Cytochrome P450 1A2 co-determines neuroleptic load and may diminish tardive dyskinesia by increased inducibility

Objectives. The aim of this study was to investigate a possible association between tardive dyskinesia (TD) and CYP1A2 (*1F, -163C>А, rs762551) polymorphism in Russian psychiatric inpatients. Methods. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale (AIMS). Orofacial and limb-truncal dyskinesia were assessed with AIMS 1–4 and 5–7, respectively. Standard protocols were applied for genotyping. Analysis of covariance (ANCOVA) was used to compare the mean AIMS scores for each of the genotypic classes. Results. A total of 319 Caucasian patients from West Siberia with schizophrenia and 117 healthy volunteers were investigated. No significant differences between the patients and the controls in genotype frequencies were found. Analysis of covariance (ANCOVA) with age, sex, duration of disease, chlorpromazine equivalent (CPZEQ) incorporated as covariates showed that limb-truncal, but not orofacial TD, is associated with CYP1A2 (?163C>, rs762551) polymorphism (F = 3.27, P = 0.039). Patients with the C/C genotype had a higher mean AIMS 5–7 score than those with the A/C or the A/A genotype. Conclusions. Our results support the hypothesis that not only with clozapine, but also with other classical and atypical antipsychotics, smoking may decrease plasma levels; this is most extensively expressed in carriers of the CYP1A2*1F (-163C> A) polymorphism.     

A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia

Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the CYP1A2 enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of CYP1A2 induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the CYP1A2 gene was found to be associated with variation in CYP1A2 inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in CYP1A2 in relation to TD severity. A total of 85 patients with schizophrenia were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in CYP1A2. The mean AIMS score in patients with the (C/C) genotype (associated with reduced CYP1A2 inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the CYP1A2 gene may serve as a genetic risk factor for the development of TD in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications.     

细胞色素P450酶1A2和2C19基因多态性与难治性抑郁症的关联分析

目的探讨细胞色素P450酶(cytochromeP450enzymes,CYP)1A2、2C19基因多态性与难治性抑郁症的关联。方法应用聚合酶链反应(PCR)扩增技术及限制性片段长度多态性(RFLP)测定79例难治性抑郁症患者及107名正常对照者CYP1A2C163A、CYP2C19G681A基因多态性。结果两组间基因型及等位基因分布差异无显著性(χ2=3.605,P>0.05;χ2=3.154,P>0.05)。难治性抑郁症患者对照组间基因型及等位基因分布差异无显著性(χ2=0.853,P>0.05;χ2=0.568,P>0.05)。79名患者中46名接受氟西汀合并小剂量利培酮(0.5～2.0mg/d)治疗,将其分为治疗有效组和无效组,两组间CYP1A2C163A(χ2=0.785,P>0.05;χ2=7.142,P>0.05)CYP2C19G681A(χ2=3.008,P>0.05;χ2=2.722,P>0.05)基因型及等位基因分布差异均无显著性。根据CYP2C19G681A基因多态性将患者分为无突变组(G/G型)和突变组(G/A型和A/A型),两组患者CYP1A2C163A基因型及等位基因分布差异无显著性(χ2=0.252,P>0.05;χ2=0.682,P>0.05)。结论CYP1A2C163A和CYP2C19G681A基因多态性与难治性抑郁症无显著关联,不是影响利培酮对氟西汀增效作用的主要因素。     

Interaction between caffeine and polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2) on Parkinson's disease risk

Background : Caffeine intake has been inversely associated with Parkinson's disease (PD) risk. This relationship may be modified by polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2), but the results of previous studies have been inconsistent. Method : We examined the interaction of caffeine intake with GRIN2A‐rs4998386 and CYP1A2‐rs762551 polymorphisms in influencing PD risk among 829 incident cases of PD and 2,754 matched controls selected among participants in the following 3 large prospective ongoing cohorts: the Nurses' Health Study, the Health Professionals' Follow‐up Study, and the Cancer Prevention Study II Nutrition Cohort. Matching factors included cohort, birth year, source of DNA, date of DNA collection, and race. Relative risks and 95% confidence intervals were estimated using conditional logistic models. Interactions were tested both on the multiplicative scale and on the additive scale. Results : Overall, caffeine intake was associated with a lower PD risk (adjusted relative risk for highest versus lowest tertile = 0.70; 95% confidence interval, 0.57‐0.86; p < .001). In analyses stratified by the GRIN2A‐rs4998386 genotype, the multivariable‐adjusted relative risk of PD comparing the highest to the lowest tertile of caffeine was 0.69 (95% confidence interval, 0.55‐0.88; p < .01) among individuals homozygous for the C allele, and 0.85 (95% confidence interval, 0.55‐1.32; p = .47; p_RERI = .43) among carriers for the T allele. Interactions between caffeine and GRIN2A were not significant in either the multiplicative or additive scales. We also did not observe significant interactions for CYP1A2‐rs762551 and incident PD risk. Conclusion : Our findings do not support the hypothesis of an interaction between the GRIN2A‐rs4998386 or CYP1A2‐rs762551 polymorphism and caffeine intake in determining PD risk. © 2018 International Parkinson and Movement Disorder Society     

