RESUMEN
BACKGROUND: To implement personalized medicine, we established a large-scale patient cohort, BioBank Japan, in 2003. BioBank Japan contains DNA, serum, and clinical information derived from approximately 200,000 patients with 47 diseases. Serum and clinical information were collected annually until 2012. METHODS: We analyzed clinical information of participants at enrollment, including age, sex, body mass index, hypertension, and smoking and drinking status, across 47 diseases, and compared the results with the Japanese database on Patient Survey and National Health and Nutrition Survey. We conducted multivariate logistic regression analysis, adjusting for sex and age, to assess the association between family history and disease development. RESULTS: Distribution of age at enrollment reflected the typical age of disease onset. Analysis of the clinical information revealed strong associations between smoking and chronic obstructive pulmonary disease, drinking and esophageal cancer, high body mass index and metabolic disease, and hypertension and cardiovascular disease. Logistic regression analysis showed that individuals with a family history of keloid exhibited a higher odds ratio than those without a family history, highlighting the strong impact of host genetic factor(s) on disease onset. CONCLUSIONS: Cross-sectional analysis of the clinical information of participants at enrollment revealed characteristics of the present cohort. Analysis of family history revealed the impact of host genetic factors on each disease. BioBank Japan, by publicly distributing DNA, serum, and clinical information, could be a fundamental infrastructure for the implementation of personalized medicine.
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Bancos de Muestras Biológicas , Bases de Datos Genéticas , Enfermedad/genética , Anciano , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Japón , Masculino , Anamnesis , Persona de Mediana Edad , Medicina de PrecisiónRESUMEN
BACKGROUND: We established a patient-oriented biobank, BioBank Japan, with information on approximately 200,000 patients, suffering from any of 47 common diseases. This follow-up survey focused on 32 diseases, potentially associated with poor vital prognosis, and collected patient survival information, including cause of death. We performed a survival analysis for all subjects to get an overview of BioBank Japan follow-up data. METHODS: A total of 141,612 participants were included. The survival data were last updated in 2014. Kaplan-Meier survival analysis was performed after categorizing subjects according to sex, age group, and disease status. Relative survival rates were estimated using a survival-rate table of the Japanese general population. RESULTS: Of 141,612 subjects (56.48% male) with 1,087,434 person-years and a 97.0% follow-up rate, 35,482 patients died during follow-up. Mean age at enrollment was 64.24 years for male subjects and 63.98 years for female subjects. The 5-year and 10-year relative survival rates for all subjects were 0.944 and 0.911, respectively, with a median follow-up duration of 8.40 years. Patients with pancreatic cancer had the least favorable prognosis (10-year relative survival: 0.184) and patients with dyslipidemia had the most favorable prognosis (1.013). The most common cause of death was malignant neoplasms. A number of subjects died from diseases other than their registered disease(s). CONCLUSIONS: This is the first report to perform follow-up survival analysis across various common diseases. Further studies should use detailed clinical and genomic information to identify predictors of mortality in patients with common diseases, contributing to the implementation of personalized medicine.
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Bancos de Muestras Biológicas , Enfermedad , Causas de Muerte , Estudios de Seguimiento , Encuestas Epidemiológicas , Humanos , Japón/epidemiología , Análisis de SupervivenciaRESUMEN
BACKGROUND: The BioBank Japan (BBJ) Project was launched in 2003 with the aim of providing evidence for the implementation of personalized medicine by constructing a large, patient-based biobank (BBJ). This report describes the study design and profile of BBJ participants who were registered during the first 5-year period of the project. METHODS: The BBJ is a registry of patients diagnosed with any of 47 target common diseases. Patients were enrolled at 12 cooperative medical institutes all over Japan from June 2003 to March 2008. Clinical information was collected annually via interviews and medical record reviews until 2013. We collected DNA from all participants at baseline and collected annual serum samples until 2013. In addition, we followed patients who reported a history of 32 of the 47 target diseases to collect survival data, including cause of death. RESULTS: During the 5-year period, 200,000 participants were registered in the study. The total number of cases was 291,274 at baseline. Baseline data for 199,982 participants (53.1% male) were available for analysis. The average age at entry was 62.7 years for men and 61.5 years for women. Follow-up surveys were performed for participants with any of 32 diseases, and survival time data for 141,612 participants were available for analysis. CONCLUSIONS: The BBJ Project has constructed the infrastructure for genomic research for various common diseases. This clinical information, coupled with genomic data, will provide important clues for the implementation of personalized medicine.
