Pharmacogenetics and Genomics (PHARMACOGENET GENOM)

Publications in this journal

• Article: The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c

  Mette M.H. Christensen, Charlotte Brasch-Andersen, Henrik Green, Flemming Nielsen, Per Damkier, Henning Beck-Nielsen, Kim Brosen
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  ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
  Pharmacogenetics and Genomics 11/2011; 21(12):837–850.
• Article: Cytochrome P450 CYP2B6 genotypes and haplotypes in a Colombian population: identification of novel variant CYP2B6 alleles

  Juan Gonzalo Restrepo, Carmen Martínez, Augusto García-Agúndez, Elmer Gaviria, José Julio Laguna, Elena García-Martín, José A.G. Agúndez
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  ABSTRACT: Objective: Information on CYP2B6 allele frequencies and detrimental genotypes in mixed human populations is scarce. The aim of this study was to analyze the frequencies and haplotypes of nonsynonymous CYP2B6 single nucleotide polymorphisms (SNPs) in a Colombian population. Methods: One hundred and fifty-two healthy individuals were analyzed for five nonsynonymous CYP2B6 SNPs, namely rs8192709, rs3745274, rs2279343 rs28399499, and rs3211371. Results: Besides eight known variant alleles, we identified two as yet unknown variant alleles combining, respectively, the SNPs rs3745274 and rs3211371 and rs8192709 and rs3745274. Comparison of Colombian mestizo individuals with other mestizo population indicates statistically significant differences (P<0.001) for the gain-of-function CYP2B6*4 allele and for combined detrimental CYP2B6 alleles. In addition, we observed a low linkage between the SNPs rs3745274 and rs2279343, which are often assumed as linked. Conclusion: In conclusion, large interethnic and intraethnic variability exists for CYP2B6 polymorphisms, thus reinforcing the need for tailored genotyping protocols for CYP2B6 testing as a biomarker of drug response.
  Pharmacogenetics and Genomics 11/2011; 21(12):773–778.
• Article: Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose

  Ichiro Ieiri, Chisa Nishimura, Kazuya Maeda, Tomohiro Sasaki, Miyuki Kimura, Takeshi Chiyoda, Tekeshi Hirota, Shin Irie, Hitoshi Shimizu, Takanori Noguchi, Kenji Yoshida, Yuichi Sugiyama
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  ABSTRACT: Objectives: In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms. Methods: Telmisartan was orally administered at MD condition (100 μg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed. Results: No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0–24 (±standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701±970 ng hr/ml; MD, 978±537 pg hr/ml) and *4a variants (TD, 5340±1168; MD, 3145±1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969±1456; MD, 1669±726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose–exposure relationship was observed between the MD and TD. Conclusion: The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs.
  Pharmacogenetics and Genomics 07/2011; 21(8):495–505.
• Article: Gamma-aminobutyric acid GABRA4, GABRE, and GABRQ receptor polymorphisms and risk for essential tremor

  Elena García-Martín, Carmen Martínez, Hortensia Alonso-Navarro, Julián Benito-León, Oswaldo Lorenzo-Betancor, Pau Pastor, Inmaculada Puertas, Lluisa Rubio, Tomás López-Alburquerque, José A.G. Agúndez, Félix Javier Jiménez-Jiménez
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  ABSTRACT: Some clinical and experimental data suggest a possible role of γ-aminobutyrate (GABA)-ergic mechanisms in the pathophysiology of essential tremor (ET). We studied the allelic and genotype frequencies of the single nucleotide polymorphisms, such as GABRA4-L26M (Leu26Met, rs2229940), GABRE-S102A (Ser26Ala, rs1139916), and GABRQ-I478F (Ile26Phe, rs3810651), in 200 patients with familial ET and 250 healthy controls using TaqMan genotyping. GABRA4-L26M, GABRE-S102A, and GABRQ-I478F genotype and allelic frequencies did not differ significantly between patients with ET and controls, and were unrelated to the age at onset of tremor or sex. The GABRQ-478F allele seemed to be related to improvement of tremor with ethanol use among men (odds ratio=2.32, 95% confidence interval=0.26–4.3, P=0.007, Pc=0.021). The results of this study suggest that the single nucleotide polymorphisms studied in the GABRA4, GABRE, and GABRQ genes are not related to the risk for familial ET.
  Pharmacogenetics and Genomics 06/2011; 21(7):436–439.
• Article: Doxorubicin pathways: pharmacodynamics and adverse effects

