Hum Pathol. 2022 Jul 21:S0046-8177(22)00187-3. doi: 10.1016/j.humpath.2022.07.014. Online ahead of print.

ABSTRACT

The identification of mismatch repair deficient (dMMR) and microsatellite unstable (MSI) endometrial cancers (ECs) is important in screening, diagnosis and therapeutic stratification of patients. We compared the diagnostic performance of four MSI molecular tests based on fragment length assay in capillary electrophoresis (OncoMate™ MSI assay, Promega) and in microcapillary electrophoresis (TapeStation 4200, Agilent); with high-resolution melting (HRM) analysis approaches (Idylla™ MSI Test, Biocartis; EasyPGX® ready MSI, Diatech Pharmacogenetics) on a series of 56 ECs, which was well characterized for MMR status with immunohistochemical approach (IHC, non-molecular reference test). The concordance of fluorescence capillary electrophoresis with IHC (AUC 0.98) was higher respect to the other molecular methodologies. Otherwise, HRM approaches and microcapillary electrophoresis platform failed to detect MSI-ECs showing minimal microsatellite shifts. In conclusion, whereas in colorectal site several technologies are eligible for MSI test, in ECs MSI test should be based on fluorescent capillary electrophoresis as it identifies a higher proportion of cases that could be misdiagnosed with other strategies.

PMID:35872156 | DOI:10.1016/j.humpath.2022.07.014

Pancreatology. 2022 Jul 19:S1424-3903(22)00463-X. doi: 10.1016/j.pan.2022.07.008. Online ahead of print.

ABSTRACT

BACKGROUND: Acute pancreatitis remains the most common and morbid complication of endoscopic retrograde cholangiopancreatography (ERCP). The use of rectal indomethacin and pancreatic duct stenting has been shown to reduce the incidence and severity of post-ERCP pancreatitis (PEP), but these interventions have limitations. Recent clinical and translational evidence suggests a role for calcineurin inhibitors in the prevention of pancreatitis, with multiple retrospective case series showing a reduction in PEP rates in tacrolimus users.

METHODS: The INTRO trial is a multicenter, international, randomized, double-blinded, controlled trial. A total of 4,874 patients undergoing ERCP will be randomized to receive either oral tacrolimus (5 mg) or oral placebo 1-2 h before ERCP, and followed for 30 days post-procedure. Blood and pancreatic aspirate samples will also be collected in a subset of patients to quantify tacrolimus levels. The primary outcome of the study is the incidence of PEP. Secondary endpoints include the severity of PEP, ERCP-related complications, adverse drug events, length of hospital stay, cost-effectiveness, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of tacrolimus immune modulation in the pancreas.

CONCLUSIONS: The INTRO trial will assess the role of calcineurin inhibitors in PEP prophylaxis and develop a foundation for the clinical optimization of this therapeutic strategy from a pharmacologic and economic standpoint. With this clinical trial, we hope to demonstrate a novel approach to PEP prophylaxis using a widely available and well-characterized class of drugs.

TRIAL REGISTRATION: NCT05252754, registered on February 14, 2022.

PMID:35872074 | DOI:10.1016/j.pan.2022.07.008

Pharmacogenomics J. 2022 Jul 22. doi: 10.1038/s41397-022-00285-5. Online ahead of print.

ABSTRACT

The successful implementation of pharmacogenetics (PGx) into clinical practice requires patient genomic data to be shared between stakeholders in multiple settings. This creates a number of barriers to widespread adoption of PGx, including privacy concerns related to the storage and movement of identifiable genomic data. Informatic solutions that support secure and equitable data access for genomic data are therefore important to PGx. Here we propose a methodology that uses smart contracts implemented on a blockchain-based framework, PGxChain, to address this issue. The design requirements for PGxChain were identified through a systematic literature review, identifying technical challenges and barriers impeding the clinical implementation of pharmacogenomics. These requirements included security and privacy, accessibility, interoperability, traceability and legal compliance. A proof-of-concept implementation based on Ethereum was then developed that met the design requirements. PGxChain's performance was examined using Hyperledger Caliper for latency, throughput, and transaction success rate. The findings clearly indicate that blockchain technology offers considerable potential to advance pharmacogenetic data sharing, particularly with regard to PGx data security and privacy, large-scale accessibility of PGx data, PGx data interoperability between multiple health care providers and compliance with data-sharing laws and regulations.

