A genetic risk score to predict treatment nonresponse in psychotic depression.

Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = -0.32, p = 0.0023, n = 88) and remission (r = -0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression.

A common germline variant in CYP11B1 is associated with adverse clinical outcome of treatment with abiraterone or enzalutamide.

Extragonadal androgens play a pivotal role in prostate cancer disease progression on androgen receptor signaling inhibitors (ARSi), including abiraterone and enzalutamide. We aimed to investigate if germline variants in genes involved in extragonadal androgen synthesis contribute to resistance to ARSi and may predict clinical outcomes on ARSi. We included ARSi naive metastatic prostate cancer patients treated with abiraterone or enzalutamide and determined 18 germline variants in six genes involved in extragonadal androgen synthesis. Variants were tested in univariate and multivariable analysis for the relation with overall survival (OS) and time to progression (TTP) by Cox regression, and PSA response by logistic regression. A total of 275 patients were included. From the investigated genes CYP17A1, HSD3B1, CYP11B1, AKR1C3, SRD5A1 and SRD5A2, only rs4736349 in CYP11B1 in homozygous form (TT), present in 54 patients (20%), was related with a significantly worse OS (HR = 1.71, 95% CI 1.09 - 2.68, p = 0.019) and TTP (HR = 1.50, 95% CI 1.08 - 2.09, p = 0.016), and was related with a significantly less frequent PSA response (OR = 0.48, 95% CI 0.24 - 0.96, p = 0.038) on abiraterone or enzalutamide in a multivariable analysis. The frequent germline variant rs4736349 in CYP11B1 is, as homozygote, an independent negative prognostic factor for treatment with abiraterone or enzalutamide in ARSi naive metastatic prostate cancer patients. Our findings warrant prospective investigation of this potentially important predictive biomarker.

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis.

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

Genome-wide association study on pharmacological outcomes of musculoskeletal pain in UK Biobank.

The pharmacological management of musculoskeletal pain starts with NSAIDs, followed by weak or strong opioids until the pain is under control. However, the treatment outcome is usually unsatisfying due to inter-individual differences. To investigate the genetic component of treatment outcome differences, we performed a genome-wide association study (GWAS) in ~23,000 participants with musculoskeletal pain from the UK Biobank. NSAID vs. opioid users were compared as a reflection of the treatment outcome of NSAIDs. We identified one genome-wide significant hit in chromosome 4 (rs549224715, P = 3.88 × 10-8). Suggestive significant (P < 1 × 10-6) loci were functionally annotated to 18 target genes, including four genes linked to neuropathic pain processes or musculoskeletal development. Pathway and network analyses identified immunity-related processes and a (putative) central role of EGFR. However, this study should be viewed as a first step to elucidate the genetic background of musculoskeletal pain treatment.

Evaluating the Frequencies of CNOT3, GRIA1, NFATC2, and PNPLA3 Variant Alleles and Their Association with L-Asparaginase Hypersensitivity in Pediatric Acute Lymphoblastic Leukemia in Addis Ababa, Ethiopia.

Introduction: L-asparaginase is a vital component for the treatment of childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions and hepatotoxicity hinder its anti-neoplastic efficacy. Previous reports indicated that genetic variants in CNOT3, GRIA1, and NFATC2 genes might be associated with hypersensitivity reactions and PNPLA3 with liver function. Objective: In this study, it was investigated whether this association also exists in a pediatric ALL cohort from Ethiopia. Methods: Three variants GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were genotyped in a cohort of 160 patients. Association analysis to investigate the association with hypersensitivity reactions was performed using logistic regression analyses. Besides these variants, a variant in PNPLA3 (rs738409) was genotyped to assess the association with liver function. Results: Genotype frequencies of GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were higher/lower than previously reported. One hundred and forty-four patients were included in the association analysis of which, 18 (12.5%) developed L-ASP hypersensitivity. Though the frequency of hypersensitivity was higher in patients that carried the risk alleles of the three investigated genes, no statistically significant differences were observed. Association analysis between PNPLA3 rs738409 and liver function could not be investigated due to a lack of clinical information. Conclusion: In conclusion, none of the tested genes did predict L-asparaginase hypersensitivity in an Ethiopian pediatric ALL patients.

Incidence and determinants of hematotoxicity in acute lymphoblastic leukemia children who received 6-mercaptopurine based maintenance therapy in Addis Ababa, Ethiopia.

