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1.
Am J Hum Genet ; 108(8): 1540-1548, 2021 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-34246321

RESUMEN

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10-8). The HLA-DPB1∗02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10-9), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10-8). A meta-analysis performed in the combined set revealed that the HLA-DPB1∗02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10-14). Individuals carrying the HLA-DPB1∗02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.


Asunto(s)
Anafilaxia/patología , Ejercicio Físico , Estudio de Asociación del Genoma Completo , Cadenas beta de HLA-DP/genética , Polimorfismo Genético , Hipersensibilidad al Trigo/patología , Adulto , Alelos , Anafilaxia/etiología , Anafilaxia/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hipersensibilidad al Trigo/etiología , Hipersensibilidad al Trigo/metabolismo
2.
J Hum Genet ; 68(8): 533-541, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37059825

RESUMEN

CYP2A6 metabolically inactivates nicotine. Faster CYP2A6 activity is associated with heavier smoking and higher lung cancer risk. The CYP2A6 gene is polymorphic, including functional structural variants (SV) such as gene deletions (CYP2A6*4), duplications (CYP2A6*1 × 2), and hybrids with the CYP2A7 pseudogene (CYP2A6*12, CYP2A6*34). SVs are challenging to genotype due to their complex genetic architecture. Our aims were to develop a reliable protocol for SV genotyping, functionally phenotype known and novel SVs, and investigate the feasibility of CYP2A6 SV imputation from SNP array data in two ancestry populations. European- (EUR; n = 935) and African- (AFR; n = 964) ancestry individuals from smoking cessation trials were genotyped for SNPs using an Illumina array and for CYP2A6 SVs using Taqman copy number (CN) assays. SV-specific PCR amplification and Sanger sequencing was used to characterize a novel SV. Individuals with SVs were phenotyped using the nicotine metabolite ratio, a biomarker of CYP2A6 activity. SV diplotype and SNP array data were integrated and phased to generate ancestry-specific SV reference panels. Leave-one-out cross-validation was used to investigate the feasibility of CYP2A6 SV imputation. A minimal protocol requiring three Taqman CN assays for CYP2A6 SV genotyping was developed and known SV associations with activity were replicated. The first domain swap CYP2A6-CYP2A7 hybrid SV, CYP2A6*53, was identified, sequenced, and associated with lower CYP2A6 activity. In both EURs and AFRs, most SV alleles were identified using imputation (>70% and >60%, respectively); importantly, false positive rates were <1%. These results confirm that CYP2A6 SV imputation can identify most SV alleles, including a novel SV.


Asunto(s)
Pueblo Africano , Pueblo Europeo , Nicotina , Cese del Hábito de Fumar , Humanos , Pueblo Africano/genética , Secuencia de Bases , Población Negra/genética , Citocromo P-450 CYP2A6/genética , Citocromo P-450 CYP2A6/metabolismo , Pueblo Europeo/genética , Genotipo , Nicotina/genética , Nicotina/metabolismo , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Cese del Hábito de Fumar/etnología
3.
Pharmacogenet Genomics ; 32(4): 159-172, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35190513

RESUMEN

OBJECTIVES: We evaluated multiple genotyping/sequencing approaches in a homologous region of chromosome 19, and investigated associations of two common 3'-UTR CYP2A6 variants with activity in vivo. METHODS: Individuals (n = 1704) of European and African ancestry were phenotyped for the nicotine metabolite ratio (NMR), an index of CYP2A6 activity, and genotyped/sequenced using deep amplicon exon sequencing, SNP array, genotype imputation and targeted capture sequencing. Amplicon exon sequencing was the gold standard to which other methods were compared within-individual for CYP2A6, CYP2A7, CYP2A13, and CYP2B6 exons to identify highly discordant positions. Linear regression models evaluated the association of CYP2A6*1B and rs8192733 genotypes (coded additively) with logNMR. RESULTS: All approaches were ≤2.6% discordant with the gold standard; discordant calls were concentrated at few positions. Fifteen positions were discordant in >10% of individuals, with 12 appearing in regions of high identity between homologous genes (e.g. CYP2A6 and CYP2A7). For six, allele frequencies in our study and online databases were discrepant, suggesting errors in online sources. In the European-ancestry group (n = 935), CYP2A6*1B and rs8192733 were associated with logNMR (P < 0.001). A combined model found main effects of both variants on increasing logNMR. Similar trends were found in those of African ancestry (n = 506). CONCLUSION: Multiple genotyping/sequencing approaches used in this chromosome 19 region contain genotyping/sequencing errors, as do online databases. Gene-specific primers and SNP array probes must consider gene homology; short-read sequencing of related genes in a single reaction should be avoided. Using improved sequencing approaches, we characterized two gain-of-function 3'-UTR variants, including the relatively understudied rs8192733.


