RESUMO
Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle hypoplasia. A genome-wide association study (GWAS) was conducted of 711 Japanese patients with esotropia (n= 253), exotropia (n = 356), and idiopathic superior oblique muscle palsy (n = 102). The genotypes of single nucleotide polymorphisms (SNPs) were determined by Infinium Asian Screening Array. Three control cohorts from the Japanese population were used: two cohorts from BioBank Japan (BBJ) and the Nagahama Cohort. BBJ (180K) was genotyped by a different array, Illumina Infinium OmniExpressExome or HumanOmniExpress, while BBJ (ASA) and the Nagahama Cohort were genotyped by the same Asian array. After quality control of SNPs and individuals, common SNPs between the case cohort and the control cohort were chosen in the condition of genotyping by different arrays, while all SNPs genotyped by the same array were used for SNP imputation. The SNPs imputed with R-square values ≥ 0.3 were used to compare the case cohort of each entity or the combined entity with the control cohort. In comparison with BBJ (180K), the esotropia group and the exotropia group showed CDCA7 and HLA-F, respectively, as candidate genes at a significant level of p < 5 × 10-8, while the idiopathic superior oblique muscle palsy group showed DAB1 as a candidate gene which is involved in neuronal migration. DAB1 was also detected as a candidate in comparison with BBJ (ASA) and the Nagahama Cohort at a weak level of significance of p < 1 × 10-6. In comparison with BBJ (180K), RARB (retinoic acid receptor-ß) was detected as a candidate at a significant level of p < 5 × 10-8 in the combined group of esotropia, exotropia, and idiopathic superior oblique muscle palsy. In conclusion, a series of GWASs with three different control cohorts would be an effective method with which to search for candidate genes for multifactorial diseases such as strabismus.
Assuntos
Esotropia , Exotropia , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Humanos , Estudos de Casos e Controles , Estudos de Coortes , População do Leste Asiático/genética , Esotropia/genética , Exotropia/genética , Predisposição Genética para Doença , Genótipo , JapãoRESUMO
Although chronic kidney disease (CKD) is recognized as a major public health concern, effective treatment strategies have yet to be developed. Identification and validation of drug targets are key issues in the development of therapeutic agents for CKD. Uric acid (UA), a major risk factor for gout, has also been suggested to be a risk factor for CKD, but the efficacy of existing urate-lowering therapies for CKD is controversial. We focused on five uric acid transporters (ABCG2, SLC17A1, SLC22A11, SLC22A12, SLC2A9) as potential drug targets and evaluated the causal association between serum UA levels and estimated glomerular filtration rate (eGFR) using single-SNP Mendelian Randomization. The results showed a causal association between genetically predicted changes in serum UA levels and eGFR when genetic variants were selected from the SLC2A9 locus. Estimation based on a loss-of-function mutation (rs16890979) showed that the changes in eGFR per unit increase in serum UA level was -0.0082 ml/min/1.73 m2 (95% CI -0.014 to -0.0025, P = 0.0051). These results indicate that SLC2A9 may be a novel drug target for CKD that preserves renal function through its urate-lowering effect.
Assuntos
Gota , Transportadores de Ânions Orgânicos , Insuficiência Renal Crônica , Humanos , Ácido Úrico , Análise da Randomização Mendeliana , Gota/genética , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/genética , Fatores de Risco , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas Facilitadoras de Transporte de Glucose/genéticaRESUMO
BACKGROUND: HDL has been proposed to possess anti-inflammatory properties; however, the detail mechanisms have not been fully elucidated. METHODS: We investigated the roles of Apolipoprotein D (ApoD) in the pathogenesis of inflammation in the mouse model of diet-induced obesity and that of lipopolysaccharide-induced sepsis and the in vitro experiments. Furthermore, we analyzed serum ApoD levels in human subjects. RESULTS: The overexpression of human ApoD decreased the plasma IL-6 and TNF-a levels in both mice models. Lipidomics analyses demonstrated association of ApoD with increase of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, as well as of their metabolites, and of the anti-inflammatory molecule sphingosine 1-phosphate, and decrease of proinflammatory lysophosphatidic acids and lysophosphatidylinositol. ApoD-containing lipoproteins might directly bind eicosapentaenoic acid and docosahexaenoic acid. The modulations of the lysophosphatidic acid and sphingosine 1-phosphate levels resulted from the suppression of autotaxin expression and elevation of apolipoprotein M (ApoM), respectively. Moreover, ApoD negatively regulated osteopontin, a proinflammatory adipokine. The activation of PPARg by ApoD might suppress autotaxin and osteopontin. Serum ApoD levels were negatively correlated with the serum osteopontin and autotaxin levels and, positively with serum ApoM levels. CONCLUSION: ApoD is an anti-inflammatory apolipoprotein, which modulates lipid mediators and osteopontin in an anti-inflammatory direction.