  Caroline F. Thorn, Connie Oshiro, Sharon Marsh, Tina Hernandez-Boussard, Howard McLeod, Teri E. Klein, Russ B. Altman
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  ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
  Pharmacogenetics and Genomics 06/2011; 21(7):440–446.
• Article: Genetic and nongenetic factors associated with warfarin doserequirements in Egyptian patients

  Mohamed Hossam A. Shahin, Sherief I. Khalifa, Yan Gong, Lamiaa N. Hammad, Mohamed T.H. Sallam, Mostafa El Shafey, Shawky S. Ali, Mohamed-Eslam F. Mohamed, Taimour Langaee, Julie A. Johnson
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  ABSTRACT: Background and objective: Warfarin is a commonly used oral anticoagulant with a narrow therapeutic index and various genetic and clinical factors that influence interpatient variability in dose requirements. This study investigated the impact of genetic and nongenetic factors on warfarin dose requirements in Egyptians. Methods: DNA was extracted from 207 patients taking warfarin for more than 2 months and genotyped for VKORC1 (3673 G>A), CYP2C9 *2*3*4*5*8, CYP4F2 (V33M; rs2108622), APOE (rs429358, rs7412), and CALU(rs339097) gene polymorphisms. Linear regression modeling was conducted to identify the genetic and nongenetic factors that independently influence warfarin dose requirements. Results: VKORC1 3673 AA or GA genotype (P<0.0001), one or two variant alleles of CYP2C9 gene (P=0.0004), APOE ε2 haplotype (P=0.01), and increasing age (P<0.0001) were all associated with lower warfarin dose, whereas smoking (P=0.025) and pulmonary embolism (P=0.0059) showed association with higher warfarin doses. These factors explained 31% of the warfarin dose variability. This is the first independent confirmation of the association of the CALU rs339097 variant with higher warfarin dose requirement, although inclusion of thissinglenucleotide polymorphism in the multiple regressionmodel failed to achieve significance (P=0.066). CYP4F2 (V33M) polymorphism was not significant (P=0.314), despite itshigh frequency in the studied population (42%). Conclusion: The study shows that VKORC1, CYP2C9 polymorphisms, APOE ε2 variant, and several clinical/demographic variables are important determinants of warfarin dose requirements in Egyptian patients. The percentage of variability explained by these factors is lowerthan in those of European ancestry, but similar tothevariability explained in Asians and African ancestry.
  Pharmacogenetics and Genomics 02/2011; 21(3):130–135.
• Article: The effects of the SLCO2B1 c.1457C>T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans

  Junko Imanaga, Tsutomu Kotegawa, Hiromitsu Imai, Kimiko Tsutsumi, Tsuneaki Yoshizato, Tetsuji Ohyama, Yoshiyuki Shirasaka, Ikumi Tamai, Tomonori Tateishi, Kyoichi Ohashi
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  ABSTRACT: Objective: The objective was to determine the effects of the SLCO2B1 c.1457C>T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. Methods: Individuals were divided based on the genotype of SLCO2B1 c.1457C>T (n=14, c.[1457C]+c.[=] 5, c.[1457C]+c.[1457C>T] 5, and c.[1457C>T]+c.[1457C>T] 4). The oral pharmacokinetics of 60 mg fexofenadine and 5 mg midazolam were assessed with water or apple juice (1200 ml/day) in a randomized crossover study. OATP2B1-mediated uptake of fexofenadine and midazolam was evaluated with Xenopus laevis oocyte gene-expression system. Results: When fexofenadine was administered with water, subjects with c.[1457C>T] allele showed a significant decrease in fexofenadine in the area under the plasma concentration–time curve (AUC) compared with c.[1457C]+c[=] subjects (1110±347 vs. 1762±542 ng·h/ml, P<0.05). When administered with apple juice, a significant decrease in the fexofenadine AUC was observed compared with water (1342±519 vs. 284±79.2 ng·h/ml, P<0.05). The apple juice induced decrease in fexofenadine AUC was significantly lower in subjects carrying the c.[1457C>T] allele. Neither the genotype nor the apple juice showed significant effects on the pharmacokinetics of midazolam except for a marginally significant decrease in Cmax after administration with apple juice. The uptake of fexofenadine by OATP2B1 cRNA-injected oocytes was significantly higher than that by water-injected oocytes. Apple juice, but not midazolam, significantly decreased the uptake of fexofenadine by OATP2B1 cRNA-injected oocytes. Conclusion: The results suggest that fexofenadine is a substrate of OATP2B1, and the transport function of OATP2B1 is subject to the genotype of SLCO2B1 c.1457C>T and apple juice. It is likely that apple juice has little effect on CYP3A.
  Pharmacogenetics and Genomics 01/2011; 21(2):84–93.
• Article: Dependency of phenprocoumon dosage on polymorphisms in the VKORC1, CYP2C9, and CYP4F2 genes

  Martina Teichert, Mark Eijgelsheim, Andre G. Uitterlinden, Peter N. Buhre, Albert Hofman, Peter A.G.M. De Smet, Loes E. Visser, Bruno H.Ch. Stricker
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  ABSTRACT: Background: Genome-wide association studies (GWAS) on warfarin and acenocoumarol showed that interindividual dosage variation is mainly associated with single nucleotide polymorphisms (SNPs) in VKORC1 and to a lesser extent in CYP2C9 and CYP4F2. For phenprocoumon dosage, the genes encoding CYP3A4 and ApoE might play a role. Objective: To assess the association between common genetic variants within VKORC1, CYP2C9, CYP4F2, CYP3A4, and ApoE and phenprocoumon maintenance dosage, and to identify novel signals using GWAS. Methods: We selected all participants from the Rotterdam study who were treated with phenprocoumon. For each SNP, we tested the association between the above-mentioned genotypes and age, sex, body mass index, and target INR adjusted-phenprocoumon maintenance dosage. Results: Within our study population (N=244), VKORC1, CYP2C9, CYP4F2 genotypes together explained 46% of phenprocoumon maintenance dosage variation. Each additional VKORC1 variant allele reduced phenprocoumon maintenance dosage by 4.8 mg/week (P<0.0001) and each additional CYP2C9 variant allele by 2.2 mg/week (P=0.002). Each additional variant allele of CYP4F2 increased phenprocoumon dosage by 1.5 mg/week (P=0.022). Variant alleles of CYP3A41*B and ApoE showed no association with phenprocoumon dosage. Genome-wide significant SNPs were all related to VKORC1 activity. Best associated were two SNPs in complete linkage disequilibrium with each other and with SNPs within VKORC1: rs10871454 [Syntaxin 4A (STX4A)] and rs11150604 (ZNF646), each with a P value of 2.1×10−22. Each reduced phenprocoumon maintenance dosage weekly by 4.9 mg per variant allele. Conclusion: Similar to earlier findings with warfarin and acenocoumarol, phenprocoumon maintenance dosage depended on polymorphisms in the VKORC1 gene. CYP2C9 and CYP4F2 were of modest relevance.
  Pharmacogenetics and Genomics 12/2010; 21(1):26–34.
• Article: Exon sequencing and association analysis of EPHX1 genetic variants with maintenance warfarin dose in a multiethnic Asian population