Asunto(s)
Población Negra , Secuencia de Bases , Población Negra/genética , Citocromo P-450 CYP2A6/genética , Exones , Frecuencia de los Genes , Genotipo , Humanos
4.
Pharmacol Res ; 176: 106087, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35033648

RESUMEN

Inter-individual variability in pharmacokinetics and drug response is heavily influenced by single-nucleotide variants (SNVs) and copy-number variations (CNVs) in genes with importance for drug disposition. Nowadays, a plethora of studies implement next generation sequencing to capture rare and novel pharmacogenomic (PGx) variants that influence drug response. To address these issues, we present a comprehensive end-to-end analysis workflow, beginning from targeted PGx panel re-sequencing to in silico analysis pipelines and in vitro validation assays. Specifically, we show that novel pharmacogenetic missense variants that are predicted or putatively predicted to be functionally deleterious, significantly alter protein activity levels of CYP2D6 and CYP2C19 proteins. We further demonstrate that variant priorization pipelines tailored with functional in vitro validation assays provide supporting evidence for the deleterious effect of novel PGx variants. The proposed workflow could provide the basis for integrating next-generation sequencing for PGx testing into routine clinical practice.


Asunto(s)
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Variantes Farmacogenómicas , Algoritmos , Línea Celular , Simulación por Computador , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Citocromos b5/genética , Dextrometorfano/metabolismo , Humanos , Mefenitoína/metabolismo , Microsomas/metabolismo , Mutación Missense , Reproducibilidad de los Resultados
5.
J Hum Genet ; 66(2): 139-149, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32759992

RESUMEN

Next-generation sequencing (NGS) has identified variations in cytochrome P450 (CYP) 2D6 associated with drug responses. However, determination of novel haplotypes is difficult because of the short reads generated by NGS. We aimed to identify novel CYP2D6 variants in the Japanese population and predict the CYP2D6 phenotype based on in vitro metabolic studies. Using a targeted NGS panel (PKSeq), 990 Japanese genomes were sequenced, and then novel CYP2D6 haplotypes were determined. Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl-tamoxifen 4-hydroxylation were calculated by in vitro metabolic studies using cDNA-expressed CYP2D6 proteins. After determination of the CYP2D6 diplotypes, phenotypes of the individuals were predicted based on the in vitro metabolic activities. Targeted NGS identified 14 CYP2D6 variants not registered in the Pharmacogene Variation Consortium (PharmVar) database. Ten novel haplotypes were registered as CYP2D6*128 to *137 alleles in the PharmVar database. Based on the Vmax/Km value of each allele, *128, *129, *130, *131, *132, and *133 were predicted to be nonfunctional alleles. According to the results of the present study, six normal metabolizers (NM) and one intermediate (IM) metabolizers were designated as IM and poor metabolizers (PM), respectively. Our findings provide important insights into novel haplotypes and haplotypes of CYP2D6 and the effects on in vitro metabolic activities.


Asunto(s)
Citocromo P-450 CYP2D6/genética , Fibroblastos/patología , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Trastornos Mentales/patología , Neoplasias/patología , Tamoxifeno/farmacología , Citocromo P-450 CYP2D6/metabolismo , Antagonistas de Estrógenos/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Genotipo , Humanos , Trastornos Mentales/genética , Neoplasias/genética , Fenotipo
6.
Pharmacol Res ; 167: 105538, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33705851