Assuntos
Ácido Eicosapentaenoico , Osteopontina , Humanos , Camundongos , Animais , Apolipoproteínas D/metabolismo , Ácido Eicosapentaenoico/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Anti-Inflamatórios/farmacologia , Lisofosfolipídeos/metabolismo , Eicosanoides , Esfingosina/metabolismoRESUMO
The objective of the study is to develop genetic and clinical prediction models for the efficacy and hepatotoxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). Among RA patients treated with MTX, 1966 polymorphisms of 246 enzymes/transporters relevant to pharmacokinetics and pharmacodynamics were measured by the Drug Metabolism Enzymes and Transporters (DMET) microarray and direct sequencing, and clinical variables at baseline were collected. For efficacy, response criteria of the European League Against Rheumatism were used to classify patients as responders or non-responders. Hepatotoxicity was defined as elevations of aspartate aminotransferase or alanine aminotransferase ≥1.5 times the reference range upper limit. Among 166 patients, a genetic prediction model for efficacy using seven polymorphisms showed the area under the receiver operating characteristic curve (AUC) was 0.822, with 74.3% sensitivity and 76.8% specificity. A combined genetic and clinical model indicated the AUC was 0.844, with 81.5% sensitivity and 76.9% specificity. By incorporating clinical variables into the genetic model, the overall category-free net reclassification improvement (NRI) was 0.663 (P < 0.0001) and the overall integrated discrimination improvement (IDI) was 0.083 (P = 0.0009). For hepatotoxicity, a genetic prediction model using seven polymorphisms showed the AUC was 0.783 with 70.0% sensitivity and 80.0% specificity, while the combined model indicated the AUC was 0.906 with 85.1% sensitivity and 87.8% specificity (overall category-free NRI: 1.002, P < 0.0001; overall IDI: 0.254, P < 0.0001). Our genetic and clinical models demonstrated moderate diagnostic accuracy for MTX efficacy and high accuracy for hepatotoxicity. These findings should, however, be validated and interpreted with a caution until external validation.
Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Metotrexato/efeitos adversos , Modelos Genéticos , Idoso , Artrite Reumatoide/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Estudos de Coortes , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Individual disease risk estimated based on the data from single or multiple genetic loci is generally calculated using the genotypes of a subject, frequencies of alleles of interest, odds ratios and the average population risk. However, it is often difficult to estimate accurately the average population risk, and therefore it is often expressed as an interval. To better estimate the risk of a subject with given genotypes, we built R scripts using the R environment and constructed graphs to examine the change in the estimated risk as well as the relative risk according to the change of the average population risk. In most cases, the graph of the relative risk did not cross the line of y=1, thereby indicating that the order of the relative risk for given genotypes and the population average risk does not change when the average risk increases or decreases. In rare cases, however, the graph of the relative risk crossed the line of y=1, thereby indicating that the order of the relative risk for given genotypes and the population average risk does change owing to the change in the population risk. We propose that the relative risk should be estimated for not only the point average population risk but also for an interval of the average population risk. Moreover, when the graph crosses the line of y=1 within the interval, this information should be reported to the consumer.
