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2.
Ann Epidemiol ; 36: 33-39, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31387775

RESUMO

PURPOSE: Telomere length is considered a biomarker of human aging and premature morbidity and mortality which has been associated with chronic stress. METHODS: We assessed the relation between perceived racism and telomere length in the Black Women's Health Study, a follow-up study of U.S. black women begun in 1995. Participants were asked about frequency of "everyday racism" (e.g., "people act as if they think you are not intelligent") and "institutional racism" (e.g., "ever treated unfairly due to race by police"). Using quantitative real-time polymerase chain reaction assay, relative telomere lengths (RTL) were measured as the copy number ratio of telomere repeat to a single control gene in 997 participants. Associations of racism variables with log-RTL were estimated by multivariable linear regression, with adjustment for age at blood draw and potential confounders. RESULTS: Participants were aged 40-70 years (mean = 55.6 years), and mean telomere length was 0.77 (range 0.21-1.38). In stratified analyses, there was an inverse association between everyday racism and log-RTL among women who did not discuss their experiences of racism with others (ß = -0.1104; 95% CI = -0.2140 to -0.0067; P = .045). CONCLUSIONS: Everyday racism was associated with shorter telomere length among women who reported not discussing those experiences with others.

3.
Int J Cancer ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469419

RESUMO

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of follistatin [FST]), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

4.
Epidemiology ; 30(5): 679-686, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31259848

RESUMO

BACKGROUND: Prenatal exposure to diethylstilbestrol (DES), an endocrine-disrupting chemical, may be associated with depression in adulthood, but previous findings are inconsistent. METHODS: Women (3,888 DES exposed and 1,729 unexposed) and men (1,021 DES exposed and 1,042 unexposed) participating in the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study were queried in 2011 for any history of depression diagnosis or treatment. Hazard ratios (HRs; 95% confidence intervals [CIs]) estimated the associations between prenatal DES exposure and depression risk. RESULTS: Depression was reported by 993 (26%) exposed and 405 (23%) unexposed women, and 177 (17%) exposed and 181 (17%) unexposed men. Compared with the unexposed, HRs for DES and depression were 1.1 (95% CI = 0.9, 1.2) in women and 1.0 (95% CI = 0.8, 1.2) in men. For medication-treated depression, the HRs (CIs) were 1.1 (0.9, 1.2) in women and 0.9 (0.7, 1.2) in men. In women, the HR (CI) for exposure to a low cumulative DES dose was 1.2 (1.0, 1.4), and for DES exposure before 8 weeks' gestation was 1.2 (1.0, 1.4). In men, the HR for low dose was 1.2 (95% CI = 0.9, 1.6) and there was no association with timing. In women, associations were uninfluenced by the presence of DES-related vaginal epithelial changes or a prior diagnosis of DES-related adverse outcomes. CONCLUSIONS: Prenatal DES exposure was not associated overall with risk of depression in women or men. In women, exposure in early gestation or to a low cumulative dose may be weakly associated with an increased depression risk.

5.
Breastfeed Med ; 14(4): 249-255, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30839228

RESUMO

Background: The incidence of diabetes is rising, and with it, the number of pregnancies affected by diabetes. U.S. black women have a disproportionately high prevalence of diabetes and lower rates of breastfeeding. Objective: The objective of this study was to quantify the relationship between diabetes before pregnancy and breastfeeding duration among black women in the United States. Materials and Methods: We analyzed women from the Black Women's Health Study (N = 59,000) to assess the relationship between prepregnancy diabetes and time to breastfeeding cessation occurring up to 24 months postdelivery using Kaplan-Meier survival curves, log rank tests, and Cox proportional hazards models. The study population included primiparous women with births between 1995 and 2009 (N = 3,404). Obesity, hypertension before pregnancy, and family history of diabetes were examined for effect modification. Results: Survival curves demonstrated a markedly reduced duration of breastfeeding in women who had been diagnosed with prepregnancy diabetes (p < 0.01). The hazard ratio for breastfeeding cessation for women with prepregnancy diabetes was 1.5 (95% confidence interval 1.1-2.0) compared with women without prepregnancy diabetes after control for age, body mass index (BMI) at age 18, prepregnancy BMI, other metabolic factors, demographics, and health behaviors. Conclusions: Our results suggest that prepregnancy diabetes is a strong predictor of curtailed breastfeeding duration, even after control for BMI. This underscores the need for targeted lactation support for diabetic women.

6.
Cancer Epidemiol Biomarkers Prev ; 28(4): 675-679, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30923045

RESUMO

BACKGROUND: Incidence of pancreatic cancer is higher in African Americans than in U.S. whites. We hypothesized that poor oral health, disproportionately common in African Americans and associated with increased risk of pancreatic cancer in several studies of predominantly white populations, may play a role in this disparity. METHODS: We examined the relation of self-reported measures of oral health (periodontal disease and adult tooth loss) in relation to pancreatic cancer incidence in the prospective Black Women's Health Study (BWHS). Cox proportional hazard analyses were used to calculate HRs of pancreatic cancer for women with periodontal disease, tooth loss, or both, relative to women who reported neither. Multivariable models adjusted for age, cigarette smoking, body mass index (BMI), type 2 diabetes, and alcohol consumption. RESULTS: Participants aged 33 to 81 were followed for an average of 9.85 years from 2007 through 2016, with occurrence of 78 incidence cases of pancreatic cancer. Multivariable HRs for pancreatic cancer incidence were 1.77 [95% confidence interval (CI) 0.57-5.49] for periodontal disease with no tooth loss, 2.05 (95% CI, 1.08-3.88) for tooth loss without report of periodontal disease, and 1.58 (95% CI, 0.70-3.57) for both tooth loss and periodontal disease. The HR for loss of at least five teeth, regardless of whether periodontal disease was reported, was 2.20 (95% CI, 1.11-4.33). CONCLUSIONS: The poor oral health experienced by many African Americans may contribute to their higher incidence of pancreatic cancer. IMPACT: Future research will assess associations between the oral microbiome and pancreatic cancer risk in this population.

7.
Ann Intern Med ; 170(1): 22-30, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30534999

RESUMO

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated. Objective: To characterize breast cancer risk in relation to recent childbirth. Design: Pooled