INTRODUCTION: The maintenance phase of acute lymphoblastic leukemia treatment is the final and longest stage of treatment, mainly focused on antimetabolite therapy. This phase is essential to eliminate residual leukemic clones and prevent relapse. However, dose-limiting hematotoxicity is a major problem during this phase resulting in dose reduction or treatment discontinuation. OBJECTIVE: In this cohort study, the clinical features and risk factors of hematological toxicity during the maintenance phase of treatment were analyzed in pediatric patients from Ethiopia. METHODS: A total of 160 patients from Tikur Anbessa specialized hospital were included in the study of which 142 had sufficient data available for analysis. Patient characteristics as well as information about the care-givers, sides-effects as reported by the care-givers and clinical factors were collected. Bivariable followed by multivariable analysis was performed to investigate which factors were associated with hematological toxicity during the maintenance phase. RESULTS: During the first six months of maintenance phase treatment grade 4 neutropenia was detected in 52.8% of the patients. The risk of developing grade 4 neutropenia was increased by about two fold in children with the age of 6 years and less compared to those with the age of more than 6 years. Similarly, the rate of developing grade 4 neutropenia among children with less than 4,500 maintenance day 1 white blood cell counts was significantly higher than that of children with normal maintenance day 1 white blood cell counts (AHR 2.477, 95% CI = 1.461-4.200, p = 0.001). CONCLUSION: In conclusion, child's age and day 1 maintenance white blood cell/absolute neutrophil counts significantly affected the occurrence of grade 4 hematotoxicity. Close monitoring for white blood cell and absolute neutrophil counts during maintenance phase treatment is recommended for early diagnosis of hematotoxicity.

A systematic review of genome-wide association studies for pain, nociception, neuropathy, and pain treatment responses.

ABSTRACT: Pain is the leading cause of disability worldwide, imposing an enormous burden on personal health and society. Pain is a multifactorial and multidimensional problem. Currently, there is (some) evidence that genetic factors could partially explain individual susceptibility to pain and interpersonal differences in pain treatment response. To better understand the underlying genetic mechanisms of pain, we systematically reviewed and summarized genome-wide association studies (GWASes) investigating the associations between genetic variants and pain/pain-related phenotypes in humans. We reviewed 57 full-text articles and identified 30 loci reported in more than 1 study. To check whether genes described in this review are associated with (other) pain phenotypes, we searched 2 pain genetic databases, Human Pain Genetics Database and Mouse Pain Genetics Database. Six GWAS-identified genes/loci were also reported in those databases, mainly involved in neurological functions and inflammation. These findings demonstrate an important contribution of genetic factors to the risk of pain and pain-related phenotypes. However, replication studies with consistent phenotype definitions and sufficient statistical power are required to validate these pain-associated genes further. Our review also highlights the need for bioinformatic tools to elucidate the function of identified genes/loci. We believe that a better understanding of the genetic background of pain will shed light on the underlying biological mechanisms of pain and benefit patients by improving the clinical management of pain.

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Evidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects. Objective: To determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD). Design, Setting, and Participants: This randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications. Intervention: In the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage. Main Outcomes and Measures: The primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores). Results: Of 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Meier χ21 = 4.30; P = .04). No significant difference in reduction of depressive symptoms was observed. Linear mixed-model analyses showed that the interaction between group and time differed for the frequency (F6,125 = 4.03; P = .001), severity (F6,114 = 3.10; P = .008), and burden (F6,112 = 2.56; P = .02) of adverse effects, suggesting that adverse effects decreased relatively more for those receiving PIT. Conclusions and Relevance: In this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in personalizing treatment for patients with MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03548675.

Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia.

Introduction: Genetic variation in the thiopurine S-methyltransferase (TPMT) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in TPMT still develop toxicity that necessitates 6-MP dose reduction or interruption. Genetic variants of other genes in the thiopurine pathway have been linked to 6-MP related toxicities previously. Objective: The aim of this study was to evaluate the effect of genetic variants in ITPA, TPMT, NUDT15, XDH, and ABCB1 on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia. Methods: Genotyping of ITPA, and XDH was performed using KASP genotyping assay, while that of TPMT, NUDT15, and ABCB1 with TaqMan® SNP genotyping assays. Clinical profile of the patients was collected for the first 6 months of the maintenance phase treatment. The primary outcome was the incidence of grade 4 neutropenia. Bivariable followed by multivariable cox regression analysis was performed to identify genetic variants associated with the development of grade 4 neutropenia within the first 6 months of maintenance treatment. Results: In this study, genetic variants in XDH and ITPA were associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) for XDH rs2281547 were 2.956 times (AHR 2.956, 95% CI = 1.494-5.849, p = 0.002) more likely to develop grade 4 neutropenia than those with the TT genotype. Conclusion: In conclusion, in this cohort, XDH rs2281547 was identified as a genetic risk factor for grade 4 hematologic toxicities in ALL patients treated with 6-MP. Genetic polymorphisms in enzymes other than TPMT involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