RESUMEN

Undoubtedly, pharmacogenomics (PGx) aims in optimizing drug treatment responses whilst also improving the patients' quality of life, either via a reduction of adverse drug reactions and/or an enhancement of drug treatment efficacy. To achieve this, PGx guidance is provided by the two major regulatory bodies in a worldwide level, specifically the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and occasionally some research consortia, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) or the Dutch Pharmacogenomics Working Group (DPWG). However, so far, there is a limited number of studies focusing on the delineation of the similarities and more importantly, the discrepancies in the PGx guidance by the different regulatory bodies and consortia. Herein, we use real-life clinical PGx data to highlight such discrepancies and similarities for genome-guided interventions in psychiatric disorders, thus demonstrating the need for harmonization of the guidelines and recommendations. More precisely, we used the PharmCAT genome-informed drug treatment reports from 304 Greek individuals with psychiatric disorders in order to emphasize on the discrepancies in the PGx guidance/guidelines between FDA vs EMA and CPIC vs DPWG, respectively. For example, CYP2D6-pimozide pair is characterized as 'Testing Required' according to FDA and is accompanied by a DPWG PGx guideline, whilst no EMA or CPIC PGx guidance is found for this drug-gene pair. Moreover, discrepancies are observed regarding the type of PGx guidance for CYP2C19-doxepin pair, with 89 individuals from our study cohort requiring a dose prescribing change based on FDA, whilst only 5 individuals have to receive genome-guided treatment adjustment according to CPIC. To our knowledge, this is the first study, in which discrepancies regarding the type of PGx guidance and the number of actionable drug-gene pairs amongst FDA and EMA, as well as CPIC and DPWG, are brought to light with an emphasis on psychiatric disorders.


Asunto(s)
Trastornos Mentales/genética , Europa (Continente) , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Trastornos Mentales/diagnóstico , Farmacogenética , Estados Unidos , United States Food and Drug Administration
7.
Vet Surg ; 50(6): 1304-1315, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34038003

RESUMEN

OBJECTIVE: Evaluate center of mass (CoM) displacement values during four-limb and three-limb standing with limb suspension in dogs before and after applying sensory stimulation to a forelimb or hindlimb. STUDY DESIGN: Experimental study. ANIMALS: Six clinically normal beagles. METHODS: A four force-plate apparatus was built to assess static weight distribution. Dogs stood on the device with one limb in contact with each force plate. We created a plastic device to induce sensory stimulation so that lameness could not be detected visually when stimulating the paw. Experimenters confirmed the degree of lameness by walking before and after measurement. Body-weight shifts were induced via suspension of each limb and transient sensory stimulation to the right forelimb or left hindlimb. CoMs of five postures were compared, with and without transient sensory stimulation. RESULTS: The four-limb CoM was located cranial to the center of the X- and Y-axis coordinates (X: -0.82 ± 9.12, Y: 61.00 ± 5.82). During three-limb standing with suspension of either forelimb, CoM shifted backward toward the contralateral side compared to four-limb standing. During hindlimb suspension, CoM shifted to the contralateral side. With right forelimb sensory stimulation, there were large CoM changes for both four-limb and three-limb standing (X: -34.53 ± 9.09, Y: 52.21 ± 6.88). CoM changes were small with left hindlimb sensory stimulation (X: 6.47 ± 13.86, Y: 69.41 ± 5.55). CONCLUSION: CoMs during four-limb and three-limb standing were influenced by sensory stimulation of a forelimb and, to a lesser extent, of a hindlimb. CLINICAL SIGNIFICANCE: Static evaluation of CoM may aid clinicians in the diagnosis and recovery of forelimb lameness.


Asunto(s)
Enfermedades de los Perros , Cojera Animal , Animales , Fenómenos Biomecánicos , Enfermedades de los Perros/terapia , Perros , Miembro Anterior , Marcha , Miembro Posterior , Extremidad Inferior
8.
Addict Biol ; 25(1): e12741, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-30815984

RESUMEN

The nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine's metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome-wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European-ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine-d2/(nicotine-d2 + cotinine-d2)). CYP2A6 genotypes and the NMR were assessed in European-ancestry participants. The wGRS training set included N = 933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N = 196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory-based pharmacokinetic study (N = 92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P < 0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ = 0.70 and ρ = 0.79, respectively; P < 0.001), and to one another (ρ = 0.82; P < 0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC = 0.79; P < 0.001), and to replicate previous NMR-stratified cessation outcomes showing unique treatment outcomes between metabolizer groups.


