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Combination chemotherapy using docetaxel, cisplatin and 5‑fluorouracil (DCF) is a promising treatment option for patients with advanced esophageal squamous cell carcinoma (ESCC), although its clinical application is limited by severe systemic toxicities. There are no validated markers for predicting the adverse effects caused by this regimen. This pharmacogenetic study enrolled 57 patients with chemotherapy‑naive advanced ESCC between July 2012 and March 2016 (UMIN000008462). All patients received at least one course of DCF chemotherapy (docetaxel, 60 mg/m2 on day 1; cisplatin, 70 mg/m2 on day 1; 5‑fluorouracil, 600 mg/m2 on days 1‑5). The associations between four gene polymorphisms (ERCC1 rs11615, GSTP1 rs1695, TYMS rs151264360 and XPD rs13181) and the development of grade 3/4 adverse events during the first course of chemotherapy were prospectively investigated. The patients had a median age of 66 years (range, 45‑77 years) and the majority were male (51 males vs. 6 females). The treatment settings were neoadjuvant (47 patients), adjuvant (1 patient) and salvage (9 patients), with dose intensities of 100% (51 patients) or 80% (6 patients). The severe adverse events were leukopenia (70.2%), neutropenia (86.0%), febrile neutropenia (36.8%), acute kidney injury (29.1%) and hyponatremia (43.9%). Two polymorphisms were independently associated with the development of severe hyponatremia among patients carrying the minor allele (vs. patients with major homozygote genotype): TYMS 3'‑UTR rs151264360 (odds ratio, 3.64; 95% confidence interval, 1.11‑11.9) and XPD Lys751Gln rs13181 (odds ratio, 10.1; 95% confidence interval, 1.10‑93.3). Therefore, the presence of the TYMS and XPD polymorphisms may aid in identifying patients with a high risk of developing severe hyponatremia during DCF chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: We sought to determine if specific genetic single nucleotide polymorphisms (SNPs) influence vascular endothelial growth factor inhibition response to ranibizumab in neovascular age‐related macular degeneration (AMD). Methods: A total of 403 Caucasian patients diagnosed with exudative AMD were included. After a three‐injection loading phase, a pro re nata regimen was followed. Nine SNPs from six different genes (CFH, CFB, ARMS2, SERPINF1, VEGFR1, VEGF) were genotyped. Non‐genetic risk factors (gender, smoking habit and hypertension) were also assessed. Patients were classified as good or poor responders (GR or PR) according to functional (visual acuity), anatomical (foveal thickness measured by OCT) and fluid criteria (fluid/no fluid measured by OCT). Results: Hypertension was the environmental factor with the strongest poor response association with ranibizumab in the anatomical measure after the loading phase (p = 0.0004; OR 3.7; 95% CI, 2.4–5.8) and after 12 months of treatment (p = 10−5; OR 2.3; 95% CI, 1.5–3.4). The genetic variants rs12614 (CFB), rs699947 (VEGFA) and rs7993418 (VEGFR1) predisposed patients to a good response, while rs12603486 and rs1136287 (SERPINF1) were associated with a poor response. The protective genotype of rs800292 variant (CFH) was also associated with a poor anatomical response (p 0.0048). Conclusion: All these data suggest that genetics play an important role in treatment response in AMD patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Tetrahydrobiopterin (BH4) plays an important role in the biosynthesis of serotonin, melatonin and catecholamines, all of which are implicated in the pathophysiology of mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Production of BH4 is regulated by GTP cyclohydrolase transcription and activity. Thus, we considered the GTP cyclohydrolase gene (GCH1) to be a good candidate gene in the pathophysiology of MDs and of the serotonin selective reuptake inhibitors (SSRIs) response in MDD, and conducted a case-control study utilizing three SNPs (rs8007267, rs3783641 and rs841) and moderate sample sizes (405 MDD patients, including 262 patients treated by SSRIs, 1022 BP patients and 1805 controls). Method: A multiple logistic regression analysis was carried out to compare the frequencies of each SNP genotype for the target phenotype across patients and controls in several genetic models, while adjusting for possible confounding factors. A clinical response was defined as a decrease of more than 50% from the baseline score on the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D) within 8 weeks, and clinical remission as a SIGH-D score of less than 7 at 8 weeks. Result: No associations between three SNPs in GCH1 and MDD or BP were observed; however, GCH1 was associated with SSRI therapeutic response in MDD in all the marker’s haplotype analysis (Global P value=0.0379). Conclusions: Results suggest that GCH1 may predict response to SSRI in MDD in the Japanese population. Nevertheless, a replication study using larger samples may be required for conclusive results, since our sample size was small. [Copyright &y& Elsevier]

Qbjectives. The aim of the study was to examine the associations between genetic variations in the human PAWR gene and major depressive disorder (MDD) as well as the response to antidepressant treatment. Methods. Six-hundred and two patients with MDD and 543 controls were included in the study; among the MDD patients, 268 were followed-up for a further 8 weeks in order to assess their response to treatment with selective serotonin reuptake inhibitors (SSRIs). Six polymorphisms (rs17005769, rs4842318, rs7305141, rs2307223, rs8176874 and rs2307220) of the PAWR gene were investigated with regard to their association with MDD and antidepressant treatment efficacy. Results. One polymorphism, rs8176874, was in genotypic (uncorrected P == 0.005) and allelic (uncorrected P == 0.0015) association with MDD. Several haplotypes spanning rs7305141--rs2307223--rs8176874 were also significantly associated with MDD after correction for multiple testing (corrected P < 0.05). However, neither single-marker nor haplotype-based analyses suggested an association between the studied markers and SSRI treatment response. Conclusions. Genetic variations in the PAWR gene are related to susceptibility to MDD but not to SSRI treatment response. [ABSTRACT FROM AUTHOR]

