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1.
Salud Publica Mex ; 61(5): 601-608, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31661737

RESUMO

OBJECTIVE: To describe the rationale and the methodology of a multicenter project to study the etiology of breast cancer in young Latin American women. MATERIALS AND METHODS: The International Agency for Research on Cancer has established an international collaborative population-based case-control study in four countries in Latin America: Chile, Colombia, Costa Rica, and Mexico (the PRECAMA study). Standardized methodologies were developed to collect information on reproductive variables, lifestyle, anthropometry, diet, clinical and pathological data, and biological specimens. The study will be extended to other countries in the region. CONCLUSIONS: PRECAMA is unique in its multidisciplinary approach that combines genetics, genomics, and metabolomics with lifestyle factors. Then data generated through this project will be instrumental to identify major risk factors for molecular subtypes of breast cancer in young women, which will be important for pre- vention and targeted screening programs in Latin America.

2.
BMC Med ; 17(1): 178, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31547832

RESUMO

BACKGROUND: Metabolomics is a promising molecular tool to identify novel etiologic pathways leading to cancer. Using a targeted approach, we prospectively investigated the associations between metabolite concentrations in plasma and breast cancer risk. METHODS: A nested case-control study was established within the European Prospective Investigation into Cancer cohort, which included 1624 first primary incident invasive breast cancer cases (with known estrogen and progesterone receptor and HER2 status) and 1624 matched controls. Metabolites (n = 127, acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose, sphingolipids) were measured by mass spectrometry in pre-diagnostic plasma samples and tested for associations with breast cancer incidence using multivariable conditional logistic regression. RESULTS: Among women not using hormones at baseline (n = 2248), and after control for multiple tests, concentrations of arginine (odds ratio [OR] per SD = 0.79, 95% confidence interval [CI] = 0.70-0.90), asparagine (OR = 0.83 (0.74-0.92)), and phosphatidylcholines (PCs) ae C36:3 (OR = 0.83 (0.76-0.90)), aa C36:3 (OR = 0.84 (0.77-0.93)), ae C34:2 (OR = 0.85 (0.78-0.94)), ae C36:2 (OR = 0.85 (0.78-0.88)), and ae C38:2 (OR = 0.84 (0.76-0.93)) were inversely associated with breast cancer risk, while the acylcarnitine C2 (OR = 1.23 (1.11-1.35)) was positively associated with disease risk. In the overall population, C2 (OR = 1.15 (1.06-1.24)) and PC ae C36:3 (OR = 0.88 (0.82-0.95)) were associated with risk of breast cancer, and these relationships did not differ by breast cancer subtype, age at diagnosis, fasting status, menopausal status, or adiposity. CONCLUSIONS: These findings point to potentially novel pathways and biomarkers of breast cancer development. Results warrant replication in other epidemiological studies.

3.
Am J Ind Med ; 62(10): 838-846, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31380573

RESUMO

BACKGROUND: Breast cancer is the most frequent cancer among Moroccan women. Environmental and occupational factors may play a role in breast cancer etiology. This study aimed to investigate the association between occupation, industry, and breast cancer risk among Moroccan women. METHODS: A total of 300 breast cancer cases and 300 controls (matched by age and area of residence) were included in this study. Full occupational history was collected, with a detailed description of each job held for at least 6 months. Occupations were coded according to the International Standard Classification of Occupations (ISCO 08) and the Moroccan Analytical Classification of Professions (2001). Industries were coded according to the Statistical Classification of Economic Activities in the European Community (2008). Odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for potential confounders were estimated by using conditional logistic regression. RESULTS: An overall decreased risk of breast cancer was observed among women doing only household work (OR = 0.32; 95% CI = 0.18-0.55). An increased risk of breast cancer was observed among women in agricultural occupations, particularly those employed as agricultural laborers (ISCO 08 code: 921; OR = 2.91; 95% CI = 1.51-5.60) and the risk increased with duration of employment (P trend = .01). Analyses by industry corroborated these findings. CONCLUSIONS: Our findings suggest that occupational exposures may be associated with increased risk of breast cancer among female agricultural workers in this population. Further investigations, with advanced methods of occupational exposure assessment, are warranted to clarify the role of chemicals involved in this high-risk occupation and to suggest preventive actions and screening.