Asunto(s)
Citocromo P-450 CYP2A6/genética , Estudio de Asociación del Genoma Completo/métodos , Fumar/genética , Adulto , Biomarcadores/metabolismo , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Medición de Riesgo , Sensibilidad y Especificidad , Fumar/metabolismo
9.
Artículo en Inglés | MEDLINE | ID: mdl-31109976

RESUMEN

Antituberculosis drug-induced liver injury (ATDILI) is a common side effect leading to tuberculosis (TB) treatment disruption. The mechanism of the disease remains poorly understood. We conducted a genomewide association study (GWAS) to investigate all possible genetic factors of ATDILI in Thai patients. This study was carried out in Thai TB patients, including 79 ATDILI cases and 239 tolerant controls from our network hospitals in Thailand. Nearly 1 million single-nucleotide polymorphisms (SNPs) were genotyped across the whole genome using an Illumina OmniExpress Exome BeadChip array. In the discovery stage, we identified strong association signals on chromosome 8 originating from the N-acetyltransferase (NAT2) region. The A allele of rs1495741, the top SNP in the intergenic region of NAT2 and PSD3 (14 kb from NAT2), was significantly associated with ATDILI (recessive model, odds ratio of 6.01 [95% confidence interval, 3.42 to 10.57]; P = 6.86E-11). This particular SNP was reported as a tag SNP for NAT2 inferred phenotypes. The AA, AG, and GG genotypes represented NAT2 slow acetylators, intermediate acetylators, and fast acetylators, respectively. The tag SNP genotypes demonstrated a concordance rate of 94.98% with NAT2 acetylator phenotypes. This GWAS shows that NAT2 is the most important risk factor for ATDILI in the Thai population.


Asunto(s)
Antituberculosos/efectos adversos , Arilamina N-Acetiltransferasa/genética , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Tailandia
10.
Dig Dis Sci ; 64(2): 401-408, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30377885

RESUMEN

BACKGROUND: There is considerable individual variability in nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. AIM: To identify the SNP that is most significantly involved with NSAID-induced enteropathy. METHODS: One hundred fifty human subjects who were known to have a certain degree of loxoprofen- or celecoxib-induced small-intestinal damage from a previous study were enrolled. The subjects were divided into groups based on treatments and also on the increased number of small intestinal mucosal breaks. The candidate SNP was selected by an initial analysis of GWAS among the groups in various combinations. After the initial analysis, the gene including the specified SNP was analyzed in detail using GWAS and genotype imputation. RESULTS: After analysis, 70 subjects receiving the loxoprofen treatment and 69 subjects receiving celecoxib treatment were determined to be eligible for the analysis. The minimum p value in GWAS was detected in the analysis of 16 cases with an increase of five or more mucosal breaks and 123 controls with zero to four mucosal breaks. In the GWAS, five SNPs in the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene showed the lowest p value (p = 2.69 × 10-7 with an odds ratio of 40.9). Of the five SNPs, four were nonsynonymous SNPs (rs2070325: V268I, rs2889732: T320N, rs11699009: F527L, rs11696307: T533I, and rs11696310: intronic). Furthermore, 23 SNPs in BPIFB4 detected by genotype imputation based on the GWAS data also showed suggestive associations (p < 1 × 10-6). CONCLUSION: The results indicate that SNPs in BPIFB4 were associated with NSAID-induced small intestinal mucosal injury (UMIN: 000007936).


Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Enfermedades Intestinales/genética , Mucosa Intestinal/patología , Intestino Delgado/patología , Fosfoproteínas/genética , Adulto , Endoscopía Capsular , Celecoxib/efectos adversos , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Péptidos y Proteínas de Señalización Intercelular , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/patología , Masculino , Persona de Mediana Edad , Fenilpropionatos/efectos adversos , Polimorfismo de Nucleótido Simple
11.
Pharmacogenet Genomics ; 28(7): 167-176, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29781872

RESUMEN

BACKGROUND: NAT2 slow acetylator is a confirmed risk of anti-tuberculosis drug-induced liver injury (ATDILI). However, NAT2 ultra-slow acetylators, a new refinement among NAT2 slow acetylators, have been recently proposed. The patients with NAT2 genotypes of *6A/*6A, *6A/*7B and *7B/*7B are referred to in this group. OBJECTIVE: We aim to prove an association of the NAT2 ultra-slow acetylators with the risk of ATDILI. MATERIALS AND METHODS: Systematic review and meta-analysis were performed based on each NAT2 genotype and risk of ATDILI cases and also new classification of the ultra-slow acetylators up to 31 October 2016. Meta-analysis of 18 studies with 822 ATDILI cases and 4630 controls was carried out in the RevMan software, version 5.3 with fixed-effect (low heterogeneity) and random effect (moderate to high heterogeneity) methods. RESULTS: The strong associations between each NAT2 slow acetylator genotypes and ATDILI were confirmed in meta-analysis except for NAT2*5B/*5B [odds ratio (OR): 1.69; 95% confidence interval (CI): 0.96-2.95; P=0.0679]. The NAT2 ultra-slow acetylators contribute to higher risk of ATDILI (OR: 3.60; 95% CI: 2.30-5.63; P=1.76E-08) than all NAT2 slow acetylators (OR: 2.80; 95% CI: 2.20-3.57; P=5.73E-18) as well as fast acetylators. Additional in-vitro study using isoniazid as a substrate supports the existence of ultra-slow acetylator alleles (NAT2*6A and NAT2*7B). CONCLUSION: This is the first meta-analysis of NAT2 and the risk of ATDILI at the genotypic level. The result demonstrated that NAT2 ultra-slow acetylator genotypes will have the most effect on the increased risk of ATDILI.