Lack of impact of CYP1A2 genetic polymorphism (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position -2964 in the 5'-flanking region of CYP1A2) on the plasma concentration of haloperidol in smoking male Japanese with schizophrenia

The impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of haloperidol (HAL) in 40 male smokers with schizophrenia was investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position -2964 in the 5'-flanking region of CYP1A2 were identified by polymerase chain-reaction-restricted fragment length polymorphism method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A (n = 21), A/C (n = 14) and C/C (n = 5) genotypes (one-way analysis of variance: 63.1 +/- 18.5, 47.8 +/- 12.5 and 50.8 +/- 15.1 ng/ml/mg/kg, respectively, F(2,37) = 2.556, P = .09). Regarding G/A polymorphism at position -2964 in the 5'-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G (n = 24) and G/A (n = 15) (two-tailed t test: G/G and G/A = 51.2 +/- 16.6 and 59.0 +/- 17.6 ng/ml/mg/kg, respectively, df = 28, P = .22). The present study suggests that the genotyping of CYP1A2 cannot predict the steady state plasma levels of HAL in male smoking schizophrenics.     

Influence of CYP4F2 genotype on warfarin dose requirement-a systematic review and meta-analysis

Introduction

Warfarin is a commonly used oral anticoagulant and the dosage is individually adjusted on the basis of the international normalized ratio (INR) monitoring. It is well known that gene polymorphisms of CytochromeP450 (CYP) 2 C9 gene and the vitamin K epoxide reductase complex 1 (VKORC1) were significantly associated with warfarin dose. However, the association between Cytochrome P450 4 F2 (CYP4F2) polymorphism and warfarin dose requirement is still controversial. This study was to investigate the influence of the CYP4F2 polymorphism, V433M (rs2108622) on warfarin dose for patients by meta-analysis.

Methods

Strict inclusion and exclusion criteria were set, and the studies prior to December 19, 2010 were searched in PubMed, EMBASE and CNKI. References were examined and experts of primary studies were consulted for additional information. Revman 5.0.2 software was used to analyze the relationship between warfarin maintenance dose and CYP4F2 polymorphism

Results

Thirteen studies were included in the meta-analysis which consisted of Caucasian, Asian and African populations. Compared to individuals with the homozygous CYP4F2 genotype (CC), carriers of CT, TT genotypes required 10.0% (95% confidence interval(CI) 4.0-15.0) and 21.0% (95% CI 9.0-33.0) higher warfarin doses respectively (P value < 0.05). In addition, T carriers required 11.0% (95% CI 6.0-17.0) higher warfarin dose than CC genotype.

Conclusions

Our study showed that polymorphism of CYP4F2 had a moderate but statistically significant association with the variation of interindividual warfarin dose. However, whether CYP4F2 can improve the prediction of warfarin dose warrants need further investigation when combined with environmental factors.     

A regression model to predict warfarin dose from clinical variables and polymorphisms in CYP2C9, CYP4F2, and VKORC1: Derivation in a sample with predominantly a history of venous thromboembolism

Background

Pharmacogenomic warfarin dosing has been suggested to produce more accurate dosing and an improved patient safety profile; however, very few models have been derived in patients with venous thromboembolism. We sought to develop a new algorithm to predict maintenance dose in a cohort of patients, using clinical variables and genetic polymorphism in CYP2C9, VKORC1, and CYP4F2.

Methods

Patients on a stable maintenance dose of warfarin, with observed dose ranging from 0.6 to 12 mg were recruited from a specialized anticoagulation clinic (Ottawa Hospital Thrombosis Clinic) with genotyping and standardized patient interviews being conducted to collect clinical and genomic variables known to impact warfarin dose. Multivariate linear regression was used to develop the model using a stepwise backwards elimination approach.