Assuntos
Alelos , Interpretação Estatística de Dados , Predisposição Genética para Doença , Genótipo , Algoritmos , Genoma , Humanos , Razão de Chances , Fenótipo , RiscoRESUMO
Previous reports have described several associations of PR, QRS, QT and heart rate with genomic variations by genome-wide association studies (GWASs). In the present study, we examined the association of â¼2.5 million SNPs from 2994 Japanese healthy volunteers obtained from the JPDSC database with electrocardiographic parameters. We confirmed associations of PR interval, QRS duration and QT interval in individuals of Japanese ancestry with 11 of the 45 SNPs (6 of 20 for QT, 5 of 19 for PR and 0 of 6 for QRS) observed among individuals of European, African and Asian (Indian and Korean) ancestries. Those results indicate that many of the electrocardiographic associations with genes are shared by different ethnic groups including Japanese. Possible novel associations found in this study were validated by Korean data. As a result, we identified a novel association of SNP rs4952632[G] (maps near SLC8A1, sodium-calcium exchanger) (P = 7.595 × 10(-6)) with PR interval in Japanese individuals, and replication testing among Koreans confirmed the association of the same SNP with prolonged PR interval. Meta-analysis of the Japanese and Korean datasets demonstrated highly significant associations of SNP rs4952632[G] with a 2.325-ms (95% CI, 1.693-2.957 ms) longer PR interval per minor allele copy (P = 5.598 × 10(-13)). Cell-type-specific SLC8A1 knockout mice have demonstrated a regulatory role of sodium-calcium exchanger in automaticity and conduction in sinoatrial node, atrium and atrioventricular node. Our findings support a functional role of sodium-calcium exchanger in human atrial and atrioventricular nodal conduction as suggested by genetically modified mouse models.
Assuntos
Sistema de Condução Cardíaco/fisiologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Trocador de Sódio e Cálcio/genética , Adulto , Idoso , Alelos , Animais , Povo Asiático , Eletrocardiografia , Feminino , Deleção de Genes , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Trocador de Sódio e Cálcio/metabolismoRESUMO
Previous reports including genome-wide association studies (GWASs) have described associations of serum lipids with genomic variations. In the present study, we examined the association of â¼2.5 million single-nucleotide polymorphisms (SNPs) from 3041 Japanese healthy volunteers obtained from the Japan Pharmacogenomics Data Science Consortium (JPDSC) database with serum lipids. We confirmed the previously reported associations of 14 SNPs in 5 regions for low-density lipoprotein (LDL) cholesterol, 23 SNPs in 12 regions for high-density lipoprotein (HDL) cholesterol, 16 SNPs in 6 regions for triglyceride and 5 SNPs in 1 region for phospholipid. Furthermore, we identified 16 possible novel candidate genes associated with LDL cholesterol, HDL cholesterol or triglycerides, where SNPs had P-values of <1 × 10(-5). Further replication analyses of these genes with Korean data revealed significant associations of SNPs located within the PCSK7 gene and triglyceride (Pmeta=7.98 × 10(-9) and 1.91 × 10(-8) for rs508487 and rs236911, respectively). These associations remained significant even by the conditional analysis adjusting for three neighboring variations associated with triglyceride. Our present data suggest that PCSK7 as well as PCSK9 may be associated with lipids, especially triglyceride, and may serve as a candidate for a new drug target to treat lipid abnormality syndromes.
Assuntos
Estudo de Associação Genômica Ampla , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Subtilisinas/genética , Triglicerídeos/sangue , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Fenótipo , Vigilância da PopulaçãoRESUMO
Japan Pharmacogenomics Data Science Consortium (JPDSC) has assembled a database for conducting pharmacogenomics (PGx) studies in Japanese subjects. The database contains the genotypes of 2.5 million single-nucleotide polymorphisms (SNPs) and 5 human leukocyte antigen loci from 2994 Japanese healthy volunteers, as well as 121 kinds of clinical information, including self-reports, physiological data, hematological data and biochemical data. In this article, the reliability of our data was evaluated by principal component analysis (PCA) and association analysis for hematological and biochemical traits by using genome-wide SNP data. PCA of the SNPs showed that all the samples were collected from the Japanese population and that the samples were separated into two major clusters by birthplace, Okinawa and other than Okinawa, as had been previously reported. Among 87 SNPs that have been reported to be associated with 18 hematological and biochemical traits in genome-wide association studies (GWAS), the associations of 56 SNPs were replicated using our data base. Statistical power simulations showed that the sample size of the JPDSC control database is large enough to detect genetic markers having a relatively strong association even when the case sample size is small. The JPDSC database will be useful as control data for conducting PGx studies to explore genetic markers to improve the safety and efficacy of drugs either during clinical development or in post-marketing.