PMID:35869255 | DOI:10.1038/s41397-022-00285-5

Int J Infect Dis. 2022 Jul 19:S1201-9712(22)00434-9. doi: 10.1016/j.ijid.2022.07.040. Online ahead of print.

ABSTRACT

OBJECTIVES: This study investigated the steady-state pharmacokinetic profiles of 3-month weekly rifapentine plus isoniazid (3HP) in children with latent tuberculosis infection (LTBI). Factors including tablet integrity, food, and pharmacogenetics were also assessed.

METHODS: During the 3HP treatment, blood and urine samples were collected on week 4. Isoniazid and rifapentine levels were measured using a high-performance liquid chromatography technique. Genetic variation of arylamine N-acetyltransferase 2 (NAT2) and arylacetamide deacetylase (AADAC) were assessed by the MassARRAY®. Safety and clinical outcomes at week 48 were monitored.

RESULTS: Twelve LTBI children [age 3.8 (range 2.1-4.9 years old)] completed the treatment [isoniazid and rifapentine dose 25.0 (range 21.7-26.8) and 25.7 (range 20.7-32.1) mg/kg, respectively]. No serious adverse events or active tuberculosis occurred. Tablet integrity was associated with decreased area under the concentration-time curve (91 vs 73 mg.hr/L, p = 0.026) and increased apparent oral clearance of isoniazid (0.27 vs 0.32 L/hr/kg, p = 0.019) and decreased rifapentine's renal clearance (CLR, 0.005 vs 0.003 L/hr, p = 0.014). Food was associated with increased CLR of isoniazid (3.45 vs 8.95 L/hr, p = 0.006) but not rifapentine. Variability in NAT2 and AADAC did not affect the pharmacokinetics of both drugs.

CONCLUSIONS: There is high variability in the pharmacokinetic profiles of isoniazid and rifapentine in young LTBI children. The variability was partly influenced by tablet integrity and food, but not pharmacogenetics. Further study in a larger cohort is warranted to display the relationship of these factors to treatment outcomes.

PMID:35868608 | DOI:10.1016/j.ijid.2022.07.040

Fam Cancer. 2022 Jul 22. doi: 10.1007/s10689-022-00307-y. Online ahead of print.

ABSTRACT

During Covid-19 pandemic most hospitals have restricted in-person delivery of non-essential healthcare services, including genetic testing delivery, to slow the spread of the virus. Our Onco-Genetic Service also faced this challenging period and had to re-organize its clinical practice with the use of tele-health. Aim of the present paper is to understand whether and how Covid-19-related changes in medical practice influenced patients' satisfaction about the health service provided. 125 BRCA1/2 non carriers (109/125, 87.2% female and 16/125, 12.8% male) in Istituto Tumori "Giovanni Paolo II" of Bari were enrolled. All participants were asked to choose whether they prefer in-person or remote post-test counselling session. Basing on patients' choice, two groups of subjects were composed. One week after the post-test counselling session, participants were phone called and asked to complete: a socio-demographic form, a brief structured interview about their Covid-19 related worries and their satisfaction with the health service provided, Hospital Anxiety and Depression Scale and Fear of Covid-19 scale. Qualitative information about patients' choice were also collected. No significant difference about patients' satisfaction with the health service provided emerged between groups. Patients who preferred remote post-test counselling had higher anxiety, worries and fear-of Covid-19 than the others. All remote-counselling subjects preferred tele-genetics because of Covid-19 security, would choose it again and would recommend it to others. Cancer tele-genetics offers good guarantees of comfort and efficacy, but patients' choices are related to personal and psychological variables. The use of tele-genetics has to be a patient's choice.

PMID:35867288 | DOI:10.1007/s10689-022-00307-y

Methods Mol Biol. 2022;2535:187-210. doi: 10.1007/978-1-0716-2513-2_15.