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Bancos de Muestras Biológicas , Sistema de Registros , Femenino , Investigación Genética , Humanos , Japón , Masculino , Persona de Mediana Edad , Medicina de Precisión , Proyectos de InvestigaciónRESUMEN
Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 x 10(-7), crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCeta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.
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Infarto Cerebral/genética , Polimorfismo de Nucleótido Simple , Proteína Quinasa C/genética , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/genética , Estudios de Seguimiento , HumanosRESUMEN
Histone modification is a crucial step in transcriptional regulation, and deregulation of the modification process is important in human carcinogenesis. We previously reported that upregulation of SMYD3, a histone methyltransferase, promoted cell growth in human colorectal and hepatocellular carcinomas. Here we report significant associations between homozygosity with respect to an allele with three tandem repeats of a CCGCC unit in the regulatory region of SMYD3 and increased risk of colorectal cancer (P = 9.1 x 10(-6), odds ratio = 2.58), hepatocellular carcinoma (P = 2.3 x 10(-8), odds ratio = 3.50) and breast cancer (P = 7.0 x 10(-10), odds ratio = 4.48). This tandem-repeat sequence is a binding site for the transcriptional factor E2F-1. In a reporter assay, plasmids containing three repeats of the binding motif (corresponding to the high-risk allele) had higher activity than plasmids containing two repeats (the low-risk allele). These data suggest that the common variable number of tandem repeats polymorphism in SMYD3 is a susceptibility factor for some types of human cancer.
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Factor de Transcripción E2F1/metabolismo , Predisposición Genética a la Enfermedad , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias/genética , Polimorfismo Genético , Secuencias Repetidas en Tándem/genética , Región de Flanqueo 5'/genética , Alelos , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Factores de Riesgo , Células Tumorales CultivadasRESUMEN
Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here we identify a SNP in the promoter region of FCRL3, a member of the Fc receptor-like family, that is associated with susceptibility to rheumatoid arthritis (odds ratio = 2.15, P = 0.00000085). This polymorphism alters the binding affinity of nuclear factor-kappaB and regulates FCRL3 expression. We observed high FCRL3 expression on B cells and augmented autoantibody production in individuals with the disease-susceptible genotype. We also found associations between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FCRL3 may therefore have a pivotal role in autoimmunity.
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Artritis Reumatoide/genética , Autoinmunidad/genética , Receptores Inmunológicos/genética , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Autoinmunidad/inmunología , Autoinmunidad/fisiología , Estudios de Casos y Controles , Cromosomas Humanos Par 1 , Regulación de la Expresión Génica/fisiología , Antígenos HLA-DR/genética , Antígenos HLA-DR/inmunología , Cadenas HLA-DRB1 , Humanos , Desequilibrio de Ligamiento , Datos de Secuencia Molecular , Familia de Multigenes , Mutación , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos/metabolismoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes, we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P= 9.3 × 10(-10), odds ratio = 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-ß (TGF-ß) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-ß signaling and that decreased ZNF512B expression increases susceptibility to ALS.