Results

From 249 enrolled patients with a mean clinical maintenance dose of 5.58 mg/day, a model with an R² of 58% was developed as: Dose = 1.85-0.048(Age) + 0.041(BMI) + 0.05(Height in cm) - 0.73(Less Exercise) - 1.13(2C9*2 Hetero) - 2.09(2C9*2 Homo) - 1.51(2C9*3 Hetero) -1.43(VKORC1 GA) - 2.86(VKORC1 AA) - 1.33(4F2 CC) -1.24(4F2 CT) - 1.46(Angiotensin II Receptor Antagonist) - 0.84(β-Blockers). Analysis of residual plots revealed that prediction errors were a function of observed maintenance dose with the model tending to predict higher doses than observed in those with low dose requirements and lower doses than observed in those with higher dose requirement.

Conclusion

Our study confirms the importance of the CYP4F2 polymorphism. Our model may prove useful in clinical practice but further validation studies are required before implementation into clinical practice.     

Resequencing of VKORC1, CYP2C9 and CYP4F2 genes in Italian patients requiring extreme low and high warfarin doses

Purpose

The aim of the present study was to investigate the genetic variability of VKORC1, CYP2C9 and CYP4F2 genes in patients who required a very low and high warfarin dose, in order to identify novel variants that could help to explain the particular extreme dose requirements.

Methods

Among patients followed and treated with warfarin at the Center of Haemostasis and Thrombosis of the PTV, we selected twelve patients showing a high divergence from warfarin standard doses required to achieve the therapeutic effect.All VKORC1, CYP2C9 and CYP4F2 coding regions, 3’ and 5’ UTR and exon/intron boundaries were analyzed by direct sequencing.

Results

The 1173T and -1639A allele variants in VKORC1 gene, associated with warfarin sensitivity, were present, as expected, mostly in low dose patients while 3730A allele, linked to warfarin resistance, has been found only in high dose patients. Interestingly, we found that three out of six low dose subjects presented CYP2C9*3/*3 homozygous genotype, very rare in Caucasians.Besides these common polymorphisms, we identified 5 SNPs in CYP2C9 gene and 19 SNPs in CYP4F2 gene. Among these, all polymorphisms identified in CYP2C9 gene were present only in low dose patients and three of them resulted in linkage with CYP2C9*2 and CYP2C9*3. Regarding CYP4F2 SNPs, we did not observe differences between the high and low dose patients. At the end, the whole sequencing did not reveal any novel polymorphism/mutation.

Conclusion

Further studies are required to identify other genetic factors contributing to extreme warfarin requirement.     

心电图QT间期与抗精神病药及代谢等的关系

目的：观察心电图叩间期与抗精神病药及代谢等的关系。方法：对390例应用抗精神病药至少6个月住院患者的代谢参数作评估，测量他们的校正QT间期（帆）。结果：25例（6．4％）出现QTc间期延长。联用与单一应用抗精神病药患者的QR间期差异无显著性（P=0．884）。服氯氮平患者的叽间期较其他药物明显延长。结论：QT间期延长并不多见，与三酰甘油相关，与其他代谢参数无显著相关。     

The Effects of Genetic Polymorphisms of CYP2C9 and CYP2C 19 on Phenytoin Metabolism in Japanese Adult Patients with Epilepsy: Studies in Stereoselective Hydroxylation and Population Pharmacokinetics

Summary: Purpose : The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed.
Methods: The genotype of CYP2C9 (Arg¹⁴⁴/Cys, Ile³⁵⁹/Leu) and CYP2C19 (*1, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose-serum concentration data.
Results: The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis-Menten constants (K,) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)- and (5')- p -HPPHPHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without mutations.
Conclusions: Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu359 allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.     

CYP1A2基因C734A多态性和奥氮平临床效应的关联研究

目的探讨细胞色素P450(CYP)1A2酶基因C734A多态性和奥氮平临床效应的关系。方法随机选取113例精神分裂症患者给予奥氮平足量治疗8周,治疗前后以阳性和阴性症状量表(PANSS)评定疗效,测定治疗前后的血糖、血脂和体重,采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)技术检测患者的基因多态性。从3个角度分析C734A多态性与疗效的关系。结果以PANSS减分率50％为界将患者分为有效组(69例)和无效组(44例),两组间CYP1A2基因C734A多态性的基因型和等位基因频率差异无显著性(X2=3．13,P> 0．05;X2=0．48,P>0．05);以基因型不同分组比较,各组间PANSS的总分、阳性症状分、阴性症状分等指标的减分／减分率的差异均无显著性(F值为0．14-1．74,P>0．05);多元线性回归分析结果显示,未发现病程、治疗前PANSS总分、用药剂量等混杂因素对疗效具有明显的影响(P>0．05),而PANSS的总分、阳性症状分、阴性症状分的减分率等疗效指标与CYP1A2基因均不存在线性回归关系(各偏回归系数检验t值分别为-0．52,-0．04, -0．49,P>0．05)。不同基因型组间治疗后的血糖、血脂升高和体重增加的差异也无显著性(F值为0．02-0．89, P>0．05)。结论CYP1A2基因C734A多态性与奥氮平治疗精神分裂症的疗效无关,与其所致的糖脂改变和体重增加也无关联。     

Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients

The dose required for the anticoagulant effect of warfarin exhibits large inter-individual variations. This study sought to determine the contribution of four genes, vitamin K epoxide reductase (VKORC1), gamma-glutamyl carboxylase (GGCX), calumenin (CALU), and cytochrome P450 2C9 (CYP2C9) to the warfarin maintenance dose required in Japanese patients following ischemic stroke. We recruited 93 patients on stable anticoagulation with a target International Normalized Ratio (INR) of 1.6-2.6. We genotyped eleven representative single nucleotide polymorphisms (SNPs) in the three genes involved in vitamin K cycle and the 42613A>C SNP in CYP2C9, known as CYP2C93, and then examined an association of these genotypes with warfarin maintenance doses (mean+/-SD=2.96+/-1.06 mg/day). We found an association of effective warfarin dose with the -1639G>A (p=0.004) and 3730G>A genotypes (p=0.006) in VKORC1, the 8016G>A genotype in GGCX (p=0.022), and the 42613A>C genotype in CYP2C9 (p=0.015). The model using the multiple regression analysis including age, sex, weight, and three genetic polymorphisms accounted for 33.3% of total variations in warfarin dose. The contribution to inter-individual variation in warfarin dose was 5.9% for VKORC1 -1639G>A, 5.2% for CYP2C9 42613A>C, and 4.6% for GGCX 8016G>A. In addition to polymorphisms in VKORC1 and CYP2C9, we identified GGCX 8016G>A, resulting in the missense mutation R325Q, as a genetic determinant of warfarin maintenance dose in Japanese patients.     

A new algorithm to predict warfarin dose from polymorphisms of CYP4F2 , CYP2C9 and VKORC1 and clinical variables: derivation in Han Chinese patients with non valvular atrial fibrillation

Few pharmacogenomic dosing regimens of warfarin have been developed for Chinese patients with non valvular atrial fibrillation (NVAF). The objective of this study was to develop a new algorithm by polymorphisms of CYP2C9, VKORC1 and CYP4F2 to predict the daily stable dose of warfarin in Chinese patients with NVAF. A total of 325 Chinese NVAF patients on stable dose of warfarin with a target international normalised ratio of 1.5 to 3.0 were recruited and divided randomly into two cohorts. CYP2C9*3, VKORC1-1639, VKORC1 1173 and CYP4F2 were detected by ligase detection reaction method. The new algorithm was developed with multivariate linear regression in cohort 1 (260 patients) and assessed with Pearson Correlation Analysis (PCA) in cohort 2 (65 patients). From 260 enrolled patients, the model (R2 = 51.7%) was developed as: Dose = 3.47 - 0.022 (AGE) + 0.017 (WT) + 0.189 (PTE) - 0.283 (β-blocker) - 0.471 (AMIO) - 0.586 (CYP2C9 *1/*3) - 0.296 (VKORC1 CT) - 0.648 (VKORC1 TT) + 0.219 (CYP4F2 TT). PCA displayed that the algorithm was good (r = 0.658). The residual plots revealed that the predicted doses by the algorithm tend to be overestimated when lower doses were administered to patients and to be underestimated in higher doses. The algorithm developed by us might predict warfarin dose used by Chinese NVAF patients.     