ABSTRACT

Understanding drug resistance in cancer is paramount to improving patient outcomes, quality of life and reducing toxicities in patients receiving chemotherapy. Pharmacogenomic methods seek to understand the interaction of genomic variation and response to chemotherapeutic treatment. This chapter presents a workflow to interrogate multiple genomic inputs and individually assess their relationship with the phenotype of drug resistance using hierarchical clustering to determine the set of features that can best describe what features are associated with drug resistance. Then in a gene-centric manner regulatory features such as miRNAs, SNPs, or DNA methylation can be related back to the differential expression of genes to give understanding to the mechanism underlying resistance. In this chapter, we describe a computational method that can be adapted to a number of different diseases and phenotypes in which there are multiple genomic data types available with concordant phenotypic drug resistance information.

PMID:35867232 | DOI:10.1007/978-1-0716-2513-2_15

Am J Health Syst Pharm. 2022 Jul 22:zxac183. doi: 10.1093/ajhp/zxac183. Online ahead of print.

NO ABSTRACT

PMID:35866475 | DOI:10.1093/ajhp/zxac183

Front Pharmacol. 2022 Jul 5;13:858345. doi: 10.3389/fphar.2022.858345. eCollection 2022.

ABSTRACT

India confines more than 17% of the world's population and has a diverse genetic makeup with several clinically relevant rare mutations belonging to many sub-group which are undervalued in global sequencing datasets like the 1000 Genome data (1KG) containing limited samples for Indian ethnicity. Such databases are critical for the pharmaceutical and drug development industry where diversity plays a crucial role in identifying genetic disposition towards adverse drug reactions. A qualitative and comparative sequence and structural study utilizing variant information present in the recently published, largest curated Indian genome database (IndiGen) and the 1000 Genome data was performed for variants belonging to the kinase coding genes, the second most targeted group of drug targets. The sequence-level analysis identified similarities and differences among different populations based on the nsSNVs and amino acid exchange frequencies whereas a comparative structural analysis of IndiGen variants was performed with pathogenic variants reported in UniProtKB Humsavar data. The influence of these variations on structural features of the protein, such as structural stability, solvent accessibility, hydrophobicity, and the hydrogen-bond network was investigated. In-silico screening of the known drugs to these Indian variation-containing proteins reveals critical differences imparted in the strength of binding due to the variations present in the Indian population. In conclusion, this study constitutes a comprehensive investigation into the understanding of common variations present in the second largest population in the world and investigating its implications in the sequence, structural and pharmacogenomic landscape. The preliminary investigation reported in this paper, supporting the screening and detection of ADRs specific to the Indian population could aid in the development of techniques for pre-clinical and post-market screening of drug-related adverse events in the Indian population.

PMID:35865963 | PMC:PMC9294532 | DOI:10.3389/fphar.2022.858345

Front Pharmacol. 2022 Jul 5;13:867490. doi: 10.3389/fphar.2022.867490. eCollection 2022.