  Sze Ling Chan, Anbupalam Thalamuthu, Boon Cher Goh, Kee Seng Chia, Benjamin Chuah, Andrea Wong, Soo Chin Lee
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  ABSTRACT: Background and objectives: Warfarin inhibits vitamin K epoxide reductase, of which microsomal epoxide hydrolase is a putative member. Several studies have found signals of association with warfarin maintenance dose in the EPHX1 gene. The aim of this study was to determine the effects of EPHX1 variants on warfarin maintenance dose in a multiethnic Asian population. Methods: We sequenced the exons of EPHX1 using PCR and direct sequencing in 279 patients consisting of three major ethnic groups receiving maintenance warfarin with a stable international normalized ratio. The effects of EPHX1 variants were assessed using multiple linear regression. Results: An association between an intronic SNP rs1877724 and warfarin maintenance dose was found, with homozygous variant carriers requiring approximately 0.5mg/day lower than wild type and heterozygotes after adjustment for covariates. However, its contribution is small, explaining only an additional 0.8% of the dose variability. Rare variants were pooled but there was no association between their presence and warfarin maintenance dose. However, the presence of noncoding rare SNPs was significantly associated with warfarin maintenance dose. Conclusion: Despite a significant finding in rs1877724, which concurs with an earlier study, overall, genetic variants in EPHX1 do not have a clinically significant impact on warfarin dose requirements in our population.
  Pharmacogenetics and Genomics 12/2010; 21(1):35–41.
• Article: Genetic variance in CYP2C8 and increased risk of myocardial infarction

  Eline M. Rodenburg, Loes E. Visser, A.H. Jan Danser, Albert Hofman, Charlotte van Noord, Jacqueline C.M. Witteman, André G. Uitterlinden, Bruno H.Ch. Stricker
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  ABSTRACT: Background: Epoxyeicosatrienoic acids (EETs) are important mediators in vasodilatation, acting as endothelium-derived hyperpolarizing factors. CYP2C enzymes catalyze the metabolism of arachidonic acid to EETs. Genetic variation within the genes encoding for these enzymes may result in differences in vascular response, among others in myocardial tissue, and may therefore increase the risk of myocardial infarction (MI). CYP2C8 and CYP2C9 are encoded by the genes of the same name. CYP2C9 polymorphisms have been associated with an increased risk of MI. As CYP2C8 is genetically linked to CYP2C9 and on account of its role in EET production, we hypothesized that CYP2C8 polymorphisms are associated with the risk of MI. Methods: This study was embedded within the Rotterdam study, a prospective population-based cohort study. The study population included all participants with successful genotyping and without prevalent MI (n=5199). Twenty-five tagging single nucleotide polymorphisms within and around the gene-coding areas of CYP2C8 and CYP2C9 were tested for an association with incident MI using survival analysis techniques with multivariable adjustment for potential confounders. Results: During follow-up, 290 persons developed an incident MI. One tag-SNP in the CYP2C8 gene was associated with incident MI after Bonferroni correction, rs1058932C>T (variant genotype hazard ratio 1.54; 95% CI: 1.22–1.95). There was a significant gene–sex interaction with a relative excess risk of 1.40 (95% CI: 0.33–2.47) for men. Conclusion: SNP rs1058932C>T within the CYP2C8 gene is associated with an increased risk of MI, which is, possibly because of a vascular effect of sex steroids, highest in males.
  Pharmacogenetics and Genomics 06/2010; 20(7):426-434.
• Article: GSNO reductase and [beta]2-adrenergic receptor gene-gene interaction: bronchodilator responsiveness to albuterol