Pharmacogenetics of chemotherapy treatment response and -toxicities in patients with osteosarcoma: a systematic review.

BACKGROUND: Osteosarcoma is the most common bone tumor in children and adolescents. Despite multiagent chemotherapy, only 71% of patients survives and these survivors often experience long-term toxicities. The main objective of this systematic review is to provide an overview of the discovery of novel associations of germline polymorphisms with treatment response and/or chemotherapy-induced toxicities in osteosarcoma.  METHODS: MEDLINE and Embase were systematically searched (2010-July 2022). Genetic association studies were included if they assessed > 10 germline genetic variants in > 5 genes in relevant drug pathways or if they used a genotyping array or other large-scale genetic analysis. Quality was assessed using adjusted STrengthening the REporting of Genetic Association studies (STREGA)-guidelines. To find additional evidence for the identified associations, literature was searched to identify replication studies. RESULTS: After screening 1999 articles, twenty articles met our inclusion criteria. These range from studies focusing on genes in relevant pharmacokinetic pathways to whole genome sequencing. Eleven articles reported on doxorubicin-induced cardiomyopathy. For seven genetic variants in CELF4, GPR35, HAS3, RARG, SLC22A17, SLC22A7 and SLC28A3, replication studies were performed, however without consistent results. Ototoxicity was investigated in one study. Five small studies reported on mucosistis or bone marrow, nephro- and/or hepatotoxicity. Six studies included analysis for treatment efficacy. Genetic variants in ABCC3, ABCC5, FasL, GLDC, GSTP1 were replicated in studies using heterogeneous efficacy outcomes. CONCLUSIONS: Despite that results are promising, the majority of associations were poorly reproducible due to small patient cohorts. For the future, hypothesis-generating studies in large patient cohorts will be necessary, especially for cisplatin-induced ototoxicity as these are largely lacking. In order to form large patient cohorts, national and international collaboration will be essential.

SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin.

Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p <0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06-0.55], p = 0.002). The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001). Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.). Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.

Pain predict genetics: protocol for a prospective observational study of clinical and genetic factors to predict the development of postoperative pain.

INTRODUCTION: Postoperative pain remains a challenging medical condition impacting the quality of life of every patient. Although several predictive factors for postoperative pain have been identified, an adequate prediction of postoperative pain in patients at risk has not been achieved yet.The primary objective of this study is to identify specific genetic risk factors for the development of acute and chronic postoperative pain to construct a prediction model facilitating a more personalised postoperative pain management for each individual. The secondary objectives are to build a databank enabling researchers to identify other risk factors for postoperative pain, for instance, demographic and clinical outcome indicators; provide insight into (genetic) factors that predict pharmacological pain relief; investigate the relationship between acute and chronic postoperative pain. METHODS AND ANALYSIS: In this prospective, observational study, patients who undergo elective surgery will be recruited to a sample size of approximately 10 000 patients. Postoperative acute and chronic pain outcomes will be collected through questionnaires at different time points after surgery in the follow-up of 6 months. Potential genetic, demographic and clinical risk factors for prediction model construction will be collected through blood, questionnaires and electronic health records, respectively.Genetic factors associated with acute and/or chronic postoperative pain will be identified using a genome-wide association analysis. Clinical risk factors as stated in the secondary objectives will be assessed by multivariable regression. A clinical easy-to-use prediction model will be created for postoperative pain to allow clinical use for the stratification of patients. ETHICS AND DISSEMINATION: The Institutional Review Board of the Radboud university medical centre approved the study (authorisation number: 2012/117). The results of this study will be made available through peer-reviewed scientific journals and presentations at relevant conferences, which will finally contribute to personalised postoperative pain management. TRIAL REGISTRATION NUMBER: NCT02383342.

Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury.

