms, plasma concentrations of 9-hydroxyrisperidone, and the total active moiety. This is the first study to investigate the effects of CYP2D6 genetic polymorphisms on the plasma concentrations of risperidone in Thai children with ASD. The findings indicate that CYP2D6 polymorphisms affect the plasma concentrations of risperidone and the risperidone/9-hydroxyrisperidone ratio. Genetic screening for CYP2D6 polymorphisms could help to predict unexpected adverse events caused by the higher plasma concentration of risperidone.

The roles of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms in the predictability of responses to individualized therapy with donepezil in Han Chinese patients with Alzheimer's disease

AimPolymorphisms in the apolipoprotein E and CYP2D6 genes are widely reported to be related to Alzheimer's disease. However, few studies have focused on the relationship between polymorphisms in apolipoprotein E and CYP2D6 (rs1065852) genes and therapeutic responses to donepezil (DNP). This study explored the influence of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms on therapeutic responses to donepezil in Han Chinese patients with Alzheimer's disease. Materials and methodsA total of 85 patients with mild to moderate Alzheimer's disease who were treated with 2.5–10mg of DNP per day for at least 3 months were enrolled. Mini-Mental State Examination scores were measured before and after DNP treatment, and the apolipoprotein E3 and CYP2D6 (rs1065852) genotypes of the patients were determined. ResultsWe found that ApoE E3 non-carriers responded better to DNP treatment than E3 carriers (p=0.000) and that CYP2D6*10/*10 patients (MMSE score change: 0.29±3.27) exhibited better therapeutic responses to DNP than did CYP2D6*1/*1 and CYP2D6*1/*10 patients (p=0.033). Patients who were ApoE E3 non-carriers and who had the CYP2D6*10/*10 genotype exhibited a trend toward better clinical responses to DNP therapy. ConclusionsThe ApoE E3 allele and the CYP2D6 rs1065852 polymorphism may provide clinically relevant information for predicting therapeutic responses to DNP therapy.

Role of Genetic Polymorphism of Cyp2d6 in Tramadol Related Nephrotoxicity

One of the most important tramadol metabolizing enzymes is CYP2D6. The CYP2D6 polymorphism leads to good, poor or no enzyme activity. Genetic testing helps in identification of high risk addicts whom to develop nephrotoxicity as well as management of addicts. The objective of this study is to explore tramadol induced nephrotoxicity associated with CYP2D6 gene polymorphism.

Association between the Severity of Tramadol Toxicity and Some CYP2D6 Allelic Variants in Egyptian Tramadol Intoxicated Patients

Cytochrome P450 gene polymorphism is involved in the metabolism of tramadol. We investigated the effect of CYP2D6 gene polymorphism on tramadol metabolism by studying CYP2D6*1, CYP2D6*DUP, CYP2D6*4, and CYP2D6*10. CYP2D6 genotyping was performed using the xTAG CYP2D6 Kit v3 which incorporates multiplex PCR (Luminex kit). Tramadol levels were assessed using enzyme immunoassay. Our Study was done on 100 Egyptian patients with acute tramadol intoxication and 100 healthy control subjects. The patients were admitted to NECTR center. CYP2D6*1 was the most presented allelic variant in both groups The CYP2D6*DUP is associated with severe intoxication. There was a significant association between CYP2D6 allelic variants and tramadol metabolites level. In conclusion, our data suggests that studying CYP2D6 allelic variants may help clinicians to predict the severity of tramadol intoxication and individualize the drug treatment.

Association of CYP1A2 and CYP2D6 gene polymorphism with therapeutic efficacy of duloxetine on depression in southern region of Fujian