  Shweta Choudhry, Loretta G. Que, Zhonghui Yang, Limin Liu, Celeste Eng, Sung O. Kim, Gunjan Kumar, Shannon Thyne, Rocio Chapela, Jose R. Rodriguez-Santana, William Rodriguez-Cintron, Pedro C. Avila, Jonathan S. Stamler, Esteban G. Burchard
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  ABSTRACT: Background: Short-acting inhaled β2-agonists such as albuterol are used for bronchodilation and are the mainstay of asthma treatment worldwide. There is significant variation in bronchodilator responsiveness to albuterol not only between individuals but also across racial/ethnic groups. The β2-adrenergic receptor (β2AR) is the target for β2-agonist drugs. The enzyme, S-nitrosoglutathione reductase (GSNOR), which regulates levels of the endogenous bronchodilator S-nitrosoglutathione, has been shown to modulate the response to β2-agonists. Objective: We hypothesized that there are pharmacogenetic interactions between GSNOR and β2AR gene variants that are associated with variable response to albuterol. Methods: We performed family-based analyses to test for association between GSNOR gene variants and asthma and related phenotypes in 609 Puerto Rican and Mexican families with asthma. In addition, we tested these individuals for pharmacogenetic interaction between GSNOR and β2AR gene variants and responsiveness to albuterol using linear regression. Cell transfection experiments were performed to test the potential effect of the GSNOR gene variants. Results: Among Puerto Ricans, several GSNOR SNPs and a haplotype in the 3′UTR were significantly associated with increased risk for asthma and lower bronchodilator responsiveness (P=0.04–0.007). The GSNOR risk haplotype affects expression of GSNOR mRNA and protein, suggesting a gain of function. Furthermore, gene–gene interaction analysis provided evidence of pharmacogenetic interaction between GSNOR and β2AR gene variants and the response to albuterol in Puerto Rican (P=0.03), Mexican (P=0.15) and combined Puerto Rican and Mexican asthmatics (P=0.003). Specifically, GSNOR+17059*β2AR+46 genotype combinations (TG+GG*AG and TG+GG*GG) were associated with lower bronchodilator response. Conclusion: Genotyping of GSNOR and β2AR genes may be useful in identifying Latino individuals, who might benefit from adjuvant therapy for refractory asthma.
  Pharmacogenetics and Genomics 05/2010; 20(6):351-358.
• Article: Common genetic variation of [beta]1- and [beta]2-adrenergic receptor and response to four classes of antihypertensive treatment

  Timo Suonsyrjä, Kati Donner, Tuula Hannila-Handelberg, Heidi Fodstad, Kimmo Kontula, Timo P. Hiltunen
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  ABSTRACT: Varying results have been reported on the association of β-adrenergic receptor polymorphisms with blood pressure (BP) response to β-blockers. We investigated the influence of ADRB1 Ser49Gly and Arg389Gly, and ADRB2 Gly16Arg and Glu27Gln polymorphisms on ambulatory BP response to bisoprolol and three other antihypertensive drug monotherapies in a placebo-controlled, double-blind, cross-over study with 233 moderately hypertensive men. ADRB1 Ser49Ser homozygotes tended to have a better ambulatory BP response to bisoprolol but the difference was statistically nonsignificant. ADRB1 Arg389Arg homozygotes did not show better BP response to bisoprolol than the other genotypes. There were no significant associations of ADRB2 polymorphisms with BP responses to any of the study drugs. The results from this controlled study in hypertensive men do not support clinical use of common polymorphisms in ADRB1 and ADRB2 in predicting BP responses to β-blockers or to three other antihypertensive drugs.
  Pharmacogenetics and Genomics 04/2010; 20(5):342-345.
• Article: HLA-B*3505 allele is a strong predictor for nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients.