Nephrotoxicity is a common and dose-limiting side effect of platinum compounds, which often manifests as acute kidney injury or hypomagnesemia. This study aimed to investigate the genetic risk loci for platinum-induced nephrotoxicity. Platinum-treated brain tumor and head-neck tumor patients were genotyped with genome-wide coverage. The data regarding the patient and treatment characteristics and the laboratory results reflecting the nephrotoxicity during and after the platinum treatment were collected from the medical records. Linear and logistic regression analyses were performed to investigate the associations between the genetic variants and the acute kidney injury and hypomagnesemia phenotypes. A cohort of 195 platinum-treated patients was included, and 9,799,032 DNA variants passed the quality control. An association was identified between RBMS3 rs10663797 and acute kidney injury (coefficient -0.10 (95% confidence interval -0.13--0.06), p-value 2.72 × 10-8). The patients who carried an AC deletion at this locus had statistically significantly lower glomerular filtration rates after platinum treatment. Previously reported associations, such as BACH2 rs4388268, could not be replicated in this study's cohort. No statistically significant associations were identified for platinum-induced hypomagnesemia. The genetic variant in RBMS3 was not previously linked to nephrotoxicity or related traits. The validation of this study's results in independent cohorts is needed to confirm this novel association.

Biomarkers as predictors of treatment response to tricyclic antidepressants in major depressive disorder: A systematic review.

Tricyclic antidepressants (TCAs) are frequently prescribed in case of non-response to first-line antidepressants in Major Depressive Disorder (MDD). Treatment of MDD often entails a trial-and-error process of finding a suitable antidepressant and its appropriate dose. Nowadays, a shift is seen towards a more personalized treatment strategy in MDD to increase treatment efficacy. One of these strategies involves the use of biomarkers for the prediction of antidepressant treatment response. We aimed to summarize biomarkers for prediction of TCA specific (i.e. per agent, not for the TCA as a drug class) treatment response in unipolar nonpsychotic MDD. We performed a systematic search in PubMed and MEDLINE. After full-text screening, 36 papers were included. Seven genetic biomarkers were identified for nortriptyline treatment response. For desipramine, we identified two biomarkers; one genetic and one nongenetic. Three nongenetic biomarkers were identified for imipramine. None of these biomarkers were replicated. Quality assessment demonstrated that biomarker studies vary in endpoint definitions and frequently lack power calculations. None of the biomarkers can be confirmed as a predictor for TCA treatment response. Despite the necessity for TCA treatment optimization, biomarker studies reporting drug-specific results for TCAs are limited and adequate replication studies are lacking. Moreover, biomarker studies generally use small sample sizes. To move forward, larger cohorts, pooled data or biomarkers combined with other clinical characteristics should be used to improve predictive power.

Molecular Processes in Stress Urinary Incontinence: A Systematic Review of Human and Animal Studies.

Stress urinary incontinence (SUI) is a common and burdensome condition. Because of the large knowledge gap around the molecular processes involved in its pathophysiology, the aim of this review was to provide a systematic overview of genetic variants, gene and protein expression changes related to SUI in human and animal studies. On 5 January 2021, a systematic search was performed in Pubmed, Embase, Web of Science, and the Cochrane library. The screening process and quality assessment were performed in duplicate, using predefined inclusion criteria and different quality assessment tools for human and animal studies respectively. The extracted data were grouped in themes per outcome measure, according to their functions in cellular processes, and synthesized in a narrative review. Finally, 107 studies were included, of which 35 used animal models (rats and mice). Resulting from the most examined processes, the evidence suggests that SUI is associated with altered extracellular matrix metabolism, estrogen receptors, oxidative stress, apoptosis, inflammation, neurodegenerative processes, and muscle cell differentiation and contractility. Due to heterogeneity in the studies (e.g., in examined tissues), the precise contribution of the associated genes and proteins in relation to SUI pathophysiology remained unclear. Future research should focus on possible contributors to these alterations.

Contribution of common and rare genetic variants in CEP72 on vincristine-induced peripheral neuropathy in brain tumour patients.