4.
Nutrients ; 11(8)2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434255

RESUMO

Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor ß (TGFß) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.

5.
Environ Int ; 131: 105013, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31352264

RESUMO

The benefits of improved biomass cookstoves (ICS) depends on their adoption and sustained use. Few studies have documented if and how they are used more than five years after being introduced. We conducted a 9-year prospective cohort study among young rural women in the highlands of Michoacan, Mexico. Participants had received a Patsari ICS during a community trial either in 2005 or 2006. With retrospective information collected in 2012-13, we studied the households' energy use, ICS survival, and cooking practices during the follow-up period. Using an exposure model constructed with personal PM2.5 measurements in a subsample of homes at the time of the initial trial in 2005, we estimated the exposure associated with different energy use patterns during the follow-up period. The ICS had a mean lifespan of 4 years, after which more than half of the stoves were not in use; therefore, the use of open fire increased, particularly among the indigenous communities. ICS use peak was achieved two years after the initial trial, either exclusively or combined with open fire. Yearly household energy use and other variables were used to estimate chronic air pollution exposure. Mean PM2.5 exposure during the follow-up period ranged from 51 to 319 µg/m3; the median was 102 and 146 µg/m3 for mainly ICS and mainly open fire use, respectively. The ICS has a useful period after which it needs maintenance, repair, or replacement. Unfortunately, many programs have not afforded a follow-up component. Exposure to biomass smoke air pollutants can be reduced by using an ICS instead of the traditional open fire. Household energy strategies should ensure equitable access to clean energy options adapted to local needs and preferences with culturally appropriate technology implemented on a sustainable perspective.

6.
BMC Cancer ; 19(1): 737, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345179

RESUMO

BACKGROUND: Patients with breast cancer undergoing chemotherapy and radiotherapy experience fatigue and other treatment side effects. Integrative therapies combining physical activity and dietary counseling are recommended; however to date no large randomized controlled trial has been conducted during adjuvant therapy. The Adapted Physical Activity and Diet (APAD) intervention was evaluated for its ability to decrease fatigue (primary outcome), anxiety, depression, body mass index (BMI), and fat mass, and enhance muscular and cognitive performances, and quality-of-life (QoL). METHODS: Women diagnosed with early breast cancer (N = 143, mean age = 52 ± 10 years) were randomized to APAD or usual care (UC). APAD included thrice-weekly moderate-intensity mixed aerobic and resistance exercise sessions and 9 dietetic consultations. Patient-reported outcomes (PROs) and anthropometric, muscular, and cognitive variables were measured at baseline, 18 weeks (end of chemotherapy), and 26 weeks (end of radiotherapy and intervention), and at 6- and 12-month post-intervention follow-ups. Multi-adjusted linear mixed-effects models were used to compare groups over time. RESULTS: Significant beneficial effects of the APAD intervention were observed on all PROs (i.e., fatigue, QoL, anxiety, depression) at 18 and 26 weeks. The significant effect on fatigue and QoL persisted up to 12-month follow-up. Significant decreases in BMI, fat mass, and increased muscle endurance and cognitive flexibility were observed at 26 weeks, but did not persist afterward. Leisure physical activity was enhanced in the APAD group vs UC group at 18 and 26 weeks. No significant effect of the intervention was found on major macronutrients intake. CONCLUSIONS: A combined diet and exercise intervention during chemotherapy and radiotherapy in patients with early breast cancer led to positive changes in a range of psychological, physiological and behavioral outcomes at the end of intervention. A beneficial effect persisted on fatigue and QoL at long term, i.e., 1 year post-intervention. Diet-exercise supportive care should be integrated into the management of early breast cancer patients. TRIAL REGISTRATION: The APAD study was prospectively registered on ClinicalTrials.gov (NCT01495650; date of registration: December 20, 2011).