  Soranun Chantarangsu, Taisei Mushiroda, Surakameth Mahasirimongkol, Sasisopin Kiertiburanakul, Somnuek Sungkanuparph, Weerawat Manosuthi, Woraphot Tantisiriwat, Angkana Charoenyingwattana, Thanyachai Sura, Wasun Chantratita, Yusuke Nakamura
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  ABSTRACT: Investigation of a possible involvement of differences in human leukocyte antigens (HLA) in the risk of nevirapine (NVP)-induced skin rash among HIV-infected patients. A step-wise case-control association study was conducted. The first set of samples consisted of 80 samples from patients with NVP-induced skin rash and 80 samples from NVP-tolerant patients. These patients were genotyped for the HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 by a sequence-based HLA typing method. Subsequently, we verified HLA alleles that showed a possible association in the first screening using an additional set of samples consisting of 67 cases with NVP-induced skin rash and 105 controls. An HLA-B*3505 allele revealed a significant association with NVP-induced skin rash in the first and second screenings. In the combined data set, the HLA-B*3505 allele was observed in 17.5% of the patients with NVP-induced skin rash compared with only 1.1% observed in NVP-tolerant patients [odds ratio (OR)=18.96; 95% confidence interval (CI)=4.87-73.44, Pc=4.6x10] and 0.7% in general Thai population (OR=29.87; 95% CI=5.04-175.86, Pc=2.6x10). The logistic regression analysis also indicated HLA-B*3505 to be significantly associated with skin rash with OR of 49.15 (95% CI=6.45-374.41, P=0.00017). A strong association between the HLA-B*3505 and NVP-induced skin rash provides a novel insight into the pathogenesis of drug-induced rash in the HIV-infected population. On account of its high specificity (98.9%) in identifying NVP-induced rash, it is possible to utilize the HLA-B*3505 as a marker to avoid a subset of NVP-induced rash, at least in Thai population.
  Pharmacogenetics and Genomics 01/2010; 19(2):139-46.
• Article: Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response

  Matthijs L. Becker, Loes E. Visser, Ron H. N. van Schaik, Albert Hofman, André G. Uitterlinden, Bruno H. Ch. Stricker
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  ABSTRACT: Objective: Metformin is transported into the hepatocyte by organic cation transporter 1 (OCT1) and out of the hepatocyte by multidrug and toxin extrusion 1 (MATE1). Recently, we discovered that polymorphisms rs622342 A>C in the SLC22A1 gene, coding for OCT1, and rs2289669 G>A in the SLC47A1 gene, coding for MATE1, are associated with the degree of glucose lowering by metformin. In this study, we assessed whether there exists an interaction between these two polymorphisms. Methods: We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Multiplicative interaction between the polymorphisms and change in HbA1c levels was analyzed in 98 incident metformin users. Results: In incident metformin users with the OCT1 rs622342 AA genotype, genetic variation at the MATE1 rs2289669 polymorphism was not associated with change in HbA1c levels [−0.10; 95% confidence interval (CI): −0.35 to 0.14; P=0.39]. In users with the OCT1 rs622342 AC genotype, there was a tendency between rs2289669 polymorphisms and change in HbA1c (−0.31; 95% CI: −0.65 to 0.03; P=0.070) and in users with the OCT1 rs622342 CC genotype there was a significant association with change in HbA1c levels (−0.68; 95% CI: −1.06 to −0.30; P=0.005). The multiplicative interaction between these two genotypes was statistically significant (−0.52; 95% CI: −0.94 to −0.11; P=0.015). Conclusion: The effect of the MATE1 rs2289669 polymorphism on the glucose lowering effect of metformin is larger in incident users with the OCT1 rs622342 CC genotype than in incident users with the AA genotype. The effect in incident users with the OCT1 rs622342 AC genotype is in between.
  Pharmacogenetics and Genomics 12/2009; 20(1):38-44.
• Article: Influence of 5-HT3 receptor subunit genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E on treatment response to antipsychotics in schizophrenia