Asunto(s)
Antituberculosos/efectos adversos , Arilamina N-Acetiltransferasa/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Polimorfismo Genético , Tuberculosis/tratamiento farmacológico , Acetilación , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Genotipo , Humanos , Factores de Riesgo
12.
J Vet Pharmacol Ther ; 41(5): 684-690, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30020534

RESUMEN

Potassium bromide overdose (bromism) in the management of canine epilepsy has been known. However, a protocol to reduce bromide concentrations rapidly has not been previously established. The effects of three infusion fluids with different chloride contents on the steady-state serum concentrations of bromide in beagles were determined. After stabilization of the serum bromide concentrations, seven dogs were infused with saline (Na+ 154 mmol/L; Cl- 154 mmol/L), lactated Ringer's (Na+ 131 mmol/L; Cl- 110 mmol/L), or maintenance solutions (Na+ 35 mmol/L; Cl- 35 mmol/L) at a rate of 2 or 10 ml kg-1  hr-1 for 5 hr. Serum and urine were collected hourly, and the bromide concentrations were measured. When saline and lactated Ringer's solutions were infused at a rate of 10 ml kg-1  hr-1 for 5 hr, serum bromide concentrations were decreased by 14.24% and urine bromide concentrations by 17.63%, respectively. Of all compositions of infusion fluids, only sodium and chloride contents were associated with the decreased serum concentrations and the increased renal clearance of bromide. In summary, saline and lactated Ringer's solutions reduced serum bromide concentrations in a sodium chloride-dependent manner in dogs were found when infused at 10 ml kg-1  hr-1 for 5 hr.


Asunto(s)
Bromuros/sangre , Solución Salina/farmacocinética , Animales , Anticonvulsivantes/sangre , Anticonvulsivantes/envenenamiento , Bromuros/envenenamiento , Perros/sangre , Perros/metabolismo , Femenino , Infusiones Intravenosas/veterinaria , Soluciones Isotónicas/administración & dosificación , Soluciones Isotónicas/farmacocinética , Compuestos de Potasio/sangre , Compuestos de Potasio/envenenamiento , Solución de Ringer/administración & dosificación , Solución de Ringer/farmacocinética , Solución Salina/administración & dosificación , Cloruro de Sodio/administración & dosificación , Cloruro de Sodio/farmacocinética
13.
BMC Genet ; 17(1): 79, 2016 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-27296832

RESUMEN

BACKGROUND: To investigate the associations between atorvastatin-induced liver injury (AILI) and polymorphisms in eight genes possibly involved in the hepatic metabolism (CYP2C9, CYP2C19, CYP3A4, CYP3A5 and UGT1A1) and membrane transport (ABCB1, ABCG2 and SLCO1B1) of atorvastatin, we genotyped 30 AILI and 414 non-AILI patients recruited at BioBank Japan for 15 single nucleotide polymorphisms (SNPs). RESULTS: An SNP in ABCB1 (rs2032582: 2677G > T/A) was significantly associated with AILI (P = 0.00068, odds ratio (OR) = 2.59 with 95 % confidence interval (CI) of 1.49-4.50, G allele versus T and A alleles), indicating that the G allele might be a risk factor for AILI. The cytotoxicity test demonstrated that IC50 value of atorvastatin to inhibit the growth and/or viability of Flp-In-293/ABCB1 (2677G) cells was 5.44 ± 0.10 mM, which was significantly lower than those in Flp-In-293/ABCB1 (2677 T) (6.02 ± 0.07 mM) and Flp-In-293/ABCB1 (2677A) cells (5.95 ± 0.08 mM). CONCLUSIONS: These results indicate that ABCB1 rs2032582 may predict the risk of AILI in Japanese population.