7.
Clin Epigenetics ; 11(1): 66, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039828

RESUMO

BACKGROUND: It is well established that estrogens and other hormonal factors influence breast cancer susceptibility. We hypothesized that a woman's total lifetime estrogen exposure accumulates changes in DNA methylation, detectable in the blood, which could be used in risk assessment for breast cancer. METHODS: An estimated lifetime estrogen exposure (ELEE) model was defined using epidemiological data from EPIC-Italy (n = 31,864). An epigenome-wide association study (EWAS) of ELEE was performed using existing Illumina HumanMethylation450K Beadchip (HM450K) methylation data obtained from EPIC-Italy blood DNA samples (n = 216). A methylation index (MI) of ELEE based on 31 CpG sites was developed using HM450K data from EPIC-Italy and the Generations Study and evaluated for association with breast cancer risk in an independent dataset from the Generations Study (n = 440 incident breast cancer cases matched to 440 healthy controls) using targeted bisulfite sequencing. Lastly, a meta-analysis was conducted including three additional cohorts, consisting of 1187 case-control pairs. RESULTS: We observed an estimated 5% increase in breast cancer risk per 1-year longer ELEE (OR = 1.05, 95% CI 1.04-1.07, P = 3 × 10-12) in EPIC-Italy. The EWAS identified 694 CpG sites associated with ELEE (FDR Q < 0.05). We report a DNA methylation index (MI) associated with breast cancer risk that is validated in the Generations Study targeted bisulfite sequencing data (ORQ4_vs_Q1 = 1.77, 95% CI 1.07-2.93, P = 0.027) and in the meta-analysis (ORQ4_vs_Q1 = 1.43, 95% CI 1.05-2.00, P = 0.024); however, the correlation between the MI and ELEE was not validated across study cohorts. CONCLUSION: We have identified a blood DNA methylation signature associated with breast cancer risk in this study. Further investigation is required to confirm the interaction between estrogen exposure and DNA methylation in the blood.

8.
Breast Cancer Res ; 21(1): 62, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101124

RESUMO

BACKGROUND: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. METHODS: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing. RESULTS: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98). CONCLUSIONS: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.

9.
Obesity (Silver Spring) ; 27(6): 894-898, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004416

RESUMO

OBJECTIVE: Obesity is a likely risk factor for asthma. However, underlying mechanisms by which obesity affects asthma activity remain poorly understood. This study aimed to investigate the role of leptin, an adipocyte-derived proinflammatory protein, as a mediator in the association between body adiposity (assessed using BMI, waist circumference, and body fat percentage) and persistent asthma. METHODS: A causal approach to mediation analysis was used to disentangle total and direct effects and the indirect effect mediated by leptin, using data from the French prospective French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) (baseline: 2003-2007; follow-up: 2011-2013; mean follow-up time: 7 years). A total of 331 participants with current asthma at baseline were included. RESULTS: Per 1-SD increment in BMI, waist circumference, and body fat percentage, the adjusted odds ratios of the total effect were 1.59 (95% CI: 0.95-2.97), 2.06 (1.06-4.00), and 3.25 (1.01-9.41), respectively; the odds ratios of the indirect effect mediated by leptin were 1.68 (1.09-2.46), 1.55 (0.99-2.57), and 1.99 (0.94-4.83), respectively. CONCLUSIONS: Leptin partly (> 60%) mediated the association between high body adiposity and persistent asthma over time. Using a newly developed analytic approach, this longitudinal study brought new insight into one mechanism by which obesity may affect asthma activity.