  Anna Schuhmacher, Rainald Mössner, Boris B. Quednow, Kai-Uwe Kühn, Michael Wagner, Gabriela Cvetanovska, Dan Rujescu, Peter Zill, Hans-Jürgen Möller, Marcella Rietschel, Petra Franke, Wolfgang Wölwer, Wolfgang Gaebel, Wolfgang Maier
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  ABSTRACT: Objectives: Among serotonin (5-HT) receptors, the 5-HT3 receptor is the only ligand-gated ion channel. 5-HT3 antagonists such as ondansetron and tropisetron may improve auditory gating and neurocognitive deficits in schizophrenic patients. Moreover, many antipsychotic drugs are antagonists at 5-HT3 receptors. However, the role of 5-HT3 receptor variants on response to antipsychotic drugs in schizophrenic patients is still unclear. Methods: In a prospective, randomized, double-blind study, we have assessed six functional and coding variants of the subunit genes HTR3A, HTR3B as well as the novel HTR3C, HTR3D, and HTR3E subunits in the response to haloperidol or risperidone. Seventy patients were treated for 4 weeks and positive symptoms, negative symptoms, and general psychopathology were measured by the Positive and Negative Syndrome Scale (PANSS). Results: HTR3E had an effect on the speed of response to antipsychotics. GG-allele carriers responded more quickly to treatment on the PANSS negative symptom subscale (P = 0.03) and on the total PANSS score (P = 0.04) irrespective of medication. In a second independent study of 144 schizophrenia patients treated with atypical antipsychotics, this effect could not be confirmed. Conclusion: Our findings argue against a major effect of HTR3 variants in response to antipsychotics. Solely, the HTR3E and also the HTR3A variant could exert a weak effect on the speed of response to antipsychotics.
  Pharmacogenetics and Genomics 10/2009; 19(11):843-851.
• Article: CYP2D6: novel genomic structures and alleles.

  Whitney E Kramer, Denise L Walker, Dennis J O'Kane, David A Mrazek, Pamela K Fisher, Brian A Dukek, Jamie K Bruflat, John L Black
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  ABSTRACT: CYP2D6 is a polymorphic gene. It has been observed to be deleted, to be duplicated and to undergo recombination events involving the CYP2D7 pseudogene and surrounding sequences. The objective of this study was to discover the genomic structure of CYP2D6 recombinants that interfere with clinical genotyping platforms that are available today. Clinical samples containing rare homozygous CYP2D6 alleles, ambiguous readouts, and those with duplication signals and two different alleles were analyzed by long-range PCR amplification of individual genes, PCR fragment analysis, allele-specific primer extension assay, and DNA sequencing to characterize alleles and genomic structure. Novel alleles, genomic structures, and the DNA sequence of these structures are described. Interestingly, in 49 of 50 DNA samples that had CYP2D6 gene duplications or multiplications where two alleles were detected, the chromosome containing the duplication or multiplication had identical tandem alleles. Several new CYP2D6 alleles and genomic structures are described which will be useful for CYP2D6 genotyping. The findings suggest that the recombination events responsible for CYP2D6 duplications and multiplications are because of mechanisms other than interchromosomal crossover during meiosis.
  Pharmacogenetics and Genomics 10/2009; 19(10):813-22.
• Article: A pharmacogene database enhanced by the 1000 Genomes Project.

  Eric R Gamazon, Wei Zhang, R Stephanie Huang, M Eileen Dolan, Nancy J Cox
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  ABSTRACT: Human genetic variation is likely to be responsible for a substantial fraction of the variability in complex traits including drug response. Single nucleotide polymorphisms have been implicated in drug response using genome-wide association studies as well as candidate-gene approaches. A more comprehensive catalogue of human genetic variation should complement the current large-scale genotypic dataset from the International HapMap Project, which focuses on common genetic variants. The 1000 Genomes Project is an international research effort that aims to provide the most comprehensive map of human genetic variation using next-generation sequencing platforms. Owing to the lack of convenient tools, however, it is a challenge for the pharmacogenetic research community to take advantage of these data. Here, we present a new database of some pharmacogenes of particular interest to pharmacogenetic researchers. Our database provides a convenient portal for immediate utilization of the newly released 1000 Genomes Project data in pharmacogenetic studies.
  Pharmacogenetics and Genomics 10/2009; 19(10):829-32.
• Article: Support for the involvement of the KCNK2 gene in major depressive disorder and response to antidepressant treatment.