Objective To explore the influence of CYP1A2 and CYP2D6 gene polymorphism on blood concentration, therapeutic efficacy and adverse effects of anti-depression drug duloxetine on depression patients in southern region of Fujian. Methods 82 patients with depression were selected from southern region of FuJian, China, and all participates received duloxetine for two weeks. Blood concentrations of duloxetine were detected by HPLC-MS, and CYP1A2 and CYP2D6 genotypes were determined by sequencing with the amplified PCR products from peripheral blood DNA.The therapeutic efficacy and adverse effects of duloxetine were evaluated by Hamilton depression scale (HAMD) and treatment emergent symptom scale (TESS) respectively. Results Subjects were divided into GG, GA and AA three groups based on CYP1A2*1C genotyping. There was no significant difference in blood concentrations of duloxetine, dose-corrected blood concentrations, the reduction rate of HAMD and the reduction rate of TESS among the three groups. Results were the same with CYP1A2*1F, which were divided into CC, CA and AA three groups. Subjects was divided into CC, CT, TT three groups based on CYP2D6*10 locus genotyping.Blood concentrations of duloxetine were (13.89±3.22)ng·ml-1, (16.08±4.24)ng·ml-1, (17.25±4.62)ng·ml-1 respectively and there was significant difference(F=3.21, P 0.05). Dose-corrected blood concentrations were (304.84±103.76), (368.13±143.49), (444.50±195.58) respectively and there was significant difference(F=4.19, P<0.05), and CC group was significantly lower than TT group(P<0.05). The reduction rate of HAMD were 0.42±0.11, 0.46±0.11, 0.52±0.09 respectively and there was significant difference(F=6.29, P<0.05), and CC and CT group was significantly lower than TT group(P<0.05). The reduction rate of TESS were 1.14±0.66, 1.48±0.69, 1.69±0.69 respectively and there was significant difference(F=3.38, P<0.05). CC group was significantly lower than TT group(P<0.05). Conclusion Among the 3 loci studied, only CYP2D6*10 locus within CYP2D6 gene can affect blood concentration, efficacy and adverse effects of duloxetine, which indicate that CYP2D6 gene polymorphism may contribute to therapeutic efficacy of duloxetine on depression in southern region of Fujian. Key words: Duloxetine; CYP1A2; CYP2D6; Gene polymorphism; Blood concentration

The impact of the CYP2D6 gene polymorphism on the risk of pemphigoid.

Studies concerning the etiopathogenesis of numerous diseases emphasize the involvement of genetically determined impairments of xenobiotic metabolism. Nowadays, more attention has been drawn to the role of cytochrome P450 and its isoenzymes in the course of dermatological diseases, including pemphigoid, the most frequently occurring autoimmune bullous disease, whose etiopathogenesis has not been completely elucidated. The aim of the study was to find out whether there was any relationship between the CYP2D6 gene polymorphism and the development of bullous pemphigoid (BP). The study included 221 subjects, 71 patients with BP, and 150 healthy volunteers constituting a control group. The identification of CYP2D6 (CYP2D6*1, CYP2D6*3, CYP2D6*4) gene alleles was performed using the polymerase chain reaction-fragment length polymorphism method. A higher frequency of the CYP2D6*3/CYP2D6*4 genotype was observed in patients with BP (P = 0.0033) than in controls. The relative risk of developing BP expressed with the odds ratio was nearly four times higher in subjects in whom the presence of the CYP2D6*3 allele was detected (odds ratio 3.8; P = 0.0234). The study results may suggest the impact of CYP2D6 gene polymorphism (A2637 deletion) on a higher prevalence of bullous pemphigoid.

CYP2D6, CYP3A5, and CYP3A4 gene polymorphisms in Russian, Tatar, and Bashkir populations

The allele and genotype frequency distribution at polymorphic loci rs3892097 (184G>A) of CYP2D6 gene, rs776746 (6986A>G) of the CYP3A5 gene and rs2740574 (-392A>G) of the CYP3A4 gene in Russians, Tatars, and Bashkirs was examined. Samples were taken from residents of Bashkortostan Republic (1240 men and women aged from 20 to 109 years and consisted of 443 Russians, 517 Tatars, and 280 Bashkirs). Allele identification was conducted using PCR-RFLP or PCR with TaqMan probes. The "nonfunctional" allele rs3892097*A of the CYP2D6 gene was detected in populations of Russians, Tatars, and Bashkirs in 17.2, 9.5, and 7.1% cases, respectively. The rs776746*G allele of the CYP3A5 gene encoding the CYP3A5 isoenzyme with decreased activity was revealed with a frequency of 94.6% in populations of Russians, 94.3% in the Tatar population, and 91.5% in the Bashkir population. The share of the minor allele rs2740574*G of the CYP3A4 was 4.0% in populations of Russians, 0.5% in the Tatar population, and 0.9% in the Bashkir population. It has been previously shown that the rs3892097*A, rs776746*G, and rs2740574*G allele frequencies vary significantly in different world populations. Since allele variants of CYP2D6, CYP3A5, and CYP3A4 genes can play essential role in interindividual and in interethnic differences in the metabolism of many therapeutic agents, the obtained results could be used in the prognosis of pharmacotherapy efficacy in populations of Russians, Tatars, and Bashkirs.