ABSTRACT

Objective: This study aimed to investigate the clinical impact of HLA-B*15:02 pharmacogenomics (PGx) testing before carbamazepine (CBZ)/oxcarbazepine (OXC) prescriptions and to determine whether this PGx testing was associated with the reduction of CBZ/OXC-induced cutaneous adverse drug reactions (CADRs) in Thailand. Methods: This retrospective observational cohort study was conducted by obtaining relevant HLA-B*15:02 PGx-testing and clinical data from electronic medical records during 2011-2020. 384 patient data were included in this study to investigate the clinical decision on CBZ/OXC usage before and after the HLA-B*15:02 PGx testing, and 1,539 patient data were included in this study to demonstrate the incidence of CBZ/OXC-induced SCARs and SJS between HLA-B*15:02 tested and non-tested patients. To analyze and summarize the results, descriptive statistics were employed, and Fisher exact test was used to compare the clinical difference between the HLA-B*15:02 positive and negative groups and to compare the differences of SCARs incidence. Results: 384 patients were included in this study as per the inclusion criteria. Of these, 70 patients carried HLA-B*15:02, of which 63 and 65 patients were not prescribed with CBZ/OXC before and after the availability of genotyping results, respectively. In the remaining HLA-B*15:02 non-carriers, 48, and 189 patients were prescribed CBZ/OXC before and after genotyping results were available, respectively. The findings of this study showed that the incidence of SCARs of CBZ/OXC was significantly lower (p < 0.001) in the HLA-B*15:02 screening arm than in the non-screening arm. Conclusion: HLA-B pharmacogenetics testing influenced the selection of appropriate AEDs. The presence of mild rash in the HLA-B*15:02 negative group indicates that other genetic biomarker (HLA-A*31:01) and/or non-genetic variables are involved in CBZ/OXC-induced CADRs, emphasizing that CBZ/OXC prescriptions necessitate CADR monitoring. The hospital policy and clinical decision support (CDS) alert system is essential to overcome the barriers associated with the utilization of PGx guidelines into clinical practice.

PMID:35865943 | PMC:PMC9294359 | DOI:10.3389/fphar.2022.867490

Front Oncol. 2022 Jul 5;12:859846. doi: 10.3389/fonc.2022.859846. eCollection 2022.

ABSTRACT

BACKGROUND: Fluoropyrimidines (fluorouracil [5-FU], capecitabine) and irinotecan are commonly prescribed chemotherapy agents for gastrointestinal (GI) malignancies. Pharmacogenetic (PGx) testing for germline DPYD and UGT1A1 variants associated with reduced enzyme activity holds the potential to identify patients at high risk for severe chemotherapy-induced toxicity. Slow adoption of PGx testing in routine clinical care is due to implementation barriers, including long test turnaround times, lack of integration in the electronic health record (EHR), and ambiguity in test cost coverage. We sought to establish PGx testing in our health system following the Exploration, Preparation, Implementation, Sustainment (EPIS) framework as a guide. Our implementation study aims to address barriers to PGx testing.

METHODS: The Implementing Pharmacogenetic Testing in Gastrointestinal Cancers (IMPACT-GI) study is a non-randomized, pragmatic, open-label implementation study at three sites within a major academic health system. Eligible patients with a GI malignancy indicated for treatment with 5-FU, capecitabine, or irinotecan will undergo PGx testing prior to chemotherapy initiation. Specimens will be sent to an academic clinical laboratory followed by return of results in the EHR with appropriate clinical decision support for the care team. We hypothesize that the availability of a rapid turnaround PGx test with specific dosing recommendations will increase PGx test utilization to guide pharmacotherapy decisions and improve patient safety outcomes. Primary implementation endpoints are feasibility, fidelity, and penetrance. Exploratory analyses for clinical effectiveness of genotyping will include assessing grade ≥3 treatment-related toxicity using available clinical data, patient-reported outcomes, and quality of life measures.

CONCLUSION: We describe the formative work conducted to prepare our health system for DPYD and UGT1A1 testing. Our prospective implementation study will evaluate the clinical implementation of this testing program and create the infrastructure necessary to ensure sustainability of PGx testing in our health system. The results of this study may help other institutions interested in implementing PGx testing in oncology care.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04736472, identifier [NCT04736472].

PMID:35865463 | PMC:PMC9295185 | DOI:10.3389/fonc.2022.859846

Br J Clin Pharmacol. 2022 Jul 21. doi: 10.1111/bcp.15467. Online ahead of print.

ABSTRACT

Ketamine and its enantiomer S-ketamine (esketamine) are known to produce rapid-onset antidepressant effects in major depression. Intranasal esketamine has recently come into the market as an antidepressant. Besides experience from short-term use in anesthesia and analgesia, the experience with ketamine as long-term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychocomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice. Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene-drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug-drug interactions (DDIs). We reviewed the potential impact of polymorphic CYP variants and common DDIs in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long-term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions.

PMID:35863300 | DOI:10.1111/bcp.15467

Br J Dermatol. 2022 Jul 21. doi: 10.1111/bjd.21782. Online ahead of print.

