RESUMEN
CONTEXT: Dehydroepiandrosterone sulfate (DHEA-S), a major circulating sex steroid prohormone, declines with age. Low levels have been associated with increased cardiovascular disease (CVD) risk and all-cause mortality, although these results have not been consistently replicated, particularly in women. OBJECTIVE: Our objective was to examine the association of circulating DHEA-S levels, CVD, and mortality risk among postmenopausal women with suspected myocardial ischemia. DESIGN: In the Women's Ischemia Syndrome Evaluation, 270 postmenopausal women underwent coronary angiography and blood hormone levels for suspected ischemia and were followed annually. The primary outcome of interest was CVD mortality; secondary analyses included all-cause mortality and nonfatal CVD events (myocardial infarction, stroke, and congestive heart failure) and angiographic obstructive coronary artery disease (CAD). RESULTS: Women in the lowest DHEA-S tertile had higher CVD mortality (17% 6-yr mortality rate vs. 8%; log-rank P = 0.011), and all-cause mortality (21 vs. 10%; P = 0.011) compared with women with higher DHEA-S levels. The increased CVD mortality risk [hazard ratio (HR) = 2.55; 95% confidence interval (CI) = 1.19-5.45] remained unchanged after adjustment for multiple CVD risk factors (HR = 2.43; 95% CI = 1.06-5.56) but became nonsignificant when further adjusting for the presence or severity of angiographic obstructive CAD (HR = 1.99; 95% CI = 0.87-4.59). Results were similar for all-cause mortality. Lower DHEA-S levels were only marginally but not independently associated with obstructive CAD. CONCLUSIONS: Among postmenopausal women with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia, lower DHEA-S levels were linked with higher CVD mortality and all-cause mortality. Our study provides valuable feasibility data useful for future investigations and possible mechanistic pathways.
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Enfermedades Cardiovasculares/mortalidad , Sulfato de Deshidroepiandrosterona/sangre , Posmenopausia/sangre , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico por imagen , Causas de Muerte , Angiografía Coronaria , Femenino , Humanos , Inmunoensayo , Persona de Mediana Edad , Factores de Riesgo , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Studies indicate that estrogen receptor beta, encoded by the ESR2 gene on chromosome 14q, may play a role in ovarian carcinogenesis. Using the genetic structure data generated by the Breast and Prostate Cohort Consortium (BPC3), we have comprehensively characterized the role of haplotype diversity in ESR2 and risk of ovarian cancer. Five haplotypes with a frequency of > or =5% were observed in White subjects and five haplotype tagging SNPs (htSNP) were selected to capture the locus diversity with a minimum R(h)(2) of 0.81. The htSNPs were genotyped in 574 White controls, 417 White invasive ovarian cancer cases, and 123 White borderline ovarian cancer cases from case-control studies carried out in Los Angeles County from 1994 through 2004. No statistically significant association was observed between the five htSNPs and related haplotypes and risk of ovarian cancer overall. Haplotype D was associated with a nonstatistically significant increased risk of invasive ovarian cancer overall (odds ratio, 1.38; 95% confidence interval, 0.93-2.02; P = 0.11) relative to the most common haplotype and a statistically significant increased risk of invasive clear cell ovarian cancer (odds ratio, 3.88; 95% confidence interval, 1.28-11.73; P = 0.016). Haplotype D was also reported by the BPC3 to be associated with increased risk of breast cancer. This haplotype warrants further investigation to rule out any effect with invasive ovarian cancer risk.
