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2.
Sci Rep ; 9(1): 12524, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467304

RESUMO

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

4.
Mol Genet Genomic Med ; 7(6): e707, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31066241

RESUMO

BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium. METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models. RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537). CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.

5.
Nat Commun ; 10(1): 1741, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988301

RESUMO

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
6.
Cancer Epidemiol Biomarkers Prev ; 28(5): 987-995, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30842128

RESUMO

BACKGROUND: Shift work causing circadian disruption is classified as a "probable carcinogen" and may contribute to the pathogenesis of hormone-sensitive cancers. This study investigated shift work exposure in relation to epithelial ovarian cancer (EOC) risk. METHODS: In a population-based case-control study with 496 EOC cases and 906 controls, lifetime occupational histories were collected and used to calculate cumulative years of shift work exposure, average number of night shifts per month, and average number of consecutive night shifts per month. ORs and 95% confidence intervals (CI) for associations with EOC risk were estimated using logistic regression. Associations were also examined according to chronotype and menopausal status. RESULTS: More than half of the cases (53.4%) and controls (51.7%) worked evening and/or night shifts. There was no clear pattern of increasing EOC risk with increasing years of shift work; the adjusted OR of EOC comparing the highest shift work category versus never working shift work was 1.20 (95% CI, 0.89-1.63). This association was more pronounced among those self-identified as having a "morning" chronotype (OR, 1.64; 95% CI, 1.01-2.65). Associations did not greatly differ by menopausal status. CONCLUSIONS: These results do not strongly demonstrate a relationship between shift work and EOC risk. IMPACT: This study collected detailed shift work information and examined shift work patterns according to shift times and schedules. The findings highlight that chronotype should be considered in studies of shift work as an exposure.

7.
Chronobiol Int ; 36(5): 616-628, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30729830

RESUMO

Night work has emerged as a risk factor for many chronic diseases, including obesity, diabetes, and cardiovascular disease. While night work is linked to a number of cardiometabolic indices, few studies have explored how different parameters, such as cumulative night work and intensity of night work, may influence cardiometabolic risk. Fewer studies have also explored the relationship while considering chronotype, a potential modifier between shift-induced circadian disruption and cardiometabolic outcomes. The main objective is to determine the association between night work parameters and cardiometabolic risk factors. The secondary objective is to assess how the association between night work parameters and cardiometabolic risk factors differs by chronotype. A cross-sectional study was conducted with 325 full- and part-time female hospital employees (168 rotating night workers, 157 day workers). Night work status, cumulative night work duration, and night work intensity were determined through self-report, and cardiometabolic risk factors were assessed through clinical exams. Chronotype was determined using the Munich Chronotype Questionniare (MCTQ). Multiple linear regression was used to examine the association between night work parameters and cardiometabolic risk factors. Current night work, cumulative night work, and night work intensity are associated with a number of cardiometabolic indices, including higher waist circumference, body mass index, fasting glucose, blood pressure, and cardiometabolic risk score. When stratified by chronotype, night work parameters are associated with a number of cardiometabolic risk factors in the evening-oriented chronotype subgroup. There is no difference in cardiometabolic risk factors in morning-oriented chronotypes when comparing night work parameters, with the exception of LDL cholesterol. These results suggest that night work parameters are associated with cardiometabolic risk, and night workers with an evening-oriented chronotype may be more susceptible to the adverse cardiometabolic impacts of night work. Future studies should consider chronotype when examining the relationship between night work and cardiometabolic risk.