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Esclerosis Amiotrófica Lateral/genética , Pueblo Asiatico/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Predisposición Genética a la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/metabolismo , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Transducción de Señal , Médula Espinal/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Adulto JovenRESUMEN
Tamsulosin hydrochloride is one of the most potent drugs for treatment of benign prostatic hyperplasia (BPH), however, the efficacy of tamsulosin hydrochloride varies among individuals. In this study, we measured the maximum serum concentration (Cmax) of tamsulosin hydrochloride in 182 of BPH patients and found remarkable individual variability. To investigate the genetic factors that regulate pharmacokinetics of tamsulosin hydrochloride, we conducted a genome-wide association study in these 182 BPH patients. As a result, rs16902947 on chromosome 5p13.2, rs7779057 on 7q22.3, rs35681285 on 7p21.2 and rs2122469 on 8p21.3 indicated possible associations with Cmax of tamsulosin hydrochloride (P=1.29 × 10(-7), 2.15 × 10(-7), 4.35 × 10(-7) and 7.03 × 10(-7), respectively), although these single-nucleotide polymorphisms (SNPs) did not reach the genome-wide significance threshold after Bonferroni correction. As these associated SNPs showed additive effects on serum tamsulosin hydrochloride concentration, we defined the 'Cmax prediction index' based on genotypes of these SNPs. This index clearly associated with Cmax values (P=4.5 × 10(-6)), indicating the possible roles of these four variants in tamsulosin hydrochloride pharmacokinetics. Our findings would partially explain the variability of the response to the tamsulosin hydrochloride treatment.
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Antagonistas de Receptores Adrenérgicos alfa 1/farmacocinética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/genética , Sulfonamidas/farmacocinética , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 8/genética , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , TamsulosinaRESUMEN
By means of a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers, we identified a candidate locus on chromosome 6p21 associated with susceptibility to myocardial infarction. Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-alpha), NFKBIL1 (encoding nuclear factor of kappa light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1). Homozygosity with respect to each of the two SNPs in LTA was significantly associated with increased risk for myocardial infarction (odds ratio = 1.78, chi(2) = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls). In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery. Moreover, the SNP, in intron 1 of LTA, enhanced the transcriptional level of LTA. These results indicate that variants in the LTA are risk factors for myocardial infraction and implicate LTA in the pathogenesis of the disorder.
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Predisposición Genética a la Enfermedad , Linfotoxina-alfa/genética , Infarto del Miocardio/genética , Polimorfismo de Nucleótido Simple , Anciano , Sustitución de Aminoácidos , Estudios de Casos y Controles , Células Cultivadas , Mapeo Cromosómico , Cromosomas Humanos Par 6 , Vasos Coronarios/metabolismo , Bases de Datos Genéticas , Frecuencia de los Genes , Pruebas Genéticas , Genotipo , Haplotipos , Homocigoto , Humanos , Intrones , Células Jurkat , Desequilibrio de Ligamiento , Persona de Mediana Edad , Músculo Liso Vascular/citología , Músculo Liso Vascular/fisiología , Proteínas Recombinantes de Fusión/metabolismo , Análisis de Secuencia de ADN , Transcripción Genética , Molécula 1 de Adhesión Celular Vascular/biosíntesisRESUMEN
Myocardial infarction (MI) has become one of the leading causes of death in the world. Its pathogenesis includes chronic formation of plaque inside the vessel wall of the coronary artery and acute rupture of the artery, implicating a number of inflammation-mediating molecules, such as the cytokine lymphotoxin-alpha (LTA). Functional variations in LTA are associated with susceptibility to MI. Here we show that LTA protein binds to galectin-2, a member of the galactose-binding lectin family. Our case-control association study in a Japanese population showed that a single nucleotide polymorphism in LGALS2 encoding galectin-2 is significantly associated with susceptibility to MI. This genetic substitution affects the transcriptional level of galectin-2 in vitro, potentially leading to altered secretion of LTA, which would then affect the degree of inflammation; however, its relevance to other populations remains to be clarified. Smooth muscle cells and macrophages in the human atherosclerotic lesions expressed both galectin-2 and LTA. Our findings thus suggest a link between the LTA cascade and the pathogenesis of MI.