10.
J Steroid Biochem Mol Biol ; 189: 101-107, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30836177

RESUMO

The role of vitamin D in mammographic density is still unclear. This study examines the association between serum 25-hydroxyvitamin D (25(OH)D) and mammographic density, overall and by specific women characteristics. DDM-Madrid is a cross-sectional study that recruited 1403 premenopausal women in a breast radiodiagnosis unit of Madrid City Council. Information was collected with a questionnaire and plasma 25(OH)D was measured by solid-phase extraction on-line coupled to liquid chromatography-tandem mass spectrometry. Percent mammographic density was assessed using a semi-automated computer tool (DM-Scan). Multivariable linear regression models were used to quantify the associations, categorizing 25(OH)D levels (nmol/L) into 3 groups according to the cut-offs established by the US Endocrine Society. Models were adjusted for age, education, body mass index, age at menarche, parity, previous breast biopsies, family history of breast cancer, physical activity, energy intake, use of corticoids, hypercholesterolemia and day of sample extraction. Mean serum 25(OH)D level was 49.4 + 18.9 nmol/L. Women with sufficient concentrations of 25(OH)D showed a slight decrease in mammographic density (ß >75nmol/L=-3.40; p = 0.037). No differences were observed according to women characteristics except for parity, where the protective effect of 25(OH)D was only seen among nulliparous (ß >75nmol/L=-13.00; p-heterogeneity = 0.006). In light of the protective effect of vitamin D on mammographic density and the high prevalence of vitamin D insufficiency in our population, improving these levels could be an effective measure for the prevention of health problems related to the lack of this essential vitamin.

11.
Nutrients ; 11(3)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30871053

RESUMO

This cross-sectional study aimed to evaluate associations between a priori defined dietary patterns and anthropometric measures in Mexican women. A total of 1062 women aged 35 to 69 years old from the control participants of the CAMA (Cancer de Mama) study, a multi-center population-based case-control study on breast cancer conducted in Mexico, were interviewed and dietary intakes were assessed using questionnaires. The following indices were derived from these data: Dietary Approaches to Stop Hypertension (DASH) score, the Healthy Eating Index (HEI), the Mediterranean Diet Score (aMED), the Diet Quality Index (DQI), glycemic index (GI) and glycemic load (GL). Adjusting for age, center, educational level, physical activity and energy intake, a high GI was positively associated with a higher body mass index (BMI) and waist circumference (WC). Higher adherence to aMED was associated with lower WC and waist-to-hip ratio (WHR) but no significant association was observed with other a priori dietary patterns. In this population of Mexican women, higher adherence to Mediterranean diet was associated with lower WC but other a priori dietary scores appeared to be of limited value in exploring the association between diet and anthropometric measures.


Assuntos
Antropometria , Dieta , Comportamento Alimentar , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , México , Pessoa de Meia-Idade
12.
Br J Nutr ; 121(5): 591-600, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30704540

RESUMO

Incidence rates of breast cancer (BC) are increasing in South Africa. The aim of this study was to investigate the association between dietary intake and BC risk in black South African women. The study population included 396 BC cases and 396 population-based controls matched on age and residence, participating in the South African Breast Cancer study. Diet was assessed using a validated quantified FFQ from which twelve energy-adjusted food groups were formed and analysed. OR were estimated using conditional logistic regressions, adjusted for confounding factors, comparing highest v. lowest median intake. Fresh fruit consumption showed an inverse association with BC risk (OR=0·3, 95 % CI 0·12, 0·80) in premenopausal women, whilst red and organ meat consumption showed an overall inverse association with BC risk (OR=0·6, 95 % CI 0·49, 0·94 and OR=0·6, 95 % CI 0·47, 0·91). Savoury food consumption (sauces, soups and snacks) were positively associated with BC risk in postmenopausal women (OR=2·1, 95 % CI 1·15, 4·07). Oestrogen receptor-positive stratification showed an inverse association with BC risk and consumption of nuts and seeds (OR=0·2, 95 % CI 0·58, 0·86). Based on these results, it is recommended that black South African women follow a diet with more fruit and vegetables together with a decreased consumption of less energy-dense, micronutrient-poor foods such as savoury foods. More research is necessary to investigate the association between BC risk and red and organ meat consumption. Affordable and practical methods regarding these recommendations should be implemented within health intervention strategies.