NO ABSTRACT

PMID:35862277 | DOI:10.1111/bjd.21782

J Psychopharmacol. 2022 Jul 21:2698811221112939. doi: 10.1177/02698811221112939. Online ahead of print.

ABSTRACT

INTRODUCTION: Selective serotonin reuptake inhibitors have a common and increasing use for the treatment of patients diagnosed with depressive disorders. Some of them do not respond adequately to therapy, and numerous previous studies have indicated an increased risk of type A adverse drug reactions.

OBJECTIVE: The objective of our study was to evaluate the effect of 1846G>A polymorphism of CYP2D6 on the concentration/dose ratio of paroxetine.

MATERIAL AND METHODS: The study enrolled 267 patients with depressive episode (average age, 40.3 ± 14.3 years). Therapy included paroxetine in an average daily dose of 25.1 ± 9.5 mg per day. The efficacy and safety rates of treatment were evaluated using the international psychometric scales. For genotyping, we performed the real-time polymerase chain reaction. Therapeutic drug monitoring has been performed using high-performance liquid chromatography mass spectrometry (HPLC-MS/MS).

RESULTS: Our study revealed the statistically significant results in terms of treatment efficacy (Hamilton Depression Rating Scale scores): (GG) 2.0 [1.0; 3.0] and (GA) 4.0 [2.0; 5.0], p < 0.001; meanwhile, no statistically significant results were obtained for the safety profile (Udvalg for Kliniske Undersogelser (UKU) Scale scores): (GG) 3.0 [2.0; 3.0] and (GA) 3.0 [3.0; 4.0], p = 0.056. We revealed the statistically significant results for the concentration/dose ratio of paroxetine in patients with different genotypes: (GG) 2.803 [2.154; 4.098] and (GA) 5.098 [3.560; 7.241], p < 0.001.

CONCLUSION: The effect of CYP2D6*4 genetic polymorphism on the efficacy profile of paroxetine was demonstrated in a group of 267 patients with depressive disorder.

PMID:35861192 | DOI:10.1177/02698811221112939

Clin Pharmacol Ther. 2022 Jul 20. doi: 10.1002/cpt.2714. Online ahead of print.

ABSTRACT

Oral anticoagulants (OACs) are commonly used to reduce the risk of venous thromboembolism (VTE) and the risk of stroke in patients with atrial fibrillation (AF). Endorsed by the American Heart Association, American College of Cardiology, and the European Society of Cardiology, direct oral anticoagulants (DOACs) have displaced warfarin as the OAC of choice for both conditions, due to improved safety profiles, fewer drug-drug and drug-diet interactions, and lack of monitoring requirements. Despite their widespread use and improved safety over warfarin, DOAC related bleeding remains a major concern for patients. DOACs have stable pharmacokinetics and pharmacodynamics; however, variability in DOAC response is common and may be attributed to numerous factors, including patient-specific factors, concomitant medications, comorbid conditions, and genetics. While DOAC randomized controlled trials included patients of varying ages and levels of kidney function, they failed to include patients of diverse ancestries. Additionally, current evidence to support DOAC pharmacogenetic associations have primarily been derived from European and Asian individuals. Given differences in genotype frequencies and disease burden among patients of different biogeographic groups, future research must engage diverse populations to assess and quantify the impact of predictors on DOAC response. Current underrepresentation of patients from diverse racial groups does not allow for proper generalization of the influence of clinical and genetic factors in relation to DOAC variability. Herein, we discuss factors affecting DOAC response, such as age, sex, weight, kidney function, drug interactions, and pharmacogenetics, while offering a new perspective on the need for further research including frequently excluded groups.

PMID:35857814 | DOI:10.1002/cpt.2714

Eur Heart J. 2022 Jul 20:ehac374. doi: 10.1093/eurheartj/ehac374. Online ahead of print.

ABSTRACT

AIMS: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis.

METHODS AND RESULTS: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98).

CONCLUSION: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype.

CLINICAL TRIAL REGISTRATION: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.