CYP1A1 and GSTM1/T1 Genetic Variation in Predicting Risk for Cerebral Infarction

Cytochrome P450 1A1 (CYP1A1) is involved in the production of arachidonic acid-derived vasoactive substance. We hypothesized that CYP1A1 polymorphism might be related to pathological conditions associated with cerebral infarction (CI). We investigated the effect of genetic polymorphism in the 3′-flanking region (T6235C) of CYP1A1 gene in 353 patients with CI and 376 controls. The distributions of T6235C CYP1A1 genotypes in patients with (TT: 36.0%; TC/CT: 64.0%; n = 353) and without CI (TT: 44.7%; TC/CT: 55.3%; n = 376) indicate that the C allele is associated with CI (P = 0.017, odds ratio (O.R.) = 1.44; 95% confidence interval (C. I.) = 1.07–1.94). Furthermore, we examined whether the glutathione S-transferase (GST) gene, which is one of detoxification enzyme, influence the risk of CI. GST M1 null genotype increased the relative risk for the CI in the subjects with the CYP1A1 C allele (P = 0.015, O.R. = 1.47; C. I. = 1.08–2.00). We conclude that T6235C CYP1A1 polymorphism is a risk factor for the development of CI and suggest that GST polymorphism contribute to the odds of CI.     

Coffee,ADORA2A,and CYP1A2: the caffeine connection in Parkinson’s disease

Background and purpose: In 1‐methyl‐4‐phenyl 1,2,3,6‐tetrahydropyridine animal models of Parkinson’s disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine–PD association. Methods: Parkinson’s Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population‐based case–control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age‐ and sex‐matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in‐person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. Results: Two ADORA2A polymorphisms were inversely associated with PD risk – rs71651683, a 5′ variant (adjusted allelic OR = 0.51, 95% CI 0.33–0.80, permutation‐adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild‐type genotype were 0.76 (95% CI 0.57–1.02) and 0.37 (95% CI 0.13–1.01), respectively (permutation‐adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee–PD association was strongest among subjects homozygous for either variant allele rs762551 (P_interaction = 0.05) or rs2470890 (P_interaction = 0.04). Conclusion: In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee–PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.     

An interaction between the norepinephrine transporter and monoamine oxidase A polymorphisms, and novelty-seeking personality traits in Korean females

The personality traits associated with the noradrenergic system have not yet been clearly established. In the present study, we investigated the variable number of tandem repeats (VNTR) polymorphism of the norepinephrine transporter (NET) and monoamine oxidase A (MAOA), which are major components of the adrenergic system, to elucidate their relationship with personality. A total of 245 normal female Koreans (age 23.05+/-3.07 years, mean+/-SD) volunteered to take part in this study. They filled out a Korean version of the Temperament and Character Inventory (TCI) and were genotyped for the NET and MAOA-VNTR; the NET T-182C and MAOA-uVNTR polymorphisms were checked. We found significant main effect of NET genotype on novelty seeking (NS) score (F=5.43, p=0.021) and significant interaction between the NET and MAOA-uVNTR polymorphisms on NS score (F=11.06, p=0.001). However, there were no relationship between MAOA-uVNTR polymorphisms and NS score, and no association with other temperamental dimensions and these two polymorphisms. Our findings suggest that this functional polymorphism in the noradrenergic gene is associated with novelty seeking in Korean females.     

Positive association between ALDH1A2 and schizophrenia in the Chinese population

Vitamin A (retinol), in the biologically active form of retinoic acid (RA), has been proposed as involved in the pathogenesis of schizophrenia. We hypothesized that genetic basis of genes encoding RA metabolism enzymes, which control the cellular RA level, might be associated with this disease. This cascade genetic association model, using markers in genes of synthesis and degradation enzymes within the retinoid cascade, would better fit the biological character of the retinoid hypothesis than the single gene strategy. In the present study we chose to investigate 7 genes involved in the synthesis, degradation and transportation of RA, ALDH1A1, ALDH1A2, ALDH1A3, CYP26A1, CYP26B1, CYP26C1 and Transthyretin (TTR), for their roles in the development of schizophrenia. We genotyped 18 single nucleotide polymorphisms (SNPs) in the regulatory and coding regions of these 7 genes using LDR technology in the 617 Chinese Han subjects. Case–control analyses were performed to detect association of these 7 genes with schizophrenia. Association analyses using both allelic and genotypic single-locus tests revealed no significant association between the risk for each of investigated gene and schizophrenia. However, analyses of multiple-locus haplotypes indicated that the overall frequency of rs4646642–rs4646580 of ALDH1A2 gene showed significant difference between patients and control subjects (p = 0.0055). We also employed multifactor dimensionality reduction method to detect multilocus effects. In summary, in this work we show multiple candidate genes involved in retinoid cascade in schizophrenics. In addition, our results suggest a positive association between ALDH1A2 and schizophrenics in the Chinese population and support the retinoid hypothesis of schizophrenia.     

Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin

We examined the influence of combined genotypes on interindividual variability in warfarin dose-response. In 100 anticoagulated patients we quantified the effects of polymorphisms in: CYP2C9, VKORC1, calumenin (CALU), gamma-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G(1542)C VKORC1 polymorphism was associated with decreased warfarin doses in the hetero- and homozygous mutant patients (21% and 50% lower, respectively; p < 0.0001). Warfarin daily dose was predominantly determined by VKORC1 and CYP2C9 genotypes (partial r(2) = 0.21; 0.20, respectively). Together with age and body weight, these two genotypes explained 63% of the dose variance. A single patient, homozygous for G(11)A CALU mutant allele, required an exceptionally high warfarin dose (20 mg/day) and the prevalence of heterozygous (11)A allele carriers in the upper 10(th) dose percentile was significantly higher (0.27 vs. 0.18, p < 0.02). Combined genotype analysis revealed that CYP2C9 andVKORC1 wild type and CALU mutant patients required the highest warfarin doses (7.8 +/- 1.5mg/day; n = 9) as compared to the CYP2C9 and VKORC1 mutant and CALU wild type genotypes (2.8 +/- 0.3 mg/day; n = 18; p < 0.01). The odds ratio for doses <3mg/day was 5.9 (1.9-18.4) for this genotype. Compound genetic profiles comprising VKORC1, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anticoagulation.     

VKORC1 V66M mutation in African Brazilian patients resistant to oral anticoagulant therapy

Warfarin-based anticoagulant therapy is associated with large variability in dose response. Genetic variability in the VKORC1 and CYP2C9 genes is associated with increased warfarin sensitivity. In addition, rare coding region mutations in VKORC1 have been associated with resistance to warfarin. VKORC1 and CYP2C9 variability associated with altered warfarin response is less well characterized in African and mixed-raced populations such as Brazilians. To determine genetic variability associated with altered warfarin response among Brazilian patients, sixty-two adult patients with extreme resistance or sensitivity to warfarin were genotyped for variants in CYP2C9 and VKORC1. Of the 51 patients on low doses of warfarin, the VKORC1 - 1639 (3673) G > A polymorphism associated with warfarin sensitivity was present in 48 (94.1%), including 97% of Caucasians, 82% of African-descent patients, and all 7 (100%) patients of Indian descent. Additionally, 52.9% of warfarin sensitive patients had at least one CYP2C9*2 or CYP2C9*3 decreased metabolism allele, 63.6% of Caucasians and 54% of African-descent patients. Of the 11 patients on high doses of warfarin, sequencing of VKORC1 revealed a nonsynonymous V66M mutation in two warfarin resistant patients, both of African-descent. Brazilian patients requiring low doses of warfarin have a high frequency of VKORC1 and CYP2C9 variants associated with warfarin sensitivity. The presence of the rare VKORC1 V66M in two warfarin high dose outlier patients implies that this variant may be more frequent among African Brazilians and has implications for future warfarin studies in other populations of African descent.     

The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement

The degree of interpatient variability in the warfarin dose required to achieve the desired anticoagulant response can only partly be explained by polymorphisms in the CYP2C9 gene, suggesting that additional genetic factors such as polymorphisms in genes involved in blood coagulation may influence warfarin dose requirement. In total, 165 Caucasian outpatients on stable maintenance warfarin treatment previously genotyped for CYP2C9 were analysed for common polymorphisms in FVII, GGCX and VKORC1 genes. The -402G > A polymorphism and a variable number of repeats in intron 7 of FVII gene did not significantly influence warfarin dose. The mean warfarin doses increased with the number of (CAA) repeats in the GGCX gene, but the differences were significant only in the CYP2C9*1/*1 subgroup of patients (p = 0.032). Common polymorphism (6484C > T) in intron 1 of the VKORC1 gene led to lower warfarin dose requirement; the means were 5.70 (95% C.I. 4.95-6.45), 3.49 (3.07-3.90) and 2.11 (1.80-2.42) mg/day for 6484 CC, CT and TT genotypes, respectively (p < 0.001). In contrast, 9041G > A polymorphism in 3'UTR of theVKORC1 gene led to higher warfarin dose requirement; the means were 3.09 (2.58- 3.60), 4.26 (3.69-4.82) and 5.86 (4.53-7.19) mg/day for 9041 GG, GA and AA genotypes, respectively (p < 0.001). With a regression model we explained 60.0% of variability in warfarin dose, which was due to gene polymorphisms (CYP2C9, VKORC1), age and body-surface-area. When aiming for individualised warfarin therapy, at least VKORC1 polymorphisms should be included in predictive genotyping besides CYP2C9.