13.
PLoS One ; 14(1): e0210372, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30653559

RESUMO

BACKGROUND: In Latin America (LA), there is a high incidence rate of breast cancer (BC) in premenopausal women, and the genomic features of these BC remain unknown. Here, we aim to characterize the molecular features of BC in young LA women within the framework of the PRECAMA study, a multicenter population-based case-control study of BC in premenopausal women. METHODS: Pathological tumor tissues were collected from incident cases from four LA countries. Immunohistochemistry (IHC) was performed centrally for ER, PR, HER2, Ki67, EGFR, CK5/6, and p53 protein markers. Targeted deep sequencing was done on genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissues and their paired blood samples to screen for somatic mutations in eight genes frequently mutated in BC. A subset of samples was analyzed by exome sequencing to identify somatic mutational signatures. RESULTS: The majority of cases were positive for ER or PR (168/233; 72%), and 21% were triple-negative (TN), mainly of basal type. Most tumors were positive for Ki67 (189/233; 81%). In 126 sequenced cases, TP53 and PIK3CA were the most frequently mutated genes (32.5% and 21.4%, respectively), followed by AKT1 (9.5%). TP53 mutations were more frequent in HER2-enriched and TN IHC subtypes, whereas PIK3CA/AKT1 mutations were more frequent in ER-positive tumors, as expected. Interestingly, a higher proportion of G:C>T:A mutations was observed in TP53 in PRECAMA cases compared with TCGA and METABRIC BC series (27% vs 14%). Exome-wide mutational patterns in 10 TN cases revealed alterations in signal transduction pathways and major contributions of mutational signatures caused by altered DNA repair pathways. CONCLUSIONS: These pilot results on PRECAMA tumors give a preview of the molecular features of premenopausal BC in LA. Although the overall mutation burden was as expected from data in other populations, mutational patterns observed in TP53 and exome-wide suggested possible differences in mutagenic processes giving rise to these tumors compared with other populations. Further -omics analyses of a larger number of cases in the near future will enable the investigation of relationships between these molecular features and risk factors.


Assuntos
Neoplasias da Mama/genética , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Genes p53 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Incidência , América Latina/epidemiologia , Pessoa de Meia-Idade , Mutação , Projetos Piloto , Pré-Menopausa/genética , Pré-Menopausa/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem
14.
Cancer Epidemiol ; 58: 160-166, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30597481

RESUMO

BACKGROUND: Some modifiable risk factors have been independently associated with breast cancer (BC) risk in Moroccan women, but no studies have investigated their joint association. This study aimed to investigate the association between a Healthy Lifestyle Index (HLI) score and BC risk among Moroccan women. METHODS: In this case-control study, 300 incident BC cases and 300 controls, matched by age and area of residence were recruited. Cases were women newly-diagnosed with histopathologically-confirmed BC at the University Hospital in Fez, Morocco. Controls were randomly selected healthy women recruited from 6 primary health centers in Fez. HLI scores developed within this study were assigned to participants based on 11 factors (red and processed meat, white meat, cream, cheese, fish, fruit and vegetables, physical activity, BMI, smoking, alcohol consumption, and breastfeeding), where 0 was given to unhealthy and 0.5 or 1 to healthy levels of each factor. Conditional and unconditional logistic regression models were used to assess the association between HLI scores and BC risk. RESULTS: Mean of HLI scores were 8.1 (±1.1) and 9.0 (±0.9) in cases and controls, respectively, p < 0.01. After adjusting for potential confounders, one-point increment in the HLI score was associated with 56% (95% CI, CI: 39-68%), 49% (95% CI: 30-63%), and 59% (95% CI: 40-72%) lower risks of BC in all, premenopausal, and postmenopausal women, respectively. CONCLUSION: High HLI scores were associated with decreased risk of BC in Moroccan women. These findings suggest that BC prevention policies should include strategies for engaging Moroccan women in healthy lifestyles.