  Ying-Jay Liou, Tai-Jui Chen, Shih-Jen Tsai, Younger W-Y Yu, Chih-Ya Cheng, Chen-Jee Hong
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  ABSTRACT: The aim of this study was to examine the associations between genetic variations in the human KCNK2 gene and major depressive disorder (MDD) and response to antidepressant treatment. Four hundred and forty-nine patients with MDD and 421 normal controls were included in the study; among the MDD patients, 158 were further followed-up for 8 weeks to assess their response to antidepressant treatment. Five polymorphisms (rs12131478, rs6667764, rs10494994, rs11583745 and rs6686529) of the KCNK2 gene were investigated in terms of their association with MDD and antidepressant treatment efficacy. The genotype frequency of rs6686529 differed significantly between the MDD patients and controls (uncorrected P = 0.00052) and remained statistically significant after correction for multiple comparisons. Individuals with homozygous genotypes (CC or GG) showed greater susceptibility to MDD than those with heterozygous genotypes, indicating a possible heterosis effect of the polymorphism on MDD. In addition, this polymorphism also affected the efficacy of antidepressant treatment: the CC carriers had a greater probability of achieving remission after 8 weeks of treatment than the G-allele carriers [odds ratio = 2.55 (95% confidence interval = 1.11-5.88)]. Our findings are in line with those of animal studies, and show that KCNK2 is related to the susceptibility to MDD, and involved in antidepressant treatment response. However, the finding of heterosis association of rs6686529 and MDD may be mechanistic, and further replication studies will be essential.
  Pharmacogenetics and Genomics 10/2009; 19(10):735-41.
• Article: Effects of CYP4F2 genetic polymorphisms and haplotypes on clinical outcomes in patients initiated on warfarin therapy.

  Jieying Eunice Zhang, Andrea L Jorgensen, Ana Alfirevic, Paula R Williamson, Cheng H Toh, Brian Kevin Park, Munir Pirmohamed
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  ABSTRACT: A variant in the CYP4F2 gene, rs2108622, has been recently shown to determine stable warfarin dose requirements. CYP4F2 has also been shown recently to metabolize vitamin K. Three hundred and eleven patients were recruited prospectively from two UK hospitals and followed-up for 6 months. Fine mapping of the whole CYP4F2 region was performed to try and define the haplotype structure of CYP4F2. Genotyping was performed on the Sequenom platform. Univariate and multiple regression analyses were undertaken to assess the effect of CYP4F2 on predefined clinical outcomes of warfarin response. Fifty-nine single nucleotide polymorphisms in the CYP4F2 gene were analyzed. There was a high degree of linkage disequilibrium in the gene with two haplotype blocks. No association was found with warfarin stable dose and rs2108622 in our prospective cohort of patients even after adjustments to reduce patient heterogeneity. Interestingly, a single nucleotide polymorphism (rs2189784), which is in strong linkage disequilibrium with rs2108622, showed an association with time-to-therapeutic international normalized ratio which remained significant after the correction for multiple testing (Pc = 0.03). No association was shown with the haplotypes after false discovery rate correction. Although we were unable to demonstrate an association between rs2108622 and stable warfarin dose, our finding of an association between rs2189784 and time-to-therapeutic international normalized ratio is consistent with the recent finding that CYP4F2 plays a role in vitamin K metabolism. However, the effect of CYP4F2 is relatively small in all studies undertaken so far, and thus seems unlikely to be of clinical relevance.
  Pharmacogenetics and Genomics 10/2009; 19(10):781-9.