8.
Ind Health ; 57(2): 201-212, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30700671

RESUMO

There is no standard definition of shift work universally, and no validated report of complete biological adjustment to shift work in workers. Similarly, the evidence for shift work tolerance is limited due to a small number of studies and a narrow range of outcome measures. This paper discusses evidence to date regarding individual differences in shift work tolerance and highlights areas for future research and recommendations for workplace practice. The few factors that are consistently associated with perceived or actual shift work tolerance are young age, low scores of morningness or being a late chronotype, low scores of languidity and neuroticism, high scores on extraversion, internal locus of control and flexibility and male sex. An important first step is to differentiate between factors that are potentially modifiable, such as those that are determined by lifestyle choices, and those factors specific to the working time arrangement. Identifying determinants of shift work tolerance and the ability to adjust to shift work, whether they are innate and/or acquired mechanisms, is important so workers who are less likely to tolerate shift work well can be self-identified and supported with appropriate harm/risk minimization strategies. This paper also identifies important areas for future research with the goal of increasing the evidence base on which we can develop evidence-based harm mitigation strategies for shift workers.


Assuntos
Individualidade , Jornada de Trabalho em Turnos , Tolerância ao Trabalho Programado/fisiologia , Tolerância ao Trabalho Programado/psicologia , Cafeína , Ritmo Circadiano/fisiologia , Feminino , Humanos , Estilo de Vida , Luz , Masculino , Sono/fisiologia
9.
PLoS One ; 14(1): e0209010, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30601841

RESUMO

BACKGROUND: Inflammation contributes to breast cancer development through its effects on cell damage. This damage is usually dealt with by key genes involved in apoptosis and autophagy pathways. METHODS: We tested 206 single nucleotide polymorphisms (SNPs) in 54 genes related to inflammation, apoptosis and autophagy in a population-based breast cancer study of women of European (658 cases and 795 controls) and East Asian (262 cases and 127 controls) descent. Logistic regression was used to estimate odds ratios for breast cancer risk, and case-only analysis to compare breast cancer subtypes (defined by ER/PR/HER2 status), with adjustment for confounders. We assessed statistical interactions between the SNPs and lifestyle factors (smoking status, physical activity and body mass index). RESULTS AND CONCLUSION: Although no SNP was associated with breast cancer risk among women of European descent, we found evidence for an association among East Asians for rs1800925 (IL-13) and breast cancer risk (OR = 2.08; 95% CI: 1.32-3.28; p = 0.000779), which remained statistically significant after multiple testing correction (padj = 0.0350). This association was replicated in a meta-analysis of 4305 cases and 4194 controls in the Shanghai Breast Cancer Genetics Study (OR 1.12, 95% CI: 1.03-1.21, p = 0.011). Further, we found evidence of an interaction between rs7874234 (TSC1) and physical activity among women of East Asian descent.


Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Neoplasias da Mama/genética , Inflamação/genética , Adulto , Apoptose/genética , Autofagia/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Adulto Jovem
10.
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
11.
Am J Hum Genet ; 104(1): 21-34, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554720

RESUMO

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

12.
Occup Environ Med ; 76(1): 22-29, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30541747

RESUMO

OBJECTIVE: To estimate the association between occupational polycyclic aromatic hydrocarbon (PAH) exposure and female breast cancer. METHODS: Lifetime work histories for 1130 cases and 1169 controls from British Columbia and Ontario (Canada) were assessed for PAH exposure using a job-exposure matrix based on compliance measurements obtained during US Occupational Safety and Health Administration workplace safety inspections. RESULTS: Exposure to any level of PAHs was associated with an increased risk of breast cancer (OR=1.32, 95% CI: 1.10 to 1.59), as was duration at high PAH exposure (for >7.4 years: OR=1.45, 95% CI: 1.10 to 1.91; ptrend=0.01), compared with women who were never exposed. Increased risk of breast cancer was most strongly associated with prolonged duration at high occupational PAH exposure among women with a family history of breast cancer (for >7.4 years: OR=2.79, 95% CI: 1.25 to 6.24; ptrend<0.01). CONCLUSIONS: Our study suggests that prolonged occupational exposure to PAH may increase breast cancer risk, especially among women with a family history of breast cancer.