15.
Int J Obes (Lond) ; 43(6): 1231-1243, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30568270

RESUMO

BACKGROUND/OBJECTIVES: Maternal obesity is associated with increased risk of obesity and other symptoms of the metabolic syndrome in the offspring. Nevertheless, the molecular mechanisms and cellular factors underlying this enhanced disease susceptibility remain to be determined. Here, we aimed at identifying changes in plasma lipids in offspring of obese mothers that might underpin, and serve as early biomarkers of, their enhanced metabolic disease risk. SUBJECTS/METHODS: We performed a longitudinal lipidomic profiling in plasma samples from normal weight, overweight, and obese pregnant women and their children that participated in the Prenatal Omega-3 Fatty Acid Supplementation, Growth, and Development trial conducted in Mexico. At recruitment women were aged between 18 and 35 years and in week 18-22 of pregnancy. Blood samples were collected at term delivery by venipuncture from mothers and from the umbilical cord of their newborns and from the same infants at 4 years old under non-fasting conditions. Lipidomic profiling was done using ultra-performance liquid chromatography high-resolution mass spectrometry. RESULTS: Analysis of the lipidomic data showed that overweight and obese mothers exhibited a significant reduction in the total abundance of ceramides (Cer) in plasma, mainly of Cer (d18:1/20:0), Cer (d18:1/22:0), Cer (d18:1/23:0), and Cer (d18:1/24:0), compared with mothers of normal body weight. This reduction was confirmed by the direct quantification of these and other ceramide species. Similar quantitative differences in the plasma concentration of Cer (d18:1/22:0), Cer (d18:1/23:0), and Cer (d18:1/24:0), were also found between 4-year-old children of overweight and obese mothers compared with children of mothers of normal body weight. Noteworthy, children exhibited equal daily amounts of energy and food intake independently of the BMI of their mothers. CONCLUSIONS: Maternal obesity results in long-lasting changes in plasma ceramides in the offspring suggesting that these lipids might be used as early predictors of metabolic disease risk due to maternal obesity.

16.
Breast Cancer Res ; 20(1): 147, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30509329

RESUMO

BACKGROUND: Few published breast cancer (BC) risk prediction models consider the heterogeneity of predictor variables between estrogen-receptor positive (ER+) and negative (ER-) tumors. Using data from two large cohorts, we examined whether modeling this heterogeneity could improve prediction. METHODS: We built two models, for ER+ (ModelER+) and ER- tumors (ModelER-), respectively, in 281,330 women (51% postmenopausal at recruitment) from the European Prospective Investigation into Cancer and Nutrition cohort. Discrimination (C-statistic) and calibration (the agreement between predicted and observed tumor risks) were assessed both internally and externally in 82,319 postmenopausal women from the Women's Health Initiative study. We performed decision curve analysis to compare ModelER+ and the Gail model (ModelGail) regarding their applicability in risk assessment for chemoprevention. RESULTS: Parity, number of full-term pregnancies, age at first full-term pregnancy and body height were only associated with ER+ tumors. Menopausal status, age at menarche and at menopause, hormone replacement therapy, postmenopausal body mass index, and alcohol intake were homogeneously associated with ER+ and ER- tumors. Internal validation yielded a C-statistic of 0.64 for ModelER+ and 0.59 for ModelER-. External validation reduced the C-statistic of ModelER+ (0.59) and ModelGail (0.57). In external evaluation of calibration, ModelER+ outperformed the ModelGail: the former led to a 9% overestimation of the risk of ER+ tumors, while the latter yielded a 22% underestimation of the overall BC risk. Compared with the treat-all strategy, ModelER+ produced equal or higher net benefits irrespective of the benefit-to-harm ratio of chemoprevention, while ModelGail did not produce higher net benefits unless the benefit-to-harm ratio was below 50. The clinical applicability, i.e. the area defined by the net benefit curve and the treat-all and treat-none strategies, was 12.7 × 10- 6 for ModelER+ and 3.0 × 10- 6 for ModelGail. CONCLUSIONS: Modeling heterogeneous epidemiological risk factors might yield little improvement in BC risk prediction. Nevertheless, a model specifically predictive of ER+ tumor risk could be more applicable than an omnibus model in risk assessment for chemoprevention.