Influence of the rs1080985 Single Nucleotide Polymorphism of the CYP2D6 Gene and APOE Polymorphism on the Response to Donepezil Treatment in Patients with Alzheimer's Disease in China

Background/Aim: Recent data have indicated that the rs1080985 single nucleotide polymorphism (SNP) of the cytochrome P450 (CYP) 2D6 and the common apolipoprotein E (APOE) gene may affect the response to donepezil in patients with Alzheimer's disease (AD). We investigated this association in Chinese patients with mild-to-moderate AD. Methods: In this prospective cohort study, analyses of CYP2D6 and APOE were conducted in 208 native Chinese patients with mild-to-moderate AD. All patients were treated with donepezil 5 mg/day for 6 months, and the response to treatment was assessed using the Mini-Mental State Examination. Results: No significant differences between responders (68.9%) and nonresponders (31.1%) to donepezil treatment (6 months' duration) were observed in the distribution of the CYP2D6 rs1080985 SNP, common APOE polymorphism or a combination of the two. Conclusions: Our results suggest that neither the CYP2D6 nor the APOE polymorphism influences the 6-month response to donepezil treatment in a Chinese population with AD.

Evaluation of Endometrial Thickness and Bone Mineral Density Based on CYP2D6 Polymorphisms in Turkish Breast Cancer Patients Receiving Tamoxifen Treatment

Background: Several previous studies have examined the effect of CYP2D6 gene polymorphism on the efficacy and metabolism of tamoxifen (Tamoxifen Teva, Nolvadex) in the treatment of breast cancer. In the present study, the metabolic profiles associated with various CYP2D6 genotypes were evaluated. Method: In the present study 92 Turkish breast cancer patients with early-stage hormone receptor-positive tumors treated with adjuvant tamoxifen (20 mg) were evaluated for CYP2D6 genotype and metabolic profiles. Known side effects of tamoxifen treatment, including endometrial thickening, changes in serum lipid levels and bone density, and hepatosteatosis, were evaluated according to the CYP2D6 polymorphism. Result: The distribution of metabolic characteristics in the Turkish population was as follows: 77.1% normal metabolism, 11.5% intermediate metabolism, 5.2% ultrarapid metabolism, and 2.1% poor metabolism. The CYP2D6 genotypes associated with rapid metabolism were CYP2D6 3X*1/*1 duplication (DUP) and CYP2D6 2X*1/*2, while poor metabolism was associated with the genotypes CYP2D6 *3/*4 and CYP2D6 *6/*6. There was no statistically significant relationship between metabolic characteristics and bone density or hepatosteatosis. A statistically significant difference in total cholesterol and triglycerides was detected in lipid profile analysis (p = 0.003, p = 0.02). Assessment of endometrial thickness revealed a significant association of hyperplasia and poor metabolism, and an association between atrophy and ultrarapid metabolism (p = 0.01). Conclusion: Significant development of endometrial hyperplasia was identified among individuals with poor tamoxifen metabolism. As a result, tamoxifen may be a significant predictor of endometrial thickening among individuals with poor metabolic characteristics.

