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1.
Eur Urol ; 78(3): 316-320, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409115

RESUMO

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

3.
J Racial Ethn Health Disparities ; 6(1): 12-21, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29679333

RESUMO

PURPOSE: Independent and combined effects of air pollution and psychosocial stressors on hypertension, a risk factor for cardiovascular disease, among Hispanics are not well studied. METHODS: We administered a pilot-tested questionnaire on individual- and neighborhood-level psychosocial stressors, developed with community input, to nearly 2500 individuals from the MD Anderson Cancer Center cohort of Mexican-Americans. We used data from local air quality monitors to estimate individual exposures to ozone (O3) and fine particulate matter (PM2.5) for the 12-month period preceding enrollment using inverse distance interpolation. We applied logistic regression models to examine relationships between exposures to psychosocial stressors and air pollution with prevalent hypertension and used stratified analyses to examine the interacting effects of these two exposures on hypertension. RESULTS: There was a positive association between prevalent hypertension and a high frequency of feeling anxious or depressed (prevalence odds ratio (POR) = 1.36, 95% CI [1.06-1.75]) and experiencing aches and pains (POR = 1.29, 95% CI [1.01-1.64]). The odds of having hypertension were also elevated among those worrying about their own health (POR = 1.65, 95% CI [1.30-2.06]) or about not having enough money (POR = 1.27, 95% CI [1.01-1.6]). We observed an inverse association between O3 and hypertension. There was no interaction between psychosocial stressors and O3 on hypertension. CONCLUSION: Our findings add to the evidence of a positive association between individual and family stressors on hypertension among Hispanics and other racial/ethnic groups. Contrary to previous studies reporting positive associations, our results suggest that long-term exposure to O3 may be inversely related to prevalent hypertension.


Assuntos
Poluição do Ar/efeitos adversos , Hipertensão/etnologia , Americanos Mexicanos/psicologia , Estresse Psicológico/etnologia , Adulto , Poluição do Ar/análise , Estudos de Coortes , Feminino , Humanos , Masculino , Americanos Mexicanos/estatística & dados numéricos , Pessoa de Meia-Idade , Projetos Piloto , Prevalência , Características de Residência/estatística & dados numéricos , Fatores de Risco , Inquéritos e Questionários , Texas/epidemiologia , Adulto Jovem
4.
Nat Commun ; 9(1): 4616, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397198

RESUMO

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.


Assuntos
Cromossomos Humanos Par 8/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Mapeamento Cromossômico , Suscetibilidade a Doenças , Marcadores Genéticos , Predisposição Genética para Doença/epidemiologia , Genótipo , Haplótipos , Humanos , Masculino , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Medição de Risco , Fatores de Risco
5.
J Natl Cancer Inst ; 109(8)2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29117387

RESUMO

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Loci Gênicos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2/genética , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 22 , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Masculino
6.
Am J Mens Health ; 11(1): 73-81, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25891393

RESUMO

The optimum use of androgen deprivation therapy (ADT) in high-risk prostate cancer patients has not been defined in the setting of dose-escalated external beam radiation therapy. A retrospective analysis of 1,290 patients with high-risk prostate cancer from June 1987 through March 2010 treated with external beam radiation therapy was performed. Median follow-up was 7.2 years, and 797 patients received ADT, with 384 patients experiencing a biochemical failure and 145 with distant metastasis. ADT was associated with lower risk of biochemical failure and distant metastasis than no ADT after adjusting for age, prostate-specific antigen (PSA), Gleason score, year of diagnosis, tumor stage, and radiation dose. ADT was associated with a greater reduction in biochemical failure in the low-dose radiation group than in the high-dose group. Patients with >24 months of ADT had a lower risk of PSA failures than those with <24 months. ADT was associated with decreased risk of biochemical failure and distant metastasis in all patients. The effect of ADT on reducing risk of biochemical failure was greater among men with low-dose radiation. There was a benefit in PSA and distant metastasis-free survival with >24 months of ADT in all patients who received ADT.

