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1.
JAMA Oncol ; 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31246249

RESUMO

Importance: The United States Preventive Services Task Force (USPSTF) recommends low-dose computed tomography screening for lung cancer. However, USPSTF screening guidelines were derived from a study population including only 4% African American smokers, and racial differences in smoking patterns were not considered. Objective: To evaluate the diagnostic accuracy of USPSTF lung cancer screening eligibility criteria in a predominantly African American and low-income cohort. Design, Setting, and Participants: The Southern Community Cohort Study prospectively enrolled adults visiting community health centers across 12 southern US states from March 25, 2002, through September 24, 2009, and followed up for cancer incidence through December 31, 2014. Participants included African American and white current and former smokers aged 40 through 79 years. Statistical analysis was performed from May 11, 2016, to December 6, 2018. Exposures: Self-reported race, age, and smoking history. Cumulative exposure smoking histories encompassed most recent follow-up questionnaires. Main Outcomes and Measures: Incident lung cancer cases assessed for eligibility for lung cancer screening using USPSTF criteria. Results: Among 48 364 ever smokers, 32 463 (67%) were African American and 15 901 (33%) were white, with 1269 incident lung cancers identified. Among all 48 364 Southern Community Cohort Study participants, 5654 of 32 463 African American smokers (17%) were eligible for USPSTF screening compared with 4992 of 15 901 white smokers (31%) (P < .001). Among persons diagnosed with lung cancer, a significantly lower percentage of African American smokers (255 of 791; 32%) was eligible for screening compared with white smokers (270 of 478; 56%) (P < .001). The lower percentage of eligible lung cancer cases in African American smokers was primarily associated with fewer smoking pack-years among African American vs white smokers (median pack-years: 25.8 [interquartile range, 16.9-42.0] vs 48.0 [interquartile range, 30.2-70.5]; P < .001). Racial disparity was observed in the sensitivity and specificity of USPSTF guidelines between African American and white smokers for all ages. Lowering the smoking pack-year eligibility criteria to a minimum 20-pack-year history was associated with an increased percentage of screening eligibility of African American smokers and with equitable performance of sensitivity and specificity compared with white smokers across all ages (for a 55-year-old current African American smoker, sensitivity increased from 32.2% to 49.0% vs 56.5% for a 55-year-old white current smoker; specificity decreased from 83.0% to 71.6% vs 69.4%; P < .001). Conclusions and Relevance: Current USPSTF lung cancer screening guidelines may be too conservative for African American smokers. The findings suggest that race-specific adjustment of pack-year criteria in lung cancer screening guidelines would result in more equitable screening for African American smokers at high risk for lung cancer.

2.
Am J Phys Anthropol ; 169(3): 482-497, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31125126

RESUMO

OBJECTIVES: From a genetic perspective, relatively little is known about how mass emigrations of African, European, and Asian peoples beginning in the 16th century affected Indigenous Caribbean populations. Therefore, we explored the impact of serial colonization on the genetic variation of the first Caribbean islanders. MATERIALS AND METHODS: Sixty-four members of St. Vincent's Garifuna Community and 36 members of Trinidad's Santa Rosa First People's Community (FPC) of Arima were characterized for mitochondrial DNA and Y-chromosome diversity via direct sequencing and targeted SNP and STR genotyping. A subset of 32 Garifuna and 18 FPC participants were genotyped using the GenoChip 2.0 microarray. The resulting data were used to examine genetic diversity, admixture, and sex biased gene flow in the study communities. RESULTS: The Garifuna were most genetically comparable to African descendant populations, whereas the FPC were more similar to admixed American groups. Both communities also exhibited moderate frequencies of Indigenous American matrilines and patrilines. Autosomal SNP analysis indicated modest Indigenous American ancestry in these populations, while both showed varying degrees of African, European, South Asian, and East Asian ancestry, with patterns of sex-biased gene flow differing between the island communities. DISCUSSION: These patterns of genetic variation are consistent with historical records of migration, forced, or voluntary, and suggest that different migration events shaped the genetic make-up of each island community. This genomic study is the highest resolution analysis yet conducted with these communities, and provides a fuller understanding of the complex bio-histories of Indigenous Caribbean peoples in the Lesser Antilles.

3.
Ann Epidemiol ; 35: 1-3, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31036443

RESUMO

The under-representation of women in leadership in scientific fields presents a serious problem. Gender diversity is integral to innovation and productivity, and inequality leads to loss of gender talent in science including epidemiology. This policy brief summarizes some of the key dimensions and determinants contributing to gender-equity gaps in epidemiology and other scientific fields, relevant to developed countries where there is more published evidence. Women in scientific fields hold fewer positions on editorial boards, lack equal representation in speaking engagements at conferences, and are less likely to publish or receive top tier grant funding. Reasons for these inequities range from unconscious bias, biased promotion systems, and traditional norms in the division of family life and labor in our society leading to the attrition of women in academia. Addressing the problem of gender inequity, as a component of gender inequality, will provide an ethical basis to advance innovation. Data on gender equity in the field of epidemiology are sparse. We call on academic institutions, professional societies and associations, and editorial boards relevant to epidemiology (as well as other academic disciplines more broadly) to take meaningful action to build an evidence base as to the extent of gender inequities in epidemiologic research, teaching, policy, and practice. We outline some of the necessary steps required to achieve gender equity, such as career development and mentoring programs, institutional support, and programs to address bias.