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Receptor beta de Estrógeno/genética , Variación Genética , Haplotipos , Neoplasias Ováricas/genética , Adulto , Anciano , Cromosomas Humanos Par 14 , Femenino , Genotipo , Humanos , Modelos Logísticos , Los Angeles , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Riesgo , Población Blanca/estadística & datos numéricosRESUMEN
Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen receptors are the first step along the path of signaling cell growth and development upon stimulation with estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the estrogen receptor beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Receptor beta de Estrógeno/biosíntesis , Receptor beta de Estrógeno/genética , Regulación Neoplásica de la Expresión Génica , Haplotipos , Polimorfismo Genético , Adulto , Alelos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etnología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Análisis de Regresión , Riesgo , Población BlancaRESUMEN
BACKGROUND: Estrogen receptor beta (ESR2) may play a role in modulating prostate carcinogenesis through the regulation of genes related to cell proliferation and apoptosis. METHODS: We conducted nested case-control studies in the Breast and Prostate Cancer Cohort Consortium (BPC3) that pooled 8,323 prostate cancer cases and 9,412 controls from seven cohorts. Whites were the predominant ethnic group. We characterized genetic variation in ESR2 by resequencing exons in 190 breast and prostate cancer cases and genotyping a dense set of single nucleotide polymorphisms (SNP) spanning the locus in a multiethnic panel of 349 cancer-free subjects. We selected four haplotype-tagging SNPs (htSNP) to capture common ESR2 variation in Whites; these htSNPs were then genotyped in all cohorts. Conditional logistic regression models were used to assess the association between sequence variants of ESR2 and the risk of prostate cancer. We also investigated the effect modification by age, body mass index, and family history, as well as the association between sequence variants of ESR2 and advanced-stage (>or=T3b, N1, or M1) and high-grade (Gleason sum >or=8) prostate cancer, respectively. RESULTS: The four tag SNPs in ESR2 were not significantly associated with prostate cancer risk, individually. The global test for the influence of any haplotype on the risk of prostate cancer was not significant (P = 0.31). However, we observed that men carrying two copies of one of the variant haplotypes (TACC) had a 1.46-fold increased risk of prostate cancer (99% confidence interval, 1.06-2.01) compared with men carrying zero copies of this variant haplotype. No SNPs or haplotypes were associated with advanced stage or high grade of prostate cancer. CONCLUSION: In our analysis focused on genetic variation common in Whites, we observed little evidence for any substantial association of inherited variation in ESR2 with risk of prostate cancer. A nominally significant (P < 0.01) association between the TACC haplotype and prostate cancer risk under the recessive model could be a chance finding and, in any event, would seem to contribute only slightly to the overall burden of prostate cancer.
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Neoplasias de la Mama/genética , Receptor beta de Estrógeno/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Neoplasias de la Próstata/genética , Análisis de Secuencia de ADN/métodos , Anciano , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Estudios de Cohortes , Exones/genética , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Neoplasias de la Próstata/patología , Medición de RiesgoRESUMEN
BACKGROUND: Growing evidence from animal studies suggests an interaction between antioxidants and apolipoprotein E (APOE) alleles on cognitive functioning. We used data from a 7-year cohort study of high-functioning older persons to explore whether the associations between serum beta-carotene level and subsequent decline of cognitive function differed by APOE 4 genotype. METHODS: Baseline information on sociodemographic characteristics, serum beta-carotene level, inflammation markers, APOE genotype, and cognitive functioning measured by a 9-item Short Portable Mental Status Questionnaire (SPMSQ) was obtained in 455 survivors. Multivariable logistic regression analyses were used to examine the relation between high serum beta-carotene level and risk of SPMSQ score decline in participants with or without APOE 4 alleles, while adjusting for age, sex, race, baseline SPMSQ score, and other covariates. RESULTS: Nine (2%) study participants had homozygous and 97 (21%) had heterozygous APOE 4 alleles. Two hundred forty-nine (55%) had decline of SPMSQ scores during the follow-up. The presence of an APOE 4 allele was associated with higher risk and larger magnitude of SPMSQ score decline. The adjusted odds ratio of high beta-carotene level for cognitive decline was 0.11 (95% confidence interval, 0.02-0.57) in participants with at least one APOE 4 allele and 0.89 (95% confidence interval, 0.54-1.47) among those who were APOE 4 negative. CONCLUSION: Among high-functioning older persons, antioxidants and beta-carotene in particular may offer protection from cognitive decline in persons with greater genetic susceptibility as evidenced by the presence of the APOE 4 allele.
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Actividades Cotidianas , Envejecimiento/fisiología , Apolipoproteínas E/genética , Trastornos del Conocimiento/sangre , beta Caroteno/sangre , Anciano , Alelos , Apolipoproteína E4 , Apolipoproteínas E/sangre , Biomarcadores/sangre , Trastornos del Conocimiento/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Longitudinal data from the MacArthur Study of Successful Aging were used to test for interactions between education and apolipoprotein E (APOE) genotype with respect to time trends in cognitive performance. Interactions between education, APOE-e4 status, and time were found for overall cognitive function, and for subscales measuring memory and naming: The presence of the e4 allele was associated with steeper declines in cognition for those with a greater than eighth-grade education. For those with an eighth-grade education or less, time trends did not differ by APOE genotype. A measure of cognitive impairment (i.e., scores of < or = 7 on the Short Portable Mental Status Questionnaire) yielded parallel though weaker evidence for a similar interaction with respect to risk of cognitive impairment. These findings suggest that the presence of at least one e4 allele appears to reduce the protective effects of education for those with at least a ninth-grade education or more, resulting in steeper cognitive declines with age.