7.
J Immigr Minor Health ; 19(5): 1156-1162, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-26914836

RESUMO

To better characterize the relation of acculturation, based on language use, to smoking status among Mexican-Americans, a large study sample from an ongoing cohort of Mexican-American households in Texas was stratified into current smokers and non-smokers. Four language-use groups were created based on Low/High use of Spanish and English, representing different degrees of acculturation. Participants who reported high English but low Spanish use had the highest smoking prevalence (20.1 %), followed by High English/High Spanish (13.6 %), Low English/High Spanish (8.7 %), and Low English/Low Spanish (6.4 %). Current smokers were more likely to be male, have lower than high school education, currently consume alcohol or had consumed alcohol but quit, and report low Spanish/high English use. Consistent with recent models of acculturation, individuals can differ both in their maintenance of the native language and adoption of a new language and both dimensions are important in predicting tobacco use.


Assuntos
Aculturação , Idioma , Americanos Mexicanos/estatística & dados numéricos , Fumar/etnologia , Adulto , Consumo de Bebidas Alcoólicas/etnologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores Sexuais , Fatores Socioeconômicos , Texas/epidemiologia
8.
Cancer Epidemiol Biomarkers Prev ; 25(12): 1609-1618, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27587788

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. METHODS: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. RESULTS: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. IMPACT: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Complexo Repressor Polycomb 1/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética
9.
Nat Commun ; 7: 10979, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27052111

RESUMO

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.


Assuntos
Afro-Americanos , Epigênese Genética , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Padrões de Herança , Neoplasias da Próstata/genética , Acetilação , Atlas como Assunto , Linhagem Celular Tumoral , Loci Gênicos , Estudo de Associação Genômica Ampla , Histonas/genética , Histonas/metabolismo , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia
10.
J Natl Cancer Inst ; 108(7)2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26823525

RESUMO

The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.


Assuntos
Afro-Americanos/genética , Cromossomos Humanos Par 8 , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Estados Unidos/epidemiologia
11.
Lancet Haematol ; 2(5): e186-93, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26688093

RESUMO

BACKGROUND: Tyrosine-kinase inhibitors improve overall survival in patients with chronic myeloid leukaemia in chronic phase (CML-CP). Survival compared with the general population by age, response, and type of tyrosine-kinase inhibitor is not known. With use of data from trials of tyrosine kinase inhibitors, we compared overall survival in patients with newly diagnosed CML-CP to that of general population. METHODS: In this cohort analysis, we included data from patients with CML-CP enrolled in six consecutive or parallel prospective clinical trials of tyrosine-kinase inhibitors at a single institution from July 30, 2000, to Sept 17, 2012. We analysed data for response and survival with the Kaplan-Meier method. For estimated overall survival in the general population, we obtained data from national vital statistics reports and matched to patients with CML-CP by age, sex, ethnicity, and year at diagnosis. We assessed numbers and causes of death within 1 year of beginning treatment by age group and by response to therapy. We then did univariate analysis and multivariate analysis to investigate factors associated with survival probability. FINDINGS: Our analysis included 483 patients, 271 received imatinib, 105 received nilotinib, and 107 received dasatinib. Most patients were younger than 65 years, and no patients were older than 85 years. Median follow-up was 99·4 months (IQR 44·9-121·6), by which time 53 (11%) patients had died. The most common causes of death were progression to advanced disease stage, including complications of stem-cell transplantation (17 [4%] patients), secondary malignancies (nine [2%] patients), and cardiovascular causes (nine [2%] patients). 5-year overall survival in patients with CML-CP decreased in older age categories. For the whole population of patients with CML-CP, 5-year survival was only slightly lower than that of the matched general population (relative survival 94·7% [95% 92·1-97·4]). Individuals of all ages with a report of complete cytogenetic response to treatment or deeper within 1 year had a 5-year survival similar to that of the general population. INTERPRETATION: In the era of treatment with tyrosine-kinase inhibitors, patients diagnosed with CML-CP can expect a 5-year survival that is only slightly lower than that of the general population. With access to tyrosine-kinase inhibitors, most patients with chronic myeloid leukaemia could enjoy a near normal life expectancy. FUNDING: MD Anderson Cancer Center, National Cancer Institute.