13.
Nat Genet ; 50(7): 968-978, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29915430

RESUMO

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

14.
Can J Cardiol ; 34(5): 683-689, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29731028

RESUMO

BACKGROUND: Shift work is a risk factor for many diseases, including cardiovascular disease. Although the biological pathways are still unclear, it is hypothesized that cortisol disruption during night work is an intermediate. The objective of this study is to determine whether total cortisol production and cortisol pattern mediate the relationship between current shift work and cardiometabolic risk (CMR) among female hospital employees. METHODS: A cross-sectional study was conducted among 326 female employees (166 rotating shift workers, 160 day workers), recruited from a hospital in Southeastern Ontario, Canada, during 2011 to 2014. Participants completed a baseline interview, questionnaire, and clinical exam. Urine samples were collected over two 24-hour periods and used to analyze creatinine-adjusted cortisol, which was then used to calculate total cortisol production (AUCG), and pattern (AUCI). Mediation analysis was performed to test the mediating effect of cortisol in the relationship between shift work and a continuous CMR score. RESULTS: Current shift work is associated with a 0.52 higher CMR score (95% CI: 0.15, 0.89), a lower cortisol output (AUCG), and a flatter pattern (AUCI) over a 2-day period. AUCG is a partial mediator in the relationship between shift work and CMR, whereas AUCI is not. AUCG is also associated with CMR while controlling for shift work, suggesting that lower total cortisol production is also linked to CMR in non-shift workers. CONCLUSIONS: Total cortisol production is a partial mediator in the relationship between rotating shift work and CMR among female hospital employees, whereas cortisol pattern is not a mediator.

15.
Breast Cancer Res Treat ; 170(1): 159-168, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29516373

RESUMO

PURPOSE: The association between high mammographic density (MD) and elevated breast cancer risk is well established. However, the role of absolute non-dense area remains unclear. We estimated the effect of the mammographic non-dense area and other density parameters on the risk of breast cancer. METHODS: This study utilizes data from a population-based case-control study conducted in Greater Vancouver, British Columbia, with 477 female postmenopausal breast cancer cases and 588 female postmenopausal controls. MD measures were determined from digitized screening mammograms using computer-assisted software (Cumulus). Marginal odds ratios were estimated by inverse-probability weighting using a causal diagram for confounder selection. Akaike information criteria and receiver operating characteristic curves were used to assess the goodness of fit and predictive power of unconditional logistic models containing MD parameters. RESULTS: The risk of breast cancer is 60% lower for the highest quartile compared to the lowest quartile of mammographic non-dense area (marginal OR 0.40, 95% CI 0.26-0.61, p-trend < 0.001). The cancer risk almost doubles for the highest quartile compared to the lowest quartile of dense area (marginal OR 1.81, 95% CI 1.19-2.43, p-trend < 0.001). For the highest quartile of percent density, breast cancer risk was more than three times higher than for the lowest quartile (marginal OR 3.15, 95% CI 1.90-4.40, p-trend < 0.001). No difference was seen in predictive accuracy between models using percent density alone, dense area alone, or non-dense area plus dense area. CONCLUSIONS: In this study, non-dense area is an independent risk factor after adjustment for dense area and other covariates, inversely related with the risk of breast cancer. However, non-dense area does not improve prediction over that offered by percent density or dense area alone.