Direct assessment of cytochrome P450 2D6 genotypes by high-resolution melting analysis and DNA sequencing

We developed a CYP2D6 genotyping method that required only one polymerase chain reaction (PCR) followed by a high-resolution melting curve analysis (HRM) and DNA sequencing. DNA was extracted from peripheral blood samples obtained from 100 normal individuals. From the HRM analysis using three fragments of amplicons (exons 1, 6, and 9), we successfully identified four common CYP2D6 gene polymorphisms (100C>T, 2850C>T, 2988G>A, and 4180G>C). Exons 3 and 7 were also screened by HRM analysis. The heteroduplexes, wild-type homoduplexes, and homoduplexes of compound mutations showed distinct melting plots. The other four exons (exons 2, 4, 5, and 8) were directly analyzed by DNA sequencing. In conclusion, we developed an HRM and DNA sequencing based method to assess the CYP2D6 gene directly without the need for nested PCR. This method is quick and cost-effective; it reduces the chance of PCR contamination and is suitable for clinical application.

Evaluation of CYP2D6 Polymorphic Types and Their Effect on Tamoxifen Efficacy Among Turkish Tamoxifen Users with Breast Cancer

In this study we investigated the role of the polymorphic types of CYP2D6 in the Turkish population for therapeutic efficacy among patients with early stage breast cancer who treated with tamoxifen. CYP2D6 plays an important role in tamoxifen metabolism. CYP2D6 genotypes were determined of 115 patients treated with adjuvant tamoxifen using the AmpliChip CYP450 test. Genotypes were classified by metabolizer groups and evaluated by the diagnostic and clinical characteristics of the patients and the recurrences of the disease. To create an intergroup comparison of the categorical measurements, the Chi-Square test was used. The most common CYP2D6 gene polymorphism was *1/*2 with a percentage of 19.9% (n= 19). In the Turkish population, among patients with early stage breast cancer, the normal metabolizer group was the largest with a percentage of 77.1% (n= 74). The percentage rates were determined to be 11.5% (n= 11) for intermediate metabolizers, 5.2% (n= 5) for ultrarapid metabolizers and 2.1% (n= 2) for poor metabolizers. In patients with early stage breast cancer treated with adjuvant tamoxifen. no significant correlation was detected between CYP2D6 types and recurrence and metastasis rates. This study was the first study to determine CYP2D6 genotypes and characteristics of Turkish patients with early stage breast cancer. Although no correlation was demonstrated between CYP2D6 genotype polymorphism and disease recurrence in the earlier period, long-term follow-ups seem to be warranted.

Association of CYP2D6 gene polymorphism and therapeutic efficacy of venlafaxine on depression in southern region of Fujian

Objective To explore the effect of CYP2D6 gene polymorphism on blood concentration, therapeutic efficacy and adverse effects of anti-depression drug venlafaxine. Methods 69 cases of patients with depression were selected randomly from southern region of FuJian, China. The blood concentration of venlafaxine was detected by HPLC, and the CYP2D6 genotype was determined by sequencing with the amplified PCR products from peripheral blood DNA. The therapeutic efficacy and adverse effects of venlafaxine were evaluated by Hamilton depression scale(HAMD) and treatment emergent symptom scale(TESS) respectively. Results Subjects was divided into CC, CT, TT three groups based on rs16947 locus genotyping. The blood concentrations of venlafaxine were (157.35±15.63)ng/ml, (70.17±5.11)ng/ml, (115.72±10.2)ng/ml respectively and there was no significant difference (F=1.257, P=0.301). The dose-corrected concentrations and normalized concentrations were not significantly different (F=1.683, 1.547, P>0.05). Similarly, the reduction rate of HAMD (CC: (40.6±7.23)%, CT: (51.7±7.09)%, TT: (42.8±14.1)%) and TESS scores (CC: 1.3±0.21, CT: 1.3±0.36, TT: 1.2±0.28) were not significantly different either (P>0.05). In 69 samples in this study, genotyping of rs3892097 locus only found GG type, and no further examination was performed. Genotyping divided rs1065852 locus into CC, CT, TT three groups. The blood concentrations of venlafaxine were (42.87±9.9)ng/ml, (64.25±13.59)ng/ml, (181.56±14.15)ng/ml respectively, and there was significant difference among the three groups (F=4.893, P=0.016). The dose-corrected concentrations and normalized concentrations were also significantly different (F=3.985, 3.648, P<0.05). The reduction rate of HAMD (CC: (42.6±8.23)%, CT: (48.8±10.8)%, TT: (63.4±9.15)%) was not significantly different (F=2.961, P=0.07). The difference of TESS scores was similar to that of HAMD reduction rate. Conclusion Among the 3 loci studied, only rs1065852 locus within CYP2D6 gene can affect its enzyme activity and then influence the therapeutic efficacy and adverse effects of venlafaxine. Key words: Venlafaxine; CYP2D6; Gene polymorphism; Blood concentration