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Envejecimiento/genética , Envejecimiento/psicología , Apolipoproteínas/genética , Trastornos del Conocimiento/psicología , Anciano , Alelos , Escolaridad , Femenino , Genotipo , Humanos , Estudios Longitudinales , Masculino , Salud MentalRESUMEN
The A-240T and I/D polymorphisms in the angiotensin I-converting enzyme (ACE) gene are markers of circulating ACE levels and have been associated with numerous cardiovascular disease outcomes. More recently, the low-activity A and I alleles at these polymorphic sites have been inversely related with breast cancer risk. We assessed the relationship between the A-240T and I/D ACE variants and breast cancer risk in a case-control analysis (n = 1263 cases with invasive breast cancer and 2269 controls) among African-American, Japanese, Latina, and white women in the Multiethnic Cohort Study. Odds ratios and 95% confidence intervals are presented adjusted for established breast cancer risk factors. Among all women combined, we observed no significant association between the A-240T polymorphism and breast cancer risk. For the I/D polymorphism, contrary to expectation, women with the I/I genotype had a marginally significant increase in breast cancer risk (versus DD genotype: odds ratio, 1.30; 95% confidence interval, 1.05-1.61), although associations were not entirely consistent across ethnic groups. These data do not support the hypothesis that women with lower ACE levels, as predicted by the low-activity A and I ACE alleles, are at reduced risk of breast cancer. Overall, these results suggest that the A-240T and I/D ACE polymorphisms are not likely to be strong predictors of breast cancer risk.
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Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Peptidil-Dipeptidasa A/genética , Estudios de Casos y Controles , Estudios de Cohortes , Etnicidad , Femenino , Humanos , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
Deficiencies in tasks of detecting and repairing DNA damage lead to mutations and chromosomal abnormalities, a hallmark of cancer. The gene mutated in ataxia-telangiectasia (A-T), ATM, is a proximal component in performing such tasks. Studies of A-T families have suggested an increased risk of breast cancer among obligate female heterozygous carriers of ATM mutations. Paradoxically, studies of sporadic and familial breast cancer have failed to demonstrate an elevated prevalence of mutations among breast cancer cases. We characterized the prevalence and distribution of 20 ATM missense mutations/polymorphisms in a population-based case-control study of 854 African-American, Latina, Japanese, and Caucasian women aged >/==" BORDER="0">45 years participating in the Multiethnic Cohort Study. The study population included 428 incident breast cancer cases and 426 controls. The prevalence of variants ranged from 0% to 13.6% among controls and varied by ethnicity (0-32.5%). Overall, these data provide little support for an association of ATM missense mutations with breast cancer among older women. We observed only one sequence variation (L546V), common among African-American women, to be overrepresented among all high-stage breast cancer cases (odds ratio, 3.35; 95% confidence interval, 1.27-8.84). After correction for multiple comparisons, this observed risk modification did not attain statistical significance. The distribution of ATM missense mutations and polymorphisms varied widely across the four ethnic groups studied. Although a single missense variant (L546V) appeared to act as a modest predictor of risk, the remaining variants were no more common in breast cancer cases as compared with controls.
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Neoplasias de la Mama/genética , Etnicidad , Mutación Missense/genética , Proteínas Serina-Treonina Quinasas/genética , Negro o Afroamericano/genética , Anciano , Asiático/genética , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular , Estudios de Cohortes , Proteínas de Unión al ADN , Femenino , Variación Genética , Hispánicos o Latinos/genética , Humanos , Japón , Persona de Mediana Edad , Polimorfismo Genético , Proteínas Supresoras de Tumor , Población Blanca/genéticaRESUMEN
In 1997, national recommendations for the treatment of hypertension were made in the form of the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). African American hypertensives are considered a special population with a higher prevalence of hypertension, and therefore, unique treatment needs. The study objective was to review medication use among an African American and Latino urban population in relation to the JNC recommendations. The study population was drawn from a preexisting cohort of African Americans and Latinos. Records were reviewed for self-description of hypertension and the use of any antihypertensive medication in individuals less than 60 years of age. A small subgroup of individuals was separately reviewed for specific medications used to treat hypertension. There were 34,118 individuals in the cohort greater than 45 years of age and less than 60 years of age that qualified for review; 40% were African American and 60% were Latino. Of the 13,593 African Americans, 6387 (47%) were hypertensive. Of the 20,525 Latinos, 29% were hypertensive. Only 56% of all hypertensives were on some blood pressure medication (61% of the African Americans and 48% of the Latinos). Within the subgroup of 550 individuals with detailed medication information (223 African Americans and 327 Latinos), calcium channel blockers and diuretics were the most frequently used medication among the African Americans and angiotensin-converting enzyme inhibitors were the most frequently used medication among the Latinos. Beta blockers were used only 13% of the time. The authors concluded that in this cohort of hypertensive urban Latinos and African Americans, more than 40% of individuals were not being treated for hypertension and, despite the guidelines suggested in JNC VI, few individuals were being treated for their hypertension with diuretic monotherapy or beta blockers as first-choice drugs. Instead there was extensive use of calcium channel blockers and angiotensin-converting enzyme inhibitors.