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Galectina 2/genética , Galectina 2/metabolismo , Predisposición Genética a la Enfermedad/genética , Linfotoxina-alfa/metabolismo , Infarto del Miocardio/genética , Estudios de Casos y Controles , Regulación de la Expresión Génica , Humanos , Inflamación/genética , Intrones/genética , Japón , Células Jurkat , Microtúbulos/metabolismo , Polimorfismo de Nucleótido Simple/genética , Unión Proteica , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Tubulina (Proteína)/metabolismo , Técnicas del Sistema de Dos HíbridosRESUMEN
We report the development of a real-time Invader assay combined with multiplex PCR (mPCR-RETINA), an SNP-based approach that can measure the allelic ratio in copy number variation (CNV) regions of a genome. RETINA monitors the real-time fluorescence intensity of each allele during the Invader assay and detects allelic asymmetries caused by genomic duplication/multiplication in heterozygous individuals. By combining mPCR-RETINA and real-time quantitative PCR that detects total copy number, we can estimate the copy number of each allele in CNV regions, which should be useful for investigating the functional significance of allele copy number with disease susceptibilities and drug responses. Also, mPCR-RETINA can efficiently refine the detailed structures of CNV regions. Due to the combination of RETINA with multiplex PCR, mPCR-RETINA requires a very small amount of genomic DNA for analysis (0.1-0.38 ng/locus). Additionally, mPCR-RETINA has clear advantages in its simple protocol and target-specific reaction, even in nonunique regions. We believe mPCR-RETINA will provide a significant contribution to identifying functional alleles in CNV regions.
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Alelos , Dosificación de Gen , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Nucleótido Simple , Duplicación de Gen , Variación Genética , Genoma Humano , Humanos , Modelos Biológicos , Modelos Genéticos , Población BlancaRESUMEN
MOTIVATION: The Invader assay is a fluorescence-based high-throughput genotyping technology. If the output data from the Invader assay were classified automatically, then genotypes for individuals would be determined efficiently. However, existing classification methods do not necessarily yield results with the same accuracy as can be achieved by technicians. Our clustering algorithm, Genocluster, is intended to increase the proportion of data points that need not be manually corrected by technicians. RESULTS: Genocluster worked well even when the number of clusters was unknown in advance and when there were only a few points in a cluster. The use of Genocluster enabled us to achieve an acceptance rate (proportion of assay results that did not need to be corrected by expert technicians) of 84.4% and a proportion of uncorrected points of 95.8%, as determined using the data from over 31 million points. AVAILABILITY: Information for obtaining the executable code, example data and example analysis are available at http://www.genstat.net/genocluster.
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Mapeo Cromosómico/métodos , Análisis por Conglomerados , Análisis Mutacional de ADN/métodos , Hibridación Fluorescente in Situ/métodos , Reconocimiento de Normas Patrones Automatizadas/métodos , Polimorfismo de Nucleótido Simple/genética , Espectrometría de Fluorescencia/métodos , Algoritmos , Inteligencia Artificial , Bases de Datos Genéticas , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: The strong linkage disequilibrium (LD) recently found in genic or exonic regions of the human genome demonstrated that LD can be increased by evolutionary mechanisms that select for functionally important loci. This suggests that LD might be stronger in regions conserved among species than in non-conserved regions, since regions exposed to natural selection tend to be conserved. To assess this hypothesis, we used genome-wide polymorphism data from the HapMap project and investigated LD within DNA sequences conserved between the human and mouse genomes. RESULTS: Unexpectedly, we observed that LD was significantly weaker in conserved regions than in non-conserved regions. To investigate why, we examined sequence features that may distort the relationship between LD and conserved regions. We found that interspersed repeats, and not other sequence features, were associated with the weak LD tendency in conserved regions. To appropriately understand the relationship between LD and conserved regions, we removed the effect of repetitive elements and found that the high degree of sequence conservation was strongly associated with strong LD in coding regions but not with that in non-coding regions. CONCLUSION: Our work demonstrates that the degree of sequence conservation does not simply increase LD as predicted by the hypothesis. Rather, it implies that purifying selection changes the polymorphic patterns of coding sequences but has little influence on the patterns of functional units such as regulatory elements present in non-coding regions, since the former are generally restricted by the constraint of maintaining a functional protein product across multiple exons while the latter may exist more as individually isolated units.
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Evolución Biológica , Genoma Humano , Desequilibrio de Ligamiento , Humanos , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
Although previous epidemiologic studies have suggested an association between the onset of myocardial infarction (MI) and some genetic variations, the impact of these variants on recurrent cardiovascular events after MI has not been fully elucidated. We genotyped 87 polymorphisms of 73 atherosclerosis-related genes in consecutive acute MI patients registered in the Osaka Acute Coronary Insufficiency Study and compared the incidence of death and major adverse cardiac events (MACE) among the polymorphisms of each gene. After initial screening in 507 patients, we selected nine polymorphisms for screening in all 1586 patients. Multivariate Cox regression analysis revealed that G allele carriers at the position 252 of the lymphotoxin alpha (LTA) gene were independently associated with an increased risk of death (hazard ratio [HR]: 2.46; 95% CI: 1.24-4.86). In conclusion, a 252G allele of LTA is associated with an increased risk of death after AMI and may be a useful genetic predictor.