AIMS: Studies implicated a role for a genetic variant in CEP72 in vincristine-induced peripheral neuropathy. This study aims to evaluate this association in a cohort of brain tumour patients, to perform a cross-disease meta-analysis and explore the protein-coding region of CEP72. METHODS: In total, 104 vincristine-treated brain tumour patients were genotyped for CEP72 rs924607, and sequenced for the protein-coding region. Data regarding patient and treatment characteristics, and peripheral neuropathy, were collected. Logistic regression and meta-analysis were performed for rs924607 replication. A weighted burden analysis was applied to evaluate impact of overall genetic variation in CEP72. RESULTS: Analysis of 24 cases and 80 controls did not show a significant association between CEP72 rs924607 and neuropathy (odds ratio, OR [95% confidence interval, CI] 2.076 [0.359-11.989], P = .414). When combined with 8 cohorts (1095 cancer patients), a significant increase in risk for neuropathy was found for patients with a TT genotype (OR [95% CI] 2.15 [1.35-3.43], P = .001). Additionally, a missense variant (rs12522955) was significantly associated (OR [95% CI] 2.3 [1.2-4.4], P = .041) and patients with severe neuropathy carried more impactful variants in CEP72 coding regions (P = .039). CONCLUSION: The association of CEP72 rs924607 in vincristine-induced neuropathy was not confirmed in a cohort of brain tumour patients, but did contribute to its suggested effect when combined in a cross-disease meta-analysis. The importance of other genetic variations in CEP72 on vincristine-induced neuropathy was demonstrated. This study contributes to evidence of the importance of genetic variants in CEP72 in development of vincristine-induced toxicity, and provides guidance for future prospective studies.

The Potential of Polygenic Risk Scores to Predict Antidepressant Treatment Response in Major Depression: A Systematic Review.

BACKGROUND: Understanding the genetic underpinnings of antidepressant treatment response in unipolar major depressive disorder (MDD) can be useful in identifying patients at risk for poor treatment response or treatment resistant depression. A polygenic risk score (PRS) is a useful tool to explore genetic liability of a complex trait such as antidepressant treatment response. Here, we review studies that use PRSs to examine genetic overlap between any trait and antidepressant treatment response in unipolar MDD. METHODS: A systematic search of literature was conducted in PubMed, Embase, and PsycINFO. Our search included studies examining associations between PRSs of psychiatric as well as non-psychiatric traits and antidepressant treatment response in patients with unipolar MDD. A quality assessment of the included studies was performed. RESULTS: In total, eleven articles were included which contained PRSs for 30 traits. Studies varied in sample size and endpoints used for antidepressant treatment response. Overall, PRSs for attention-deficit hyperactivity disorder, the personality trait openness, coronary artery disease, obesity, and stroke have been associated with antidepressant treatment response in patients with unipolar MDD. LIMITATIONS: The endpoints used by included studies differed significantly, therefore it was not possible to perform a meta-analysis. CONCLUSIONS: Associations between a PRS and antidepressant treatment response have been reported for a number of traits in patients with unipolar MDD. PRSs could be informative to predict antidepressant treatment response in this population, given advances in the field. Most importantly, there is a need for larger study cohorts and the use of standardized outcome measures.

Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts.

We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (ΔDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the meta-analysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated.

Association of the neutrophil to lymphocyte ratio and white blood cell count with response to pharmacotherapy in unipolar psychotic depression: An exploratory analysis.

Background: Low-grade inflammation occurs in a subgroup of patients with Major Depressive Disorder (MDD) and may be associated with response to antidepressant medications. The Neutrophil to Lymphocyte Ratio (NLR) and total White Blood cell Count (WBC) are markers of systemic inflammation which have not been investigated as predictors for outcome to pharmacotherapy in unipolar depression yet. Moreover, the association between inflammation and treatment response has not been studied in unipolar Psychotic Depression (PD). We conducted an exploratory analysis to examine the prognostic significance of NLR and WBC in pharmacotherapy of PD. Methods: Baseline NLR and WBC were examined in their association with response to seven weeks of treatment with antidepressants (venlafaxine or imipramine) and the combination of an antidepressant with an antipsychotic (venlafaxine plus quetiapine) in 87 patients with PD. Logistic regression models were adjusted for age, gender, Body Mass Index (BMI), depression severity, duration of the current episode and number of previous depressive episodes. Secondary outcomes were remission of depression and disappearance of psychotic symptoms. Results: Higher NLR was associated with increased response to pharmacotherapy (Exp(B) 1.66, 95 % CI 1.03-2.66, p = 0.036), but not with remission of depression or disappearance of psychotic symptoms. WBC was not associated with any of the outcome measures. Conclusion: NLR may be a novel, inexpensive and widely available biomarker associated with response to pharmacotherapy in PD. The association between white blood cell measures and treatment outcome should be further investigated for different types of antidepressants in PD and in non-psychotic MDD.