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Negro o Afroamericano , Adhesión a Directriz , Hispánicos o Latinos , Hipertensión/tratamiento farmacológico , Pautas de la Práctica en Medicina , Comorbilidad , Femenino , Humanos , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Población UrbanaRESUMEN
OBJECTIVE: To determine whether manually measured QT dispersion (QTD) may be a useful diagnostic adjunct for acute myocardial infarction (AMI) in emergency department patients with chest pain (CP) and nondiagnostic initial electrocardiograms (ECGs). METHODS: This was a retrospective review of a cohort of patients admitted to the coronary triage unit (CTU) at a large urban facility over a two-year period (1997-1999). Cases included all patients with nondiagnostic initial ECGs diagnosed as having AMI by enzymatic criteria. Controls consisted of patients admitted to the CTU who received a final diagnosis of "musculoskeletal pain" at discharge. The QT intervals were measured on the ECGs obtained on presentation. The ECGs were included only if the QT interval could be measured on at least eight out of 12 leads. The QTD was calculated as the difference between the longest and shortest QT intervals in all measured leads. All measurements and calculations were done by a single individual. The QTDs were compared for cases versus controls using 50 msec as a cutoff for the presence of AMI. RESULTS: The study cohort consisted of 36 cases and 124 controls. The QTDs between the two groups were markedly different, with the mean for the cases at 85.5 msec [range: 40 to 200; +/-standard deviation (SD) = 39.6] and for the controls 47.1 msec (range: 0 to 120; +/-SD = 20.4). The unadjusted odds ratio (OR) of having a QTD greater than 50 msec in the setting of AMI and a nondiagnostic initial ECG in this cohort was 11.9 [95% confidence interval (95% CI) = 5.0 to 28.4; p < 0.0001] and was 12.5 (95% CI = 4.8 to 32.3; p < 0.0001) adjusted for age, gender, and ethnicity. CONCLUSIONS: Manually measured QTD is significantly greater in patients with AMI and nondiagnostic ECGs versus healthy controls with musculoskeletal CP. Along with other data, QTD may serve as a useful diagnostic and decision-making tool in patients with acute CP and nondiagnostic ECGs.
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Electrocardiografía , Infarto del Miocardio/diagnóstico , Adulto , Estudios de Casos y Controles , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Delay in seeking care for acute myocardial infarction (AMI) has been well described in some populations, but little research has been conducted on delay by minority groups, such as Latinos and Asians. This study sought to determine the degree of delay and mode of access of patients with AMI presenting to an inner-city hospital serving an ethnically diverse population. METHODS AND RESULTS: This study was a retrospective case series of Latino, Asian, African-American and Caucasian patients diagnosed in the emergency department (ED) with chest pain (CP) and AMI, during a 2-year period. Three hundred thirty seven cases were studied, with the average delay in presentation for care being 44.3 hours, with a median of 8.8 hours. Before seeking care for symptoms of AMI, Latinos delayed an average of 41.5 hours (median 9.2 hours); African Americans delayed an average of 30.8 hours (median 3.5 hours); Asians delayed an average of 92 hours (median 12 hours); and Caucasians delayed an average of 31.6 hours (median 3.2 hours). The mode of transportation used by the different groups to travel to the ED was also significantly different, with Latinos and Asians utilizing private transportation the majority of the time (70% and 83%, respectively). CONCLUSION: There is a significant delay in presentation for care in patients experiencing AMI in Los Angeles County, greatest among the Asian and Latino populations. Once the decision to seek assistance is made, an under-utilization of EMS compounds the problem. Socioeconomic status, language, and cultural practices pose unique barriers to recognizing and addressing symptoms of AMI in this population.