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Aterosclerosis/genética , Infarto del Miocardio/genética , Polimorfismo Genético , Aterosclerosis/complicaciones , Femenino , Humanos , Linfotoxina-alfa/genética , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/mortalidad , Pronóstico , Recurrencia , Tasa de SupervivenciaRESUMEN
BACKGROUND: Although not in itself strongly predictive of coronary heart disease, Chlamydia pneumoniae infection could interact with classic risk factors in determining risk of acute myocardial infarction (AMI). METHODS: We assessed C pneumoniae immunoglobulin (Ig) G and IgA titers and classic risk factors in 618 patients with AMI and in 967 controls. RESULTS: IgG titers were not related to AMI, but a significant association was seen between IgA titers and AMI. Excess risk of AMI was noted mainly among patients with the highest IgA titers, such as those beyond 2.88 (the 95th percentile cutoff point in control subjects), showing a 1.8-fold increase in risk (odds ratio 1.75, 95% CI 1.04-2.92). Classic risk factors did not differ between subjects with IgA titers above and below the 95th percentile cutoff. However, in multivariate analyses, models incorporating both IgA titers and a classic risk factor such as obesity, hypercholesterolemia, or smoking predicted risk more effectively than single-parameter models. For example, the odds ratio for AMI among subjects with the highest IgA titers plus hypercholesterolemia was greater than the product of individual risks associated with these high IgA titers and with hypercholesterolemia. CONCLUSIONS: Interactions with classic risk factors (ie, obesity, hypercholesterolemia, and smoking), increased the predictive value of C pneumoniae IgA antibody titers in determining risk of AMI.
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Infecciones por Chlamydia/complicaciones , Chlamydophila pneumoniae/inmunología , Infarto del Miocardio/etiología , Estudios de Casos y Controles , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Infarto del Miocardio/microbiología , Oportunidad Relativa , Valor Predictivo de las Pruebas , Factores de RiesgoRESUMEN
Atrial fibrillation (AF) is a frequent complication after acute myocardial infarction (AMI) that has been associated with increased in-hospital and long-term mortality rates in the prethrombolytic and thrombolytic eras. Current therapies, including percutaneous coronary intervention (PCI), are effective in reducing mortality in patients with AMI. However, little is known concerning the incidence and prognostic significance of AF in patients with AMI who are treated with PCI. We evaluated 2,475 consecutive patients with AMI who underwent PCI within 24 hours after onset and who were enrolled in the Osaka Acute Coronary Insufficiency Study. Patients were categorized into 2 groups according to the presence of AF or atrial flutter. The incidence of AF was 12.0%. Patients with AF were older, were in higher Killip classes, had higher rates of previous myocardial infarction and previous cerebrovascular disease, had systolic blood pressure of <100 mm Hg and heart rates of > or =100 beats/min, multivessel disease, and had poorer reperfusion of the infarct-related artery than those without AF. Patients with AF had higher in-hospital (16.0% vs 6.7%, p <0.001) and 1-year (18.9% vs 7.9%, p <0.001) mortality than those without AF. Multivariate Cox regression analysis revealed that AF was an independent predictor of 1-year mortality (hazard ratio 1.64, 95% confidence interval 1.05 to 2.55) but was not a predictor of in-hospital mortality. AF is a common complication in patients with AMI who are treated with PCI and independently influences 1-year mortality.