CYP2D6 genotyping in an Argentinean population.

e13543 Background: The polymorphic CYP2D6 gene shows a high degree of interindividual and interethnic variability that influences its expression and function. CYP2D6 polymorphism influences the met...

Association of CYP1A1 and CYP2D6 gene polymorphisms with head and neck cancer in Tunisian patients

The purpose of this study was to investigate the relationship between head and neck cancer (HNC) and environmental agents and polymorphisms in CYP1A1, CYP2D6, NAT1 and NAT2 metabolic enzymes genes. To the best of our knowledge, this is the first report on polymorphisms in CYP1A1 6310C>T, CYP2D6 Arg365His, NAT1 52936A>T and NAT2 Arg268Lys (NAT2*12A) genes and susceptibility to HNC in Tunisian population. We study the prevalence of these polymorphisms in 169 patients with HNC and 261 control subjects using polymerase chain reaction based methods in a Tunisian population. We detected an association between HNC and CYP1A1 6310C>T (TT) and CYP2D6 Arg365His (His/His) variant carriers (OR 1.75, P = 0.008 and OR 1.66, P = 0.016, respectively). No association was found between the polymorphisms genotypes of NAT1 52936T>A and NAT2 Arg268Lys and risk of HNC. An association between HNC and CYP1A1 (TT) genotype was found among patients with smoking (P = 0.011) and drinking habit (P = 0.009). The combinations of NAT1 (AT or AA) and NAT2 (AA) at-risk genotypes increased HNC risk (OR 4.23, P = 0.005 and OR 3.60, P = 0.048, respectively). However, the combinations of CYP1A1 (AA) and CYP2D6 (CC) genotypes decreased risk of HNC (OR 0.20; P = 0.006). Genetic polymorphisms in CYP1A1 and CYP2D6 may significantly associate with HNC in the Tunisian population. The results of this study suggest a possible gene-environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed.

CYP2D6*4 Allele Polymorphism Increases the Risk of Parkinson’s Disease: Evidence from Meta-Analysis

BackgroundMany epidemiological studies have been conducted to explore the association between a single CYP2D6 gene polymorphism and Parkinson’s disease (PD) susceptibility. However, the results remain controversial.ObjectivesTo clarify the effects of a single CYP2D6 gene polymorphism on the risk of PD, a meta-analysis of all available studies relating to CYP2D6*4 polymorphism and the risk of PD was conducted.MethodsA comprehensive literature search of PubMed, EMBASE, and the China National Knowledge Infrastructure (CNKI) up to September 1, 2013 was conducted. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. Meta-regression, Galbraith plots, subgroup analysis, sensitivity analysis, and publication bias analysis were also performed.ResultsTwenty-two separate comparisons consisting of 2,629 patients and 3,601 controls were included in our meta-analysis. The pooled analyses showed a significant association between CYP2D6*4G/A polymorphism and PD risk in all of the comparisons (A vs. G allele: OR = 1.28, 95% CI = 1.14–1.43, P = 0.001; AA vs. GG: OR = 1.43, 95% CI = 1.06–1.93, P = 0.018; AG vs. GG: OR = 1.22, 95% CI = 1.06–1.40, P = 0.006; AG+AA vs. GG: OR = 1.26, 95% CI = 1.10–1.44, P = 0.001; AA vs. AG+GG: OR = 1.37, 95% CI = 1.02–1.83, P = 0.036). In subgroup analysis stratified by ethnicity, significant associations were also demonstrated in Caucasians but not in Asians. No significant association was found in subgroup analysis stratified by age of onset or disease form.ConclusionsWe concluded that the CYP2D6*4G/A polymorphism denotes an increased genetic susceptibility to PD in the overall population, especially in Caucasians. Further large and well-designed studies are needed to confirm this association.