PMID:35856777 | DOI:10.1093/eurheartj/ehac374

Curr Opin Pulm Med. 2022 Jul 19. doi: 10.1097/MCP.0000000000000889. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Sarcoidosis is a chronic multisystemic inflammatory disease of unknown aetiology with a wide range of highly variable clinical manifestations and unpredictable disease course. Sarcoidosis patients may present with specific organ-related symptoms involving functional impairments, and less specific symptoms. The decision whether and when to treat a sarcoidosis patient with pharmacotherapy depends on two major factors: risk of organ failure and/or death and impairment of quality of life. This decision is complex and not standardized.

RECENT FINDINGS: Glucocorticoids (GCs) are recommended as initial treatment, when needed. Subsequent GC-sparing alternatives frequently follow. Comorbidities or adverse drug reactions (ADRs) from drugs used in sarcoidosis treatment are sometimes very hard to differentiate from symptoms associated with the disease itself, which may cause diagnostic dilemmas. An ideal approach to minimalize ADRs would involve genetic screening prior to prescribing certain 'high-risk drugs' and therapeutic drug monitoring during treatment. Pharmacogenomic testing aims to guide appropriate selection of medicines, with the potential of reducing unnecessary polypharmacy while improving clinical outcomes.

SUMMARY: A multidisciplinary approach to the management of sarcoidosis may avoid unnecessary ADRs. It is important to consider the possibility of drug-induced damage in sarcoidosis, especially if the clinical situation deteriorates after the introduction of a particular drug.

PMID:35855576 | DOI:10.1097/MCP.0000000000000889

J Endocr Soc. 2022 Jun 29;6(8):bvac092. doi: 10.1210/jendso/bvac092. eCollection 2022 Aug 1.

ABSTRACT

PURPOSE: A study among Filipinos revealed that only 15% of patients with diabetes achieved glycemic control, and poor response to metformin could be one of the possible reasons. Recent studies demonstrate how genetic variations influence response to metformin. Hence, the present study aimed to determine genetic variants associated with poor response to metformin.

METHODS: Using a candidate variant approach, 195 adult Filipino participants with newly diagnosed type 2 diabetes mellitus (T2DM) were enrolled in a case-control study. Genomic DNA from blood samples were collected. Allelic and genotypic associations of variants with poor response to metformin were determined using exact statistical methods.

RESULTS: Several polymorphisms were nominally associated with poor response to metformin (P uncorr < 0.05). The most notable is the association of multiple variants in the SLC2A10 gene-rs2425911, rs3092412, and rs2425904-with common additive genetic mode of inheritance. Other variants that have possible associations with poor drug response include rs340874 (PROX-AS1), rs815815 (CALM2), rs1333049 (CDKN2B-AS1), rs2010963 (VEGFA), rs1535435 and rs9494266 (AHI1), rs11128347 (PDZRN3), rs1805081 (NPC1), and rs13266634 (SLC30A8).

CONCLUSION: In Filipinos, a trend for the association for several variants was noted, with further observation that several mechanisms may be involved. The results may serve as pilot data for further validation of candidate variants for T2DM pharmacotherapy.

PMID:35854978 | PMC:PMC9278830 | DOI:10.1210/jendso/bvac092

Pharmacogenet Genomics. 2022 Aug 1;32(6):235-241. doi: 10.1097/FPC.0000000000000471. Epub 2022 Jun 22.

ABSTRACT

OBJECTIVES: This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients.

MATERIALS AND METHODS: A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment.

RESULTS: Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073).

CONCLUSION: Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD.

PMID:35852914 | DOI:10.1097/FPC.0000000000000471

Am J Med. 2022 Jul 16:S0002-9343(22)00523-X. doi: 10.1016/j.amjmed.2022.07.003. Online ahead of print.

NO ABSTRACT

PMID:35853480 | DOI:10.1016/j.amjmed.2022.07.003

Aging (Albany NY). 2022 Jul 18;14(undefined). doi: 10.18632/aging.204180. Online ahead of print.

NO ABSTRACT

PMID:35852878 | DOI:10.18632/aging.204180