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Angioplastia Coronaria con Balón , Fibrilación Atrial/epidemiología , Aleteo Atrial/epidemiología , Mortalidad Hospitalaria , Infarto del Miocardio/mortalidad , Infarto del Miocardio/terapia , Anciano , Fibrilación Atrial/etiología , Aleteo Atrial/etiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Although the C-reactive protein (CRP) concentration measured shortly after acute myocardial infarction (AMI) is associated with infarct size, its prognostic value is controversial. The reduction of CRP is accelerated by reperfusion. Therefore, the CRP concentration, measured during the stable phase of AMI in patients treated predominantly with reperfusion therapies, may be independent of infarct size and may predict long-term mortality. We studied 1,309 patients with AMI enrolled in the Osaka Acute Coronary Insufficiency Study between April 1999 and June 2001. CRP was measured during the stable phase (mean 25 days after AMI onset). The patients were followed for an average of 522 days. Reperfusion therapies were performed in 90% of the patients. Patients in the highest quartile of CRP values (> or =0.38 mg/dl) were older, had higher prevalences of diabetes mellitus, and had higher Killip classes than patients in the lower 3 quartiles (<0.38 mg/dl). Multivariate logistic regression analysis revealed that CRP was independently associated with age and the absence of revascularization therapies. Patients in the highest quartile had a higher long-term mortality rate than patients in the lower 3 quartiles (8.9% vs 2.0%; p <0.001). Multivariate Cox regression analysis revealed that the highest quartile of CRP values was an independent predictor of long-term mortality (hazard ratio 4.94, 95% confidence interval 1.13 to 21.6). We conclude that CRP measured during the stable phase of AMI is not associated with infarct size in the reperfusion era but is significantly associated with long-term mortality of AMI.
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Proteína C-Reactiva/análisis , Infarto del Miocardio/mortalidad , Factores de Edad , Complicaciones de la Diabetes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Sensibilidad y EspecificidadRESUMEN
Leg venous pressure markedly falls during upright exercise via a muscle pump effect, creating de novo perfusion pressure. We examined physiological roles of this mechanism in increasing femoral artery blood flow (FABF) and its alterations in chronic heart failure (CHF). In 10 normal subjects and 10 patients with CHF, standard hemodynamic variables, mean ankle vein pressure (MAVP), and FABF with Doppler techniques were obtained during graded upright bicycle exercise. To evaluate a nonspecific blood flow response, normal subjects also performed supine exercise. In normal subjects, MAVP rapidly declined by 45 mmHg and FABF correspondingly increased 5.3-fold without a systemic pressor response during 10 s of light upright exercise at 5 W. Approximately 67% of the blood flow response was attributed to the venous pressure drop-dependent mechanism. In CHF patients, MAVP declined by only 36 mmHg and FABF increased only 1.7-fold during the same upright exercise. The muscle venous pump has an ability to increase FABF at least threefold via the venous pressure drop-dependent mechanism. This mechanism is impaired in CHF patients.
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Insuficiencia Cardíaca/fisiopatología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/fisiología , Anciano , Tobillo/irrigación sanguínea , Tobillo/fisiología , Arteria Femoral/fisiología , Humanos , Flujometría por Láser-Doppler , Masculino , Persona de Mediana Edad , Consumo de Oxígeno/fisiología , Esfuerzo Físico/fisiología , Flujo Sanguíneo Regional/fisiología , Venas/fisiologíaRESUMEN
SNPs are useful markers for identifying genes responsible for and/or associated with common diseases, and for directing personalized medical care. Furthermore, because they are so frequent in the genome and can be genotyped quite easily, SNPs can serve as markers for a whole genome association study. However, one of the most difficult issues to be solved for whole-genome association studies using SNPs is reduction of the amount of genomic DNA for genotyping. The presently available technologies require too much genomic DNA to be practical. To overcome this problem, we combined the Invader assay with multiplex PCR performed in the presence of Taq polymerase antibody as well as a novel 384-well card system that reduces the reaction volume. We amplified 96 genomic DNA fragments simultaneously in a single tube, and analyzed each SNP using the Invader assay. Since we used 10-20 nanograms of genomic DNA as a template for multiplex PCR, the amount needed to assay one SNP was only 0.1-0.2 nanograms. Our results strongly indicate the feasibility of undertaking genome-wide association studies using blood samples of only 5-10 milliliters. Using these technologies, which allow us to perform as many as 450,000 typings in one day, our system should let us identify the genes responsible for many diseases and/or pharmacological responsiveness.