Abstract: Certain host genetic polymorphisms in human leukocyte antigen (HLA) genes are reported to be associated with response to interferon α (IFNα) therapy. Two hundred and eighteen IFNα treatment-naïve chronic hepatitis B (CHB) patients were enrolled in the present study. HLA-A, B, C and DQA1, DQB1, DRB1 gene alleles were detected by polymerase chain reaction-sequencing based typing (PCR-SBT) and PCR-sequence specific primer (PCR-SSP), respectively. Frequencies of HLA-DQB1*0303 and DRB1*08 in response group were clearly lower than those in nonresponse group (P =0.019, OR=1.81, 95%CI=1.07–3.15; P =0.031, OR=2.43, 95%CI=1.02–5.98, respectively). Frequencies of haplotype *1101-*4601-*0102 (HLA-A, B, C) and haplotype *0302-*0303-*09 (HLA-DQA1, DQB1, DRB1) were clearly lower than those in nonresponse group (P =0.009, OR=4.84, 95%CI=1.29–19.48; P =0.031, OR=1.94, 95%CI=1.01–3.73, respectively). These results suggest that patients with HLA-DQB1*0303 or DRB1*08 alleles, and haplotype *1101-*4601-*0102 (HLA-A, B, C) or haplotype *0302-*0303-*09 (HLA-DQA1, DQB1, DRB1), might be less responsive to IFNα treatment. [Copyright &y& Elsevier]

Objective Several investigations have suggested that alterations in serotonin 6 (5-HT6) receptors might be associated with the pathophysiology of major depressive disorder (MDD), and that 5-HT6 receptors might be a therapeutic target for serotonin selective reuptake inhibitor (SSRI) in MDD. To evaluate the association between HTR6 and the efficacy of SSRI treatment in Japanese MDD patients, we conducted a case-control study in a Japanese population sample. Methods We selected five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), and performed an association analysis of HTR6 and the efficacy of SSRI treatment in 260 MDD patients. Results We did not detect an association between tagging SNPs in HTR6 and the therapeutic response to SSRI in MDD in allele/genotype or haplotype analysis. Conclusions HTR6 may not play an important role in the pathophysiology of SSRI response in the Japanese population. Because our sample was relatively small, statistical errors were possible in the results of our association analyses. To overcome these limitations, a replication study using a larger sample may be required for conclusive results. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective The aim of the study was to investigate the association between genetic variation in the tumor necrosis factor-alpha (TNF-α) gene and longitudinal weight change during long-term clozapine treatment. Methods Fifty-five patients with refractory schizophrenia treated with clozapine for 8 years were recruited. Gender, age, treatment response to clozapine in the first 14 months, baseline BMI, clozapine dose, concomitant use of mood stabilizers and other antipsychotics, and -308 G > A polymorphism in the human TNF-α gene were analyzed using generalized estimating equations. Results In addition to having a lower baseline BMI (p = 0.0013) and a longer treatment time (p = 0.050), the -308 GG carriers gained significantly more weight than the -308 A allele carriers (p = 0.0084) during 8 years of clozapine treatment, after controlling for other non-genetic factors. Conclusions The -308 G > A genetic variant of the TNF-α gene is associated with longitudinal weight change during clozapine treatment. Follow-up duration is an important factor to consider when performing pharmacogenetic study of clozapine-induced weight gain. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Certain host genetic polymorphisms in interferon (IFN) signaling pathway genes are reported to be associated with response to IFNα therapy. We studied 10 single nucleotide polymorphisms (SNPs) in IFN signaling pathway genes to examine their associations with response to IFN treatment in chronic hepatitis B (CHB) patients. Two hundred and forty-six IFNα treatment-naïve CHB patients were enrolled for the present study; all received treatment with IFNα alone for 6 months, and the efficacy of the therapy was examined. Ten SNPs in 8 IFN signaling pathway genes were genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. There were no significant differences in allele frequencies and genotype distributions of the 10 SNPs between the response and non-response groups that underwent IFNα therapy. However, the frequency of a G-T-G-A 2′,5′-oligoadenylate synthetase (OAS) haplotype was significantly higher in the non-response group than that in the response group (16.1% vs. 8.7%, p =0.015). Our study suggested that patients with a G-T-G-A OAS haplotype were less responsive to IFNα treatment. [Copyright &y& Elsevier]

Several studies have connected brain-derived neurotrophic factor (BDNF) with treatment response to neuroleptics. In recent studies, theBDNFexpression was reduced by typical neuroleptics. We conducted a retrospective study on 94 patients with schizophrenia and 98 controls. TheBDNFG196A and C270T polymorphisms are not associated with treatment response to typical neuroleptics or with age at first hospitalization. Moreover, these polymorphisms of theBDNFgene are not associated with the risk of schizophrenia. [ABSTRACT FROM AUTHOR]