4.
J Thorac Oncol ; 14(8): 1360-1369, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31009812

RESUMO

INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

5.
Cancer Epidemiol Biomarkers Prev ; 28(4): 715-723, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30894353

RESUMO

BACKGROUND: Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans. METHODS: We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status. RESULTS: We identified three novel genomic regions significantly associated (FDR-corrected P <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR = 0.43; 95% confidence interval (CI), 0.73-0.89], and functional annotation using GTEx showed rs7186207 modifies DHODH gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR = 1.47; 95% CI, 1.22-1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR = 0.80; 95% CI, 0.72-0.90). CONCLUSIONS: We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans. IMPACT: Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.

6.
Nat Commun ; 10(1): 431, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683880

RESUMO

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Neoplasias de Cabeça e Pescoço/genética , Padrões de Herança , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/etnologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Transtornos Mentais/etnologia , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia , Fumar/etnologia , Fumar/genética , Fumar/fisiopatologia
7.
Carcinogenesis ; 40(3): 432-440, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-30590402

RESUMO

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

8.
BMJ Open ; 8(9): e021059, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30206077

RESUMO

OBJECTIVES: To examine the association between neighbourhood deprivation and lung cancer risk. DESIGN: Nested case-control study. SETTING: Southern Community Cohort Study of persons residing in 12 states in the southeastern USA. PARTICIPANTS: 1334 cases of lung cancer and 5315 controls. PRIMARY OUTCOME MEASURE: Risk of lung cancer. RESULTS: After adjustment for smoking status and other confounders, and additional adjustment for individual-level measures of socioeconomic status (SES), there was no monotonic increase in risk with worsening deprivation score overall or within sex and race groups. There was an increase among current and shorter term former smokers (p=0.04) but not among never and longer term former smokers. There was evidence of statistically significant interaction by sex among whites, but not blacks, in which the effect of worsening deprivation on lung cancer existed in males but not in females. CONCLUSIONS: Area-level measures of SES were associated with lung cancer risk in current and shorter term former smokers only in this population.

9.
Nat Commun ; 9(1): 3927, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254314

RESUMO

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

10.
Emerg Infect Dis ; 24(10): 1835-1839, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30226187

RESUMO

Maps of Histoplasma capsulatum infection prevalence were created 50 years ago; since then, the environment, climate, and anthropogenic land use have changed drastically. Recent outbreaks of acute disease in Montana and Nebraska, USA, suggest shifts in geographic distribution, necessitating updated prevalence maps. To create a weighted overlay geographic suitability model for Histoplasma, we used a geographic information system to combine satellite imagery integrating land cover use (70%), distance to water (20%), and soil pH (10%). We used logistic regression modeling to compare our map with state-level histoplasmosis incidence data from a 5% sample from the Centers for Medicare and Medicaid Services. When compared with the state-based Centers data, the predictive accuracy of the suitability score-predicted states with high and mid-to-high histoplasmosis incidence was moderate. Preferred soil environments for Histoplasma have migrated into the upper Missouri River basin. Suitability score mapping may be applicable to other geographically specific infectious vectors.

11.
Nat Commun ; 9(1): 3221, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104567

RESUMO

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

12.
Int Arch Occup Environ Health ; 91(8): 937-950, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29971594

RESUMO

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

13.
Int J Epidemiol ; 2018 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-30059977

RESUMO

Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

14.
Hum Hered ; 83(2): 65-70, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29864749

RESUMO

OBJECTIVE: Lung cancer is classified as a single entity comprised of multiple histological subtypes. But how similar are these subtypes on a genetic level? This paper aims to address this question through a concise overview of germline and somatic differences between small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma. METHODS: We reveal the weak overlap found between these 3 lung cancer subtypes using published data from one of the largest germline genetic studies on lung cancer to date and somatic mutation data from Catalogue of Somatic Mutations in Cancer (COSMIC). RESULTS: These data indicate that these 3 subtypes share very little with each other at the genetic level. At the germline SNP level, only 24 independent SNPs from 2 chromosomes were shared across all 3 subtypes. We also demonstrate that only 30 unique cancer-specific mutations overlap the 3 subtypes from COSMIC, and that this is fewer than overlapping mutations chosen at random. Finally, we show that only 3 somatic mutational signatures are shared between these 3 subtypes. CONCLUSION: This paper highlights that these 3 lung cancer subtypes may be distinct diseases at the genetic level. In the era of precision medicine, we feel that these genomic differences will be of utmost importance in the choice of lung cancer therapy in the future.

15.
J Thorac Oncol ; 13(10): 1464-1473, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29885480

RESUMO

INTRODUCTION: Lung cancer is a leading cause of cancer-related death worldwide. Racial disparities in lung cancer survival exist between blacks and whites, yet they are limited by categorical definitions of race. We sought to examine the impact of African ancestry on overall survival among blacks and whites with NSCLC cases. METHODS: Incident cases of NSCLC in blacks and whites from the prospective Southern Community Cohort Study (N = 425) were identified through linkage with state cancer registries in 12 southern states. Vital status was determined by linkage with the National Death Index and Social Security Administration. We evaluated the impact of African ancestry (as estimated by using genome-wide ancestry-informative markers) on overall survival by calculating the time-dependent area under the curve (AUC) for Cox proportional hazards models, adjusting for relevant covariates such as stage and treatment. We replicated our findings in an independent population of NSCLC cases in blacks. RESULTS: Global African ancestry was not significantly associated with overall survival among NSCLC cases. There was no change in model performance when Cox proportional hazards models with and without African ancestry were compared (AUC = 0.79 for each model). Removal of stage and treatment reduced the average time-dependent AUC from 0.79 to 0.65. Similar findings were observed in our replication study. CONCLUSIONS: Stage and treatment are more important predictors of survival than African ancestry is. These findings suggest that racial disparities in lung cancer survival may disappear with similar early detection efforts for blacks and whites.

17.
Epidemiology ; 29(1): 58-66, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29068841

RESUMO

BACKGROUND: Epidemiologists have long used case-control and related study designs to enhance variability of response and information available to estimate exposure-disease associations. Less has been done for longitudinal data. METHODS: We discuss an epidemiological study design and analysis approach for longitudinal binary response data. We seek to gain statistical efficiency by oversampling relatively informative subjects for inclusion into the sample. In this methodological demonstration, we develop this concept by sampling repeatedly from an existing cohort study to estimate the relationship of chronic obstructive pulmonary disease to past-year smoking in a panel of baseline smokers. To account for oversampling, we describe a sequential offsetted regressions approach for valid inferences in this setting. RESULTS: Targeted sampling can lead to increased statistical efficiency when combined with sequential offsetted regressions. Efficiency gains are degraded with increased prevalence of the disease response variable, with decreased association between the sampling variable and the response, and with other design and analysis parameters, providing guidance to those wishing to use these types of designs in the future. CONCLUSIONS: These designs hold promise for efficient use of resources in longitudinal cohort studies.


Assuntos
Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar/epidemiologia , Adulto , Broncodilatadores/uso terapêutico , Estudos de Coortes , Métodos Epidemiológicos , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Probabilidade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Abandono do Hábito de Fumar
18.
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
19.
PLoS One ; 12(9): e0185660, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28957450

RESUMO

Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p<0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p<0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) achieved statistical significance after Bonferroni correction for multiple testing, and three suggestive SNPs (rs13021737, TMEM18; rs11583200, ELAVL4; and rs6990042, SGCZ) achieved a nominal statistical significance. Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to identify novel genetic loci of complex phenotypes.


Assuntos
Obesidade/genética , Polimorfismo de Nucleotídeo Único , Fumar/genética , Idoso , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
20.
PLoS One ; 12(7): e0180471, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28704416

RESUMO

Globally, lung cancer results in more deaths worldwide than any other cancer, indicating a need for better treatments. Members of the eicosanoid metabolism pathway represent promising therapeutic targets, as several enzymes involved in the generation of these lipids are dysregulated in many cancers and their inhibition reduces lung cancer growth in mouse models. However, genetic variation of enzymes involved in eicosanoid metabolism has not been adequately examined for association with lung cancer. The goal of this study was to determine whether germline genetic variation altering eicosanoid producing enzyme function and/or expression are associated with differences in lung cancer survival. We examined the association of genetic variation with mortality within eicosanoid metabolism genes in 395 non-small-cell lung cancer (NSCLC) cases from the Southern Community Cohort Study (SCCS). A total of 108 SNPs, both common and rare, in 19 genes, were examined for association. No common or rare variants were associated with lung cancer survival across the entire study population. However, rare variants in ALOX15B (arachidonate 15-lipoxygenase, type B) and the common variant rs12529 in AKR1C3 (prostaglandin F synthase) were associated with NSCLC mortality in women and African Americans, respectively. Rare variants in ALOX15B were associated with greater mortality in women (HR = 2.10, 95% CI = 1.25-3.54, p-value = 0.005). The major allele of rs12529 in AKCR1C3 associated with improved survival in African Americans (HR = 0.74, 95% CI = 0.59-0.92, p-value = 0.008). The lack of genetic associations among all NSCLC cases and the association among women only for rare variants in ALOX15B may, in part, explain the better NSCLC survival observed among women. These results raise the possibility that some subgroups within the NSCLC population may benefit from drugs targeting eicosanoid metabolism.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Eicosanoides/metabolismo , Redes Reguladoras de Genes , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Afro-Americanos/genética , Idoso , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Estudos Prospectivos , Análise de Sobrevida , Estados Unidos
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