Asunto(s)
Pueblo Asiatico/genética , Atorvastatina/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Polimorfismo de Nucleótido Simple , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Línea Celular , Predisposición Genética a la Enfermedad/genética , Humanos , Japón
14.
BMC Cancer ; 14: 964, 2014 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-25515134

RESUMEN

BACKGROUND: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects. CASE PRESENTATION: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient. CONCLUSION: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Antineoplásicos/efectos adversos , Pueblo Asiatico/genética , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Proteínas de Neoplasias/genética , Pirroles/efectos adversos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Anciano , Antineoplásicos/farmacocinética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Indoles/farmacocinética , Japón , Neoplasias Renales/genética , Neoplasias Renales/patología , Polimorfismo de Nucleótido Simple , Pirroles/farmacocinética , Sunitinib
15.
NPJ Aging ; 10(1): 3, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38167405

RESUMEN

Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia among those older than 65 years. The onset of LOAD is influenced by neuroinflammation. The human leukocyte antigen (HLA) system is involved in regulating inflammatory responses. Numerous HLA alleles and their haplotypes have shown varying associations with LOAD in diverse populations, yet their impact on the Japanese population remains to be elucidated. Here, we conducted a comprehensive investigation into the associations between LOAD and HLA alleles within the Japanese population. Using whole-genome sequencing (WGS) data from 303 LOAD patients and 1717 cognitively normal (CN) controls, we identified four-digit HLA class I alleles (A, B, and C) and class II alleles (DRB1, DQB1, and DPB1). We found a significant association between the HLA-DRB1*09:01-DQB1*03:03 haplotype and LOAD risk in APOE [Formula: see text]4-negative samples (odds ratio = 1.81, 95% confidence interval = 1.38-2.38, P = 2.03[Formula: see text]). These alleles not only showed distinctive frequencies specific to East Asians but demonstrated a high degree of linkage disequilibrium in APOE [Formula: see text]4-negative samples (r2 = 0.88). Because HLA class II molecules interact with T-cell receptors (TCRs), we explored potential disparities in the diversities of TCR α chain (TRA) and ß chain (TRB) repertoires between APOE [Formula: see text]4-negative LOAD and CN samples. Lower diversity of TRA repertoires was associated with LOAD in APOE [Formula: see text]4-negative samples, irrespective of the HLA DRB1*09:01-DQB1*03:03 haplotype. Our study enhances the understanding of the etiology of LOAD in the Japanese population and provides new insights into the underlying mechanisms of its pathogenesis.

16.
Immunohorizons ; 7(1): 1-16, 2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36637516

RESUMEN

NK cells are major effector cells involved in the elimination of early tumors and prevent metastasis. They often have an impaired function in patients with cancer. Preclinical studies have demonstrated NK cell activation as the adjunctive effect of invariant NKT (iNKT) cells. Activation of iNKT cells after administration of the glycolipid ligand α-galactosylceramide, loaded with CD1d-expressing human PBMC-derived APCs (APC/Gal), is an attractive cancer therapy to optimize the use of NK cells. However, the subsets of NK cells that are activated following iNKT cell activation as well as the period of NK cell activation remain unclear. In this study, we report that the granzyme B-expressing NK cell response in postoperative lung cancer patients was enhanced 49 d after administration of APC/Gal in a phase II study. We found maximum IFN-γ production on day 49 in 13 out of 27 APC/Gal-treated patients. On day 49, 14 out of 27 patients (51.9%) had higher IFN-γ production by iNKT cells (>6-fold higher than the baseline level). This increment significantly correlated with granzyme B-expressing NK cells. Although IFN-γ production was lower in patients in the nontreated group, we detected maximum IFN-γ production 12 mo after the resection of lung cancer (9 out of 29 patients [31%]). These findings suggest that elimination of cancer cells leads to increased NK cell function, which can be further enhanced by APC/Gal therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Células T Asesinas Naturales , Humanos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Granzimas , Ligandos , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/secundario , Células Asesinas Naturales
17.
Clin Transl Sci ; 15(1): 204-220, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34476898