Assuntos
Leucemia Mieloide de Fase Crônica/diagnóstico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Feminino , Humanos , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
12.
J Health Care Poor Underserved ; 26(4): 1456-71, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26548692

RESUMO

Hypertension is on the rise among Hispanics and is highest among those of Mexican origin. Recent studies have found a positive association between air pollution and blood pressure and hypertension. Moreover, a link between hypertension and adverse socioeconomic conditions is well established. However, less is known about psychosocial stressors, although their impact on coronary heart disease has been shown. To address this gap in the literature, community perspectives of the health consequences of environmental exposures and psychosocial stressors experienced among the Mexican-origin population in Houston, Texas were obtained through participation in focus groups, the establishment of a Neighborhood Council of Advisors (NCA), and the testing of a pilot questionnaire. Taken together, the findings from the community were used to develop a culturally sensitive, bilingual questionnaire for an investigation of the combined effects of environmental and psychosocial stressors on hypertension among individuals of Mexican origin.


Assuntos
Participação da Comunidade , Americanos Mexicanos/psicologia , Multilinguismo , Estresse Psicológico/etnologia , Inquéritos e Questionários , Adulto , Idoso , Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Feminino , Grupos Focais , Humanos , Hipertensão/etnologia , Masculino , Americanos Mexicanos/estatística & dados numéricos , Pessoa de Meia-Idade , Projetos Piloto , Texas/epidemiologia
13.
PLoS One ; 10(10): e0141260, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26501420

RESUMO

Higher body mass index (BMI) is a well-established risk factor for type 2 diabetes, and rates of obesity and type 2 diabetes are substantially higher among Mexican-Americans relative to non-Hispanic European Americans. Mexican-Americans are genetically diverse, with a highly variable distribution of Native American, European, and African ancestries. Here, we evaluate the role of Native American ancestry on BMI and diabetes risk in a well-defined Mexican-American population. Participants were randomly selected among individuals residing in the Houston area who are enrolled in the Mexican-American Cohort study. Using a custom Illumina GoldenGate Panel, we genotyped DNA from 4,662 cohort participants for 87 Ancestry-Informative Markers. On average, the participants were of 50.2% Native American ancestry, 42.7% European ancestry and 7.1% African ancestry. Using multivariate linear regression, we found BMI and Native American ancestry were inversely correlated; individuals with <20% Native American ancestry were 2.5 times more likely to be severely obese compared to those with >80% Native American ancestry. Furthermore, we demonstrated an interaction between BMI and Native American ancestry in diabetes risk among women; Native American ancestry was a strong risk factor for diabetes only among overweight and obese women (OR = 1.190 for each 10% increase in Native American ancestry). This study offers new insight into the complex relationship between obesity, genetic ancestry, and their respective effects on diabetes risk. Findings from this study may improve the diabetes risk prediction among Mexican-American individuals thereby facilitating targeted prevention strategies.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Adulto , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Índice de Massa Corporal , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Hispano-Americanos/estatística & dados numéricos , Humanos , Índios Norte-Americanos , Masculino , Americanos Mexicanos/estatística & dados numéricos , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fatores de Risco
14.
Hum Mol Genet ; 24(19): 5603-18, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26162851

RESUMO

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Hispano-Americanos/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Mapeamento Cromossômico/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Anotação de Sequência Molecular , Neoplasias da Próstata/etnologia , Locos de Características Quantitativas
15.
PLoS One ; 10(6): e0131106, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26125186

RESUMO

Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Estatura/genética , Polimorfismo de Nucleotídeo Único/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Modelos Lineares , Masculino , Modelos Genéticos , Fenótipo , Análise de Regressão
16.
Environ Health ; 14: 51, 2015 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-26068905