17.
Nutrients ; 10(10)2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257485

RESUMO

There have been increases in the incidence of obesity in Lebanon over the past few decades. Fatty acid intake and metabolism have been postulated to influence obesity, but few epidemiological studies have been conducted. The aim of this study was to investigate the correlation between serum fatty acid levels and indicators of obesity in a cross-sectional study nested within a cohort of 501 Lebanese adults residing in Greater Beirut. A total of 395 available serum samples (129 men, 266 women) were profiled for phospholipid fatty acid composition. Spearman correlation coefficients adjusted for relevant confounders and corrected for multiple testing were calculated between serum fatty acids, desaturation indices, and indicators of adiposity (body mass index (BMI) and waist). BMI was significantly positively correlated with saturated fatty acids in men (r = 0.40, p < 0.0001, q < 0.0001) and women (r = 0.33, p < 0.0001, q < 0.0001). BMI was significantly positively correlated with monounsaturated fatty acid palmitoleic acid in women (r = 0.15, p = 0.01, q = 0.03). This study suggests that high blood levels of some saturated fatty acids and the monounsaturated fatty acid palmitoleic acid, likely derived from both dietary intakes of saturated fatty acids and endogenous lipogenesis, may have been associated with adiposity in the Lebanese population. The causality of these associations needs to be explored in experimental settings.

18.
Cancers (Basel) ; 10(10)2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30262796

RESUMO

Hereditary breast and ovarian cancer syndrome (HBOC) represents 5⁻10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.

19.
Artigo em Inglês | MEDLINE | ID: mdl-30201514

RESUMO

BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

20.
Sci Rep ; 8(1): 13109, 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166604

RESUMO

Etiological differences among breast cancer (BC) subtypes have not been clearly established, especially among young women in Latin America. This study examined the relationship between reproductive factors and BC subtypes among 288 BC cases (20-45 years) and population-based matched controls in four Latin American countries. Immunohistochemistry was determined centrally. Associations between BC and reproductive factors were determined. Older age at first full-term pregnancy (FFTP) (Odds Ratio (OR) = 1.11; 95% Confidence Interval (CI), 1.04-1.19 per year), longer time between menarche and FFTP (OR = 1.12; 95%CI: 1.04-1.20 per year), and older age at last pregnancy (OR = 1.10; 95%CI, 1.02-1.19 per year) were associated with an increased risk of estrogen receptor positive (ER+) tumors (n = 122). Ever pregnant (OR = 0.35; 95%CI, 0.13-0.96), number of childbirths (OR = 0.64; 95%CI, 0.47-0.87 per child), time since last birth (OR = 0.92; 95%CI, 0.85-0.99 per year), and history of breastfeeding (OR = 0.23; 95%CI, 0.09-0.58) were inversely associated with the risk of ER+ tumor. Older age at menarche (OR = 0.63; 95%CI, 0.45-0.89 per year) and longer duration of breastfeeding (OR = 0.97; 95%CI, 0.94-1.01 per month) were inversely associated with estrogen receptor negative (ER-) tumors (n = 48). Reproductive factors may be differentially associated with BC subtypes in young Latin American women.

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