RESUMEN

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking-related disease risk. The heritability of the NMR is 60-80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30-35%. Rare variants (minor allele frequency <1%) are hypothesized to explain some of this missing heritability. We present two targeted sequencing studies where rare protein-coding variants are functionally characterized in vivo, in silico, and in vitro to examine this hypothesis. In a smoking cessation trial, 1687 individuals were sequenced; characterization measures included the in vivo NMR, in vitro protein expression, and metabolic activity measured from recombinant proteins. In a human liver bank, 312 human liver samples were sequenced; measures included RNA expression, protein expression, and metabolic activity from extracted liver tissue. In total, 38 of 47 rare coding variants identified were novel; characterizations ranged from gain-of-function to loss-of-function. On a population level, the portion of NMR variation explained by the rare coding variants was small (~1%). However, upon incorporation, the accuracy of the wGRS was improved for individuals with rare protein-coding variants (i.e., the residuals were reduced), and approximately one-third of these individuals (12/39) were re-assigned from normal to slow metabolizer status. Rare coding variants can alter an individual's CYP2A6 activity; their integration into wGRSs through precise functional characterization is necessary to accurately assess clinical outcomes and achieve precision medicine for all. Investigation into noncoding variants is warranted to further explain the missing heritability in the NMR.


Asunto(s)
Citocromo P-450 CYP2A6/genética , Polimorfismo de Nucleótido Simple , Resultado del Tratamiento , Ensayos Clínicos como Asunto , Frecuencia de los Genes , Genotipo , Humanos , Cese del Hábito de Fumar
18.
Cancers (Basel) ; 14(12)2022 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-35740506

RESUMEN

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

19.
Drug Metab Pharmacokinet ; 37: 100370, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33508759

RESUMEN

Genetic variation in pharmacokinetics (PK)-related genes encoding drug metabolizing enzymes or drug transporters is one of the most practical pharmacogenetic biomarkers for the prediction or explanation of an individual's response to drugs. Many pharmacogenomic variations are identified using targeted, whole-exome, and whole-genome sequencing, and the number of known novel variations and alleles in PK-related genes is increasing. The high homology of sequences among PK-related genes is suspected to lead to potential read misalignment and genotyping errors when short-read sequencing was performed. Therefore, highly efficient and accurate next generation sequencing (NGS) platforms for the sequencing of PK-related genes are needed. We have developed PKseq, a targeted sequencing panel based on multiplex PCR, which targets the coding regions of 37 drug transporters, 30 cytochrome P450 isoforms, 10 UDP-glucuronosyltransferases, 5 flavin-containing monooxygenases, 4 glutathione S-transferases, 4 sulfotransferases, and 10 other genes. In this review, we describe the current NGS platforms for the sequencing of PK-related genes. The NGS platforms, including the PKseq panel, will be useful not only for the identification of all the variants of PK-related genes associated with adverse drug reactions and drug efficacy, but also for clinical sequencing to achieve pharmacogenomics-based stratified medicine.


Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Preparaciones Farmacéuticas/metabolismo , Transferasas/genética , Biomarcadores/análisis , Biomarcadores/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Variación Genética/genética , Humanos , Reacción en Cadena de la Polimerasa Multiplex , Preparaciones Farmacéuticas/química , Transferasas/metabolismo
20.
Biomed Res ; 42(4): 121-127, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34380920

RESUMEN

Fluoropyrimidines such as 5-fluorouracil (5-FU) are well known to have drug-drug interactions with anticoagulant medications such as warfarin. This study investigated the mRNA expression of pharmacokinetic (PK)-related genes in response to 5-FU using the hepatocarcinoma cell lines after examining relevant gene expression via RNA sequencing. We used HepaRG cells for 5-FU treatment analysis because these cells displayed PK-related gene expression. 5-FU exposure significantly reduced cytochrome P450 3A4 (CYP3A4) mRNA expression. Additionally, the mRNA expression of nuclear receptor subfamily 1 group I member 2 (also known as pregnane X receptor), a nuclear receptor transcription factor that promotes the expression of many CYP genes, was also decreased in HepaRG cells following 5-FU treatment. The mRNA expressions of the CYP2B6 and ATP-binding cassette transporter genes were decreased after 5-FU treatment. This study revealed that 5-FU treatment reduced PK-related gene expression in HepaRG cells. These findings should be useful for further drug-drug interaction research.


Asunto(s)
Carcinoma Hepatocelular , Preparaciones Farmacéuticas , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Línea Celular , Citocromo P-450 CYP3A/genética , Sistema Enzimático del Citocromo P-450/genética , Fluorouracilo/farmacología , Hepatocitos , Humanos , ARN Mensajero/genética
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