RESUMO

BACKGROUND: Epidemiological studies have found that particulate matter is associated with increases in blood pressure. Yet, less is known about the effects of specific sources or constituents of particulate matter, such as diesel particulate matter or polycyclic aromatic hydrocarbons (PAHs). We evaluated associations between self-reported hypertension and residential air levels of diesel particulate matter and PAHs among individuals of Mexican origin living in a large inner city. METHODS: The Mano a Mano cohort (established in 2001 by the University of Texas MD Anderson Cancer Center) is comprised of individuals of Mexican origin residing in Houston, Texas. Using geographical information systems, we linked modeled annual estimates of PAHs and diesel particulate matter at the census tract level from the 2002 and 2005 U.S. Environmental Protection Agency's National-Scale Air Toxics Assessment to baseline residential addresses of cohort members who enrolled from 2001 to 2003 or 2004 to 2006, respectively. For each enrollment period, we applied mixed-effects logistic regression models to determine associations between diesel particulate matter and PAHs, separately, and self-reported hypertension while adjusting for confounders and the clustering of observations within census tracts and households. RESULTS: The study population consisted of 11218 participants of which 77% were women. The mean participant age at baseline was 41 years. Following adjustment for age, there was a dose-dependent, positive association between PAHs and hypertension (medium exposure, adjusted odds ratio (OR) = 1.09, 95% CI: 0.88-1.36; high exposure, OR = 1.40, 95% CI: 1.01-1.94) for individuals enrolled during 2001-2003; associations were generally similar in magnitude, but less precise, following adjustment for age, gender, smoking, and BMI. No association was detected for the later period. There was no evidence of an association between residential levels of diesel particulate matter and hypertension. CONCLUSIONS: This study builds on a limited number of prior investigations of the association between ambient air levels of PAHs or diesel particulate matter and hypertension by focusing on a relatively young cohort of predominantly adult women of Mexican origin. Future analyses are warranted to explore associations in the cohort using incident hypertension when sufficient data become available and to further examine associations between specific chemical constituents of particulate matter and hypertension in this and other populations.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Hipertensão/induzido quimicamente , Material Particulado/efeitos adversos , Material Particulado/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Emissões de Veículos/análise , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Estudos Transversais , Monitoramento Ambiental , Feminino , Gasolina , Humanos , Hipertensão/epidemiologia , Modelos Logísticos , Masculino , Americanos Mexicanos/estatística & dados numéricos , Pessoa de Meia-Idade , Razão de Chances , Fatores Sexuais , Texas/epidemiologia , Estados Unidos , Adulto Jovem
17.
BMC Cancer ; 15: 190, 2015 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-25885406

RESUMO

BACKGROUND: To determine whether the effect of androgen deprivation therapy (ADT) on the risk of biochemical failure varies at different doses of radiation in patients treated with definitive external beam radiation for intermediate risk prostate cancer (IRPC). METHODS: This study included 1218 IRPC patients treated with definitive external beam radiation therapy to the prostate and seminal vesicles from June 1987 to January 2009 at our institution. Patient, treatment, and tumor information was collected, including age, race, Gleason score, radiation dose, PSA, T-stage, and months on ADT. RESULTS: The median follow-up was 6 years. A total of 421(34.6%) patients received ADT, 211 (17.3%) patients experienced a biochemical failure, and 38 (3.1%) developed distant metastasis. On univariable analyses, higher PSA, earlier year of diagnosis, higher T-stage, lower doses of radiation, and the lack of ADT were associated with an increased risk of biochemical failure. No difference in biochemical failure was seen among different racial groups or with the use of greater than 6 months of ADT compared with less than 6 months. On multivariate analysis, the use of ADT was associated with a lower risk of biochemical failure than no ADT (HR, 0.599; 95% CI, 0.367-0.978; P<0.04) and lower risk of distant metastasis (HR, 0.114; 95% CI, 0.014-0.905; P=0.04). CONCLUSIONS: ADT reduced the risk of biochemical failure and distant metastasis in both low- and high dose radiation groups among men with intermediate-risk PCa. Increasing the duration of ADT beyond 6 months did not reduce the risk of biochemical failures. Better understanding the benefit of ADT in the era of dose escalation will require a randomized clinical trial.