Assuntos
Antígenos HLA/genética , Bases de Dados Genéticas , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Voluntários Saudáveis , Humanos , Japão , Masculino , Farmacogenética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We developed a software program, NDesign, for the design of a study intended for detecting rare variants from next-generation sequencing (NGS) data. In this study design, the optimal depth of coverage and the average depth of coverage are first evaluated, and then the ability of the designed experiment to obtain a desired power is determined. NDesign has been developed to calculate both these depths, as well as to evaluate the power of the designed experiment. It has a simple implementation in the JavaScript language, and is expected to enable researchers to design optimal NGS studies.
Assuntos
Biologia Computacional/métodos , Variação Genética , Análise de Sequência de DNA/métodos , Software , Alelos , Sequência de Bases , Distribuição Binomial , Frequência do Gene , Predisposição Genética para Doença , Genética Populacional/métodos , Genoma Humano , Heterozigoto , Humanos , Modelos GenéticosRESUMO
Our objective was to describe outpatient medical care costs of patients with rheumatoid arthritis (RA) in the prebiologics period in Japan. The outpatient costs of 6,771 RA patients (17,666 patient years) who were enrolled in an observational cohort study at the Institute of Rheumatology, Rheumatoid Arthritis (IORRA), in Tokyo, Japan, were calculated from the billing records dated from 2000 to 2004. Associations between outpatient costs and variables such as age, RA duration, RA disease activities, and disability levels were assessed. The average outpatient cost gradually increased (+7.7% in 4 years) from 271,498 JPY per year in 2000 to 292,417 JPY per year in 2004. Medications accounted for approximately 50% of total outpatient costs, which increased 29.6% during the 4 years. The outpatient costs increased in association with aging, longer RA duration, higher Disease Activity Score of 28 Joints (DAS28), and higher Japanese version of Health Assessment Questionnaire (J-HAQ) score. Generalized linear regression analysis revealed that both DAS28 and J-HAQ scores were the most significant factors associated with outpatient costs (p < 0.001). Outpatient costs for patients with RA increased year after year over the 4-year period under observation in Japan. Medical costs were higher with increasing RA disease activity and disability levels.
Assuntos
Assistência Ambulatorial/economia , Artrite Reumatoide/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Antirreumáticos/economia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Produtos Biológicos/uso terapêutico , Avaliação da Deficiência , Custos de Medicamentos , Feminino , Custos de Cuidados de Saúde/tendências , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Cellular energetics play an important role in Parkinsons disease etiology, but no treatments directly address this deficiency. Our past research showed that treatment with febuxostat and inosine increased blood hypoxanthine and ATP in healthy adults, and a preliminary trial in 3 Parkinson's disease patients suggested some symptomatic improvements with no adverse effects. METHODS: To examine the efficacy on symptoms and safety in a larger group of Parkinsons disease patients, we conducted a single-arm, open-label trial at 5 Japanese neurology clinics and enrolled thirty patients (nmalesâ=â11; nfemalesâ=â19); 26 patients completed the study (nmalesâ=â10; nfemalesâ=â16). Each patient was administered febuxostat 20âmg and inosine 500âmg twice-per-day (after breakfast and dinner) for 8 weeks. The primary endpoint was the difference of MDS-UPDRS Part III score immediately before and after 57 days of treatment. RESULTS: Serum hypoxanthine concentrations were raised significantly after treatment (Preâ=â11.4âµM; Postâ=â38.1âµM; Pâ<â.0001). MDS-UPDRS Part III score was significantly lower after treatment (Preâ=â28.1â±â9.3; Postâ=â24.7â±â10.8; meanâ±âSD; Pâ=â.0146). Sixteen adverse events occurred in 13/29 (44.8%) patients, including 1 serious adverse event (fracture of the second lumbar vertebra) that was considered not related to the treatment. CONCLUSIONS: The results of this study suggest that co-administration of febuxostat and inosine is relatively safe and effective for improving symptoms of Parkinsons disease patients. Further controlled trials need to be performed to confirm the symptomatic improvement and to examine the disease-modifying effect in long-term trials.