Statin therapy correlated CYP2D6 gene polymorphism and hyperlipidemia

Purpose:To investigate the distribution of statin therapy correlated gene polymorphism allele CYP2D6*10 (C188T) in Ningxia Hui nationality and to discuss the relationship between the gene polymorphism allele CYP2D6*10 (C188T) and the lipid-lowering efficacy of simvastatin and hyperlipidemia.Materials and methods:One hundred and fifty healthy people (80 males and 70 females) and 200 hyperlipidemia patients (105 males and 95 females) were recruited at Ningxia People’s Hospital. Genotypes were determined by using allele-specific amplification (ASA-PCR) in 150 healthy controls and 200 patients with hyperlipidemia. Relationships between genotypes and lipid levels and the lipid-lowering efficacy of simvastatin were analyzed.Results:The distribution frequency of the CYP2D6*10 allele was 47.6% in the Ningxia Hui nationality. There was no significant correlation between the CYP2D6*10 allele and hyperlipidemia. At 8 weeks after treatment with simvastatin, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were more obviously decreased with the CC genotype than the CT and TT genotypes, with significant differences.Conclusion:Distribution of the gene polymorphism of CYP2D6*10 is ethnically and geographical different. The allele T of CYP2D6*10 is not related to hyperlipidemia. CC expression seemed to increase the lipid-lowering effects of simvastatin. The hyperlipidemia patients with CC genotype should take lower doses of simvastatin than those with CT/TT genotype in the Ningxia Hui population.

Genetic polymorphism of CYP2D6 gene among Egyptian hypertensive cases

BackgroundHypertension is a cardiovascular disease that is affected by environmental, demographic and genetic factors. ObjectiveThis study aims to determine the frequency of the CYP2D6∗1, ∗3, ∗4 and ∗5 variants among hypertensive cases and cases with obesity and cases with cardiac complications. Subjects and methodsDNA was isolated from peripheral blood samples that were collected from 123 hypertensive cases and from 429 healthy non-related controls by using the Magna pure system. Genomic DNA was used to determine the frequency of CYP2D6∗1, CYP2D6∗3, CYP2D6∗4 and CYP2D6∗5 allelic variants by the application of the light cycler polymerase chain reaction (Realtime PCR) technique. ResultsComparing cases of hypertension and controls as regard to the genotypic allelic variants of CYP2D6 gene, hypertensive cases showed a significantly higher wild genotype 1/1 compared to controls (85.4% vs. 74.8%, p=0.01) with a lower frequency of mutant genotype 4/4 (1.6% vs. 8.6%, p=0.008) This phenomenon was manifested among cases of subgroups with obesity that had significantly lower mutant homozygous forms than obese controls (2.3% vs. 9.5%, p 0.04) and cases with cardiac complications (88.2% vs. 74.8%, p=0.01). ConclusionCYP2D6 polymorphism is positively associated with hypertensive cardiac complications as well as hypertensive obese cases.

Systematic Functional Study of Cytochrome P450 2D6 Promoter Polymorphisms in the Chinese Han Population

The promoter polymorphisms of drug-metabolizing genes can lead to interindividual differences in gene expression, which may result in adverse drug effects and therapeutic failure. Based on the database of CYP2D6 gene polymorphisms in the Chinese Han population established by our group, we functionally characterized the single nucleotide polymorphisms (SNPs) of the promoter region and corresponding haplotypes in this population. Using site-directed mutagenesis, all the five SNPs identified and ten haplotypes with a frequency equal to or greater than 0.01 in the population were constructed on a luciferase reporter system. Dual luciferase reporter systems were used to analyze regulatory activity. The activity produced by Haplo3(−2183G>A, −1775A>G, −1589G>C, −1431C>T, −1000G>A, −678A>G), Haplo8(−2065G>A, −2058T>G, −1775A>G, −1589G>C, −1235G>A, −678A>G) and MU3(−498C>A) was 0.7−, 0.7−, 1.2− times respectively compared with the wild type in human hepatoma cell lines(p<0.05). These findings might be useful for optimizing pharmacotherapy and the design of personalized medicine.