Assuntos
Adenocarcinoma/terapia , Antagonistas de Androgênios/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Dosagem Radioterapêutica , Adenocarcinoma/secundário , Idade de Início , Idoso , Quimiorradioterapia , Intervalo Livre de Doença , Humanos , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Neoplasias da Próstata/sangue , Radioterapia de Intensidade Modulada , Estudos Retrospectivos
18.
J Phys Act Health ; 12(7): 1023-30, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25919963

RESUMO

BACKGROUND: Existing racial/ethnic disparities in physical activity during childhood increase Hispanics' risk of developing chronic diseases, which serves to increase health disparities. This study examined associations of family cohesion and conflict with self-reported moderate-to-vigorous physical activity (MVPA), controlling for psychosocial covariates such as subjective social status, anxiety, and sensation-seeking. METHODS: 1000 Mexican origin adolescents reported their MVPA levels approximately 2 years apart. Psychosocial covariates, family cohesion and conflict were measured at the first assessment. Generalized Linear Models were used to prospectively examine the relationship between family cohesion and conflict and subsequent MVPA based on 711 participants who had low levels of baseline MVPA. RESULTS: 35% of boys and 24% of girls reported adequate MVPA levels at follow-up; girls were less likely to report adequate MVPA (RR = 0.76; 95% CI: 0.61-0.93) than boys. Overall, family cohesion was associated with MVPA (P = .01), but family cohesion was not (P = .41). Gender-based analyses revealed that adequate MVPA was associated with family cohesion (RR = 1.40; 95% CI: 1.03-1.88), sensation seeking (RR = 1.05; 95% CI: 1.00-1.10), and age (RR = 0.85; 95% CI: 0.74-0.98) among girls and with subjective social status (RR = 1.20; 95% CI: 1.08-1.33) among boys. CONCLUSIONS: The family social environment and gender differences should be addressed in health promotion programs targeting MVPA.


Assuntos
Exercício Físico/fisiologia , Relações Familiares/psicologia , Americanos Mexicanos/psicologia , Meio Social , Adolescente , Ansiedade/psicologia , Coleta de Dados , Características da Família , Relações Familiares/etnologia , Feminino , Disparidades nos Níveis de Saúde , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Caracteres Sexuais
19.
Int J Cancer ; 136(5): 1210-7, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25044450

RESUMO

Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Estudos de Coortes , Seguimentos , Humanos , Masculino , Prognóstico , Fatores de Risco
20.
Leuk Lymphoma ; 56(6): 1643-50, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25308294

RESUMO

Patients with chronic lymphocytic leukemia (CLL) are known to have an increased incidence of second cancers, but the contribution of commonly used frontline therapies to the incidence of second cancers is unclear. We report on the characteristics, incidence, outcomes and factors associated with second cancers in 234 patients receiving fludarabine, cyclophosphamide and rituximab (FCR) based regimens in the frontline setting. The risk of second cancers was 2.38 times higher than the expected risk in the general population. Ninety-three patients (40%) had other cancers before and 66 patients (28%) after FCR. Rates of therapy related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) were high, while solid tumors were not increased. Overall survival of patients with second cancers after frontline FCR was shorter (median of 4.5 years) compared to patients with and without prior cancers. Second cancer risk after frontline FCR is mainly due to high rates of t-AML/MDS and RT, and as speculated the survival of affected patients is shorter.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Mieloide Aguda/induzido quimicamente , Síndromes Mielodisplásicas/induzido quimicamente , Segunda Neoplasia Primária/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/induzido quimicamente , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Rituximab/administração & dosagem , Taxa de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
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