Assuntos
Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Inosina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Trifosfato de Adenosina/sangue , Administração Oral , Idoso , Estudos de Casos e Controles , Quimioterapia Combinada , Febuxostat/administração & dosagem , Febuxostat/efeitos adversos , Feminino , Supressores da Gota/administração & dosagem , Supressores da Gota/efeitos adversos , Humanos , Hipoxantina/sangue , Inosina/administração & dosagem , Inosina/efeitos adversos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/epidemiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Segurança , Resultado do Tratamento , Xantina Desidrogenase/antagonistas & inibidoresRESUMO
Skin trait variation impacts quality-of-life, especially for females from the viewpoint of beauty. To investigate genetic variation related to these traits, we conducted a GWAS of various skin phenotypes in 11,311 Japanese women and identified associations for age-spots, freckles, double eyelids, straight/curly hair, eyebrow thickness, hairiness, and sweating. In silico annotation with RoadMap Epigenomics epigenetic state maps and colocalization analysis of GWAS and GTEx Project eQTL signals provided information about tissue specificity, candidate causal variants, and functional target genes. Novel signals for skin-spot traits neighboured AKAP1/MSI2 (rs17833789; P = 2.2 × 10-9), BNC2 (rs10810635; P = 2.1 × 10-22), HSPA12A (rs12259842; P = 7.1 × 10-11), PPARGC1B (rs251468; P = 1.3 × 10-21), and RAB11FIP2 (rs10444039; P = 5.6 × 10-21). HSPA12A SNPs were the only protein-coding gene eQTLs identified across skin-spot loci. Double edged eyelid analysis identified that a signal around EMX2 (rs12570134; P = 8.2 × 10-15) was also associated with expression of EMX2 and the antisense-RNA gene EMX2OS in brain putamen basal ganglia tissue. A known hair morphology signal in EDAR was associated with both eyebrow thickness (rs3827760; P = 1.7 × 10-9) and straight/curly hair (rs260643; P = 1.6 × 10-103). Excessive hairiness signals' top SNPs were also eQTLs for TBX15 (rs984225; P = 1.6 × 10-8), BCL2 (rs7226979; P = 7.3 × 10-11), and GCC2 and LIMS1 (rs6542772; P = 2.2 × 10-9). For excessive sweating, top variants in two signals in chr2:28.82-29.05 Mb (rs56089836; P = 1.7 × 10-11) were eQTLs for either PPP1CB or PLB1, while a top chr16:48.26-48.45 Mb locus SNP was a known ABCC11 missense variant (rs6500380; P = 6.8 × 10-10). In total, we identified twelve loci containing sixteen association signals, of which fifteen were novel. These findings will help dermatologic researchers better understand the genetic underpinnings of skin-related phenotypic variation in human populations.
Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Pigmentação da Pele/genética , Feminino , Humanos , JapãoRESUMO
Food allergy is an increasingly important health problem in the world. Several genome-wide association studies (GWAS) focused on European ancestry samples have identified food allergy-specific loci in the HLA class II region. We conducted GWAS of self-reported reactivity with common foods using the data from 11011 Japanese women and identified shrimp and peach allergy-specific loci in the HLA-DR/DQ gene region tagged by rs74995702 (P = 6.30 × 10-17, OR = 1.91) and rs28359884 (P = 2.3 × 10-12, OR = 1.80), respectively. After HLA imputation using a Japanese population-specific reference, the most strongly associated haplotype was HLA-DRB1*04:05-HLA-DQB1*04:01 for shrimp allergy (P = 3.92 × 10-19, OR = 1.99) and HLA-DRB1*09:01-HLA-DQB1*03:03 for peach allergy (P = 1.15 × 10-7, OR = 1.68). Additionally, both allergies' associated variants were eQTLs for several HLA genes, with HLA-DQA2 the single eQTL gene shared between the two traits. Our study suggests that allergy to certain foods may be related to genetic differences that tag both HLA alleles having particular epitope binding specificities as well as variants modulating expression of particular HLA genes. Investigating this further could increase our understanding of food allergy aetiology and potentially lead to better therapeutic strategies for allergen immunotherapies.
Assuntos
Alelos , Alérgenos/imunologia , Epitopos/imunologia , Hipersensibilidade Alimentar/genética , Hipersensibilidade Alimentar/imunologia , Estudo de Associação Genômica Ampla , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Adulto , Animais , Anostraca/imunologia , Biologia Computacional/métodos , Reações Cruzadas/genética , Reações Cruzadas/imunologia , Feminino , Hipersensibilidade Alimentar/diagnóstico , Predisposição Genética para Doença , Humanos , Japão , Polimorfismo de Nucleotídeo Único , Prunus persica/efeitos adversos , AutorrelatoRESUMO
Traits related to primary and secondary sexual characteristics greatly impact females during puberty and day-to-day adult life. Therefore, we performed a GWAS analysis of 11,348 Japanese female volunteers and 22 gynecology-related phenotypic variables, and identified significant associations for bust-size, menstrual pain (dysmenorrhea) severity, and menstrual fever. Bust-size analysis identified significant association signals in CCDC170-ESR1 (rs6557160; P = 1.7 × 10-16) and KCNU1-ZNF703 (rs146992477; P = 6.2 × 10-9) and found that one-third of known European-ancestry associations were also present in Japanese. eQTL data points to CCDC170 and ZNF703 as those signals' functional targets. For menstrual fever, we identified a novel association in OPRM1 (rs17181171; P = 2.0 × 10-8), for which top variants were eQTLs in multiple tissues. A known dysmenorrhea signal near NGF replicated in our data (rs12030576; P = 1.1 × 10-19) and was associated with RP4-663N10.1 expression, a putative lncRNA enhancer of NGF, while a novel dysmenorrhea signal in the IL1 locus (rs80111889; P = 1.9 × 10-16) contained SNPs previously associated with endometriosis, and GWAS SNPs were most significantly associated with IL1A expression. By combining regional imputation with colocalization analysis of GWAS/eQTL signals along with integrated annotation with epigenomic data, this study further refines the sets of candidate causal variants and target genes for these known and novel gynecology-related trait loci.
Assuntos
Dismenorreia/genética , Locos de Características Quantitativas , RNA Longo não Codificante/genética , Proteínas de Transporte/genética , Dismenorreia/epidemiologia , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Japão/epidemiologia , Polimorfismo de Nucleotídeo Único , Receptores Opioides mu/genéticaRESUMO
Pulmonary arterial hypertension (PAH) is a lethal disease that often affects the young. Although Bone Morphogenetic Protein Receptor Type 2 gene (BMPR2) mutations are related with idiopathic and heritable PAH, the low penetrance and variable expressivity in PAH suggest the existence of other genetic and/or environmental factors. In this study, we aimed to identify novel genetic factors associated with PAH, irrespective of BMPR2 mutation. We performed genome-wide association study (GWAS) in a Japanese population comprising 44 individuals with idiopathic and heritable PAH, and 2,993 controls. Seven loci identified in the genome-wide study were submitted to the validation study, and a novel susceptibility locus, PDE1A|DNAJC10, was identified that maps to 2q32.1 (rs71427857, P = 7.9 × 10-9, odds ratio in the validation study = 5.18; 95% CI 1.86 - 14.42). We also found the augmentation of PDE1A protein in distal remodeled pulmonary artery walls in idiopathic PAH patients. Given that phosphodiesterase 5 inhibitors are effective for the treatment of idiopathic and heritable PAH, our findings suggest that PDE1A could be a novel therapeutic target of PAH.
RESUMO
Left ventricular hypertrophy (LVH) represents a common final pathway leading to heart failure. We have searched for genetic determinants of left ventricular (LV) mass using values for absolute electrocardiographic QRS voltage in a healthy Japanese population. After adjusting for covariates, the corrected S and R wave voltages in leads V1 and V5 from 2,994 healthy volunteers in the Japan Pharmacogenomics Data Science Consortium (JPDSC) database were subjected to a genome-wide association study. Potential associations were validated by an in silico replication study using an independent Japanese population obtained from the Nagahama Prospective Genome Cohort for Comprehensive Human Bioscience. We identified a novel association between the lead V5, R wave voltage in Japanese individuals and SNP rs7301743[G], which maps near the gene encoding T-box transcription factor Tbx3. Meta-analysis of two independent Japanese datasets demonstrated a marginally significant association of SNP rs7301743 in TBX3|MED13L with a 0.071 mV (95% CI, 0.038-0.11 mV) shorter R wave amplitude in the V5 lead per minor allele copy (P = 7.635 x 10(-8)). The transcriptional repressor, TBX3, is proposed to suppress the development of working ventricular myocardium. Our findings suggest that genetic variation of Tbx3 is associated with LV mass in a healthy Japanese population.
Assuntos
Estudo de Associação Genômica Ampla , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Proteínas com Domínio T/genética , Função Ventricular Esquerda , Adulto , Alelos , Bases de Dados Genéticas , Eletrocardiografia , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Japão , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Automatic measurement becomes a preference, and indeed a necessity, when analyzing 1000 s of ECGs in the setting of either drug-inducing QT prolongation screening or genome-wide association studies of QT interval. The problem is that individual manufacturers apply different computerized algorithms to measure QT interval. We conducted a comparative study to assess the outcomes with different automated measurements of QT interval between ECG machine manufacturers and validated the related heart rate correction methods. METHODS AND RESULTS: Herein, we directly compared these different commercial systems using 10,529 Fukuda Denshi ECGs and 72,754 Nihon Kohden ECGs taken in healthy Japanese volunteers. Log-transformed data revealed an equal optimal heart rate correction formula of QT interval for Fukuda Denshi and Nihon Kohden, in the form of QTcâ=âQT/RR(-0.347). However, with the raw data, the optimal heart rate correction formula of QT interval was in the form of QTcâ=âQT+0.156×(1-RR) for Fukuda Denshi and QTcâ=âQT+0.152×(1-RR) for Nihon Kohden. After optimization of heart rate correction of QT interval by the linear regression model using either log-transformed data or raw data, QTc interval was â¼10 ms longer in Nihon Kohden ECGs than in those recorded on Fukuda Denshi machines. Indeed, regression analysis revealed that differences in the ECG machine used had up to a two-fold larger impact on QT variation than gender difference. Such an impact is likely to be of considerable importance when ECGs for a given individual are recorded on different machines in the setting of multi-institutional joint research. CONCLUSIONS: We recommend that ECG machines of the same manufacturer should be used to measure QT and RR intervals in the setting of multi-institutional joint research. It is desirable to unify the computer algorithm for automatic QT and RR measurements from an ECG.
Assuntos
Eletrocardiografia/métodos , Adulto , Algoritmos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To analyze the possible beneficial effects of statins on the disease activity of patients with rheumatoid arthritis (RA) using a database from a large observational cohort study. METHODS: We studied a total of 7512 patients enrolled in a single-institute based prospective observational cohort of RA patients (IORRA); their information was collected biannually. In this study, cross-sectional data of 4152 patients (female 83.3%, average age 58.4 yrs) in October 2003 were analyzed (Mann-Whitney U-test). RESULTS: Among 4152 patients with RA, 279 (6.7%) were taking statins; patients taking statins had lower C-reactive protein (0.85 vs 1.24 mg/dl, respectively) and lower swollen joint counts (1.80 vs 2.55), but more frequently used corticosteroids (2.88 vs 2.40 mg/day) compared to patients not taking statins. Serum cholesterol level was closely related to the use of corticosteroids. Thus, an adjustment with the dose of corticosteroid was conducted; even taking account of the effects of steroids, RA disease activity indicated by patient's assessment for pain, physician's assessment, and swollen joint counts was significantly lower in patients with statins compared to those without. CONCLUSION: This study indicates that statins have beneficial effects in reducing RA disease activity in the daily practice of rheumatology.
Assuntos
Anticolesterolemiantes/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Articulações/efeitos dos fármacos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Proteína C-Reativa/análise , Colesterol/sangue , Estudos de Coortes , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Nível de Saúde , Humanos , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: For prevention of joint destruction in rheumatoid arthritis, optimal management of therapy with disease-modifying antirheumatic drugs is essential. Pharmacogenomic evidence, if reliable, may be incorporated in the treatment of rheumatoid arthritis to achieve a more efficient activity control with minimized adverse events. METHODS: We conducted retrospective studies to validate our previous three different results about the association between adverse events or efficacy of two different disease-modifying antirheumatic drugs and genomic variations. Association between single nucleotide polymorphisms in N-acetyltransferase 2 gene (NAT2) and adverse events by sulfasalazine and association between C677T or A1298C in 5,10-methylenetetrahydrofolate reductase gene (MTHFR) and responses to methotrexate were examined. RESULTS: Patients without the wild-type haplotype at NAT2 were more likely to suffer from overall adverse events [n=186, P=0.001, relative risk (RR) 3.31, 95% confidence interval (CI) 1.76-6.22] and severe adverse events (P=0.015, RR 24.6, 95% CI 2.37-254.53) by sulfasalazine. Patients with the T allele at C677T in MTHFR were more susceptible to overall adverse events (n=156, P=0.003; RR 2.4, 95% CI 1.29-4.55) while patients with the C allele at A1298C were less likely to be treated with a higher dose (>6 mg/week) of methotrexate in one year of treatment (n=159, P=0.008, RR 1.84, 95% CI 1.12-3.01). In all three association studies, the results were essentially the same as previously reported. CONCLUSION: As three studies on the associations between genomic variations and adverse events or efficacy of two different disease-modifying antirheumatic drugs were replicated, the usefulness of the tests is worth being tested in clinical practice.
Assuntos
Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Artrite Reumatoide/enzimologia , Arilamina N-Acetiltransferase/genética , Feminino , Haplótipos , Humanos , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Farmacogenética , Estudos Prospectivos , Estudos Retrospectivos , Sulfassalazina/efeitos adversos , Sulfassalazina/uso terapêuticoRESUMO
We evaluated the effects of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) on endoscopic and histological findings in patients with rheumatoid arthritis (RA) before and after the eradication of Helicobacter pylori infection. Helicobacter pylori (H. pylori) eradication using lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 mg twice daily for 1 week was conducted in 44 patients (mean age: 56.5 years) with RA. Using the updated Sydney system, endoscopic and histological findings of the greater curvature of the antrum, the greater curvature of the upper corpus, and the lesser curvature of the lower corpus were compared before and after eradication, for a mean follow-up period of 3.5 months. Overall, H. pylori eradication was successful in 32 patients (72.7%). Of these 32 patients, 23 were NSAID users. In the successful eradication group, (1) there was no significant change on endoscopic findings, including gastric erythema and erosion in all three regions irrespective of NSAIDs use; (2) of 17 active ulcers before eradication in NSAIDs users, all healed except for one duodenal ulcer that persisted, where one patient newly developed a gastric ulcer, one developed erosive duodenitis, and two developed reflux esophagitis, all in NSAID users; (3) neutrophil infiltration and chronic inflammation were significantly improved in all three regions after H. pylori eradication irrespective of use of NSAIDs, while atrophic change and intestinal metaplasia did not change. In the eradication failure group; (1) there was no significant change on endoscopic and histological findings in the three regions; (2) two of three ulcers present before eradication on NSAID users persisted even after eradication, and no new cases of gastric ulcer or erosive duodenitis occurred. In conclusion, over a mean follow-up period of 3.5 months, use of NSAIDs in Japanese patients with RA did not impair the healing process of gastric and duodenal ulcers nor did it affect the endoscopic and histological improvements associated with H. pylori eradication.