16.
Eur J Epidemiol ; 33(4): 369-379, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29464445

RESUMO

Night shift work has been suspected to increase breast cancer risk but epidemiological studies have been inconsistent due to heterogeneous assessment of exposure to night work. To overcome this limitation, we pooled data of five population-based case-control studies from Australia, Canada, France, Germany, and Spain into a single harmonized dataset using a common definition of night work including 6093 breast cancer cases and 6933 population controls. The odds ratio for breast cancer in women who ever worked at night for at least 3 h between midnight and 5 a.m. as compared to never night workers was 1.12 (95% CI 1.00-1.25). Among pre-menopausal women, this odds ratio was 1.26 [1.06-1.51], increasing to 1.36 [1.07-1.74] for night shifts ≥ 10 h, 1.80 [1.20-2.71] for work ≥ 3 nights/week, and 2.55 [1.03-6.30] for both duration of night work ≥ 10 years and exposure intensity ≥ 3 nights/week. Breast cancer risk in pre-menopausal women was higher in current or recent night workers (OR = 1.41 [1.06-1.88]) than in those who had stopped night work more than 2 years ago. Breast cancer in post-menopausal women was not associated with night work whatever the exposure metric. The increase in risk was restricted to ER+ tumors, particularly those who were both ER+ and HER2+ . These results support the hypothesis that night shift work increases the risk of breast cancer in pre-menopausal women, particularly those with high intensity and long duration of exposure. Risk difference between pre- and post-menopausal women deserves further scrutiny.

17.
J Sleep Res ; 27(4): e12579, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28707304

RESUMO

Sleep disturbance is common among shift workers, and may be an important factor in the effect of shift work on chronic disease development. In this cross-sectional study, we described sleep patterns of 294 female hospital workers (142 alternating day-night shift workers, 152 day workers) and determined associations between shift work and sleep duration. Rest-activity cycles were recorded with the ActiGraph GT3X+ for 1 week. Analyses were stratified by chronotype of shift workers. Using all study days to calculate average sleep duration, shift workers slept approximately 13 min less than day workers during main sleep periods, while 24-h sleep duration did not differ between day workers and shift workers. Results from age-adjusted models demonstrated that all shift workers, regardless of chronotype, slept 20-30 min less than day workers on day shifts during main and total sleep. Early and intermediate chronotypes working night shifts slept between 114 and 125 min less than day workers, both with regard to the main sleep episode and 24-h sleep duration, while the difference was less pronounced among late chronotypes. When sleep duration on free days was compared between shift workers and day workers, only shift workers with late chronotypes slept less, by approximately 50 min, than day workers during main sleep. Results from this study demonstrate how an alternating day-night shift work schedule impacts sleep negatively among female hospital workers, and the importance of considering chronotype in sleep research among shift workers.

18.
Occup Environ Med ; 75(2): 132-138, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28835394

RESUMO

OBJECTIVES: The main objective was to determine whether sleep duration on work shifts mediates the relationship between a current alternating day and night shift work schedule and metabolic syndrome among female hospital employees. The secondary objective was to assess whether cumulative lifetime shift work exposure was associated with metabolic syndrome. METHODS: In this cross-sectional study of 294 female hospital employees, sleep duration was measured with the ActiGraph GT3X+. Shift work status was determined through self-report. Investigation of the total, direct and indirect effects between shift work, sleep duration on work shifts and metabolic syndrome was conducted using regression path analysis. Logistic regression was used to determine the association between cumulative shift work exposure and metabolic syndrome. RESULTS: Shift work is strongly associated with metabolic syndrome (ORTotal=2.72, 95% CI 1.38 to 5.36), and the relationship is attenuated when work shift sleep duration is added to the model (ORDirect=1.18, 95% CI 0.49 to 2.89). Sleep duration is an important intermediate between shift work and metabolic syndrome (ORIndirect=2.25, 95% CI 1.27 to 4.26). Cumulative shift work exposure is not associated with metabolic syndrome in this population. CONCLUSIONS: Sleep duration mediates the association between a current alternating day-night shift work pattern and metabolic syndrome.

19.
Nat Genet ; 49(12): 1767-1778, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29058716

RESUMO

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/métodos , Heterozigoto , Humanos , Receptores Estrogênicos/metabolismo , Fatores de Risco
20.
Nature ; 551(7678): 92-94, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29059683

RESUMO

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.


Assuntos
Neoplasias da Mama/genética , Loci Gênicos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Ásia/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Sítios de Ligação/genética , Neoplasias da Mama/diagnóstico , Simulação por Computador , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Nucleico , Medição de Risco , Fatores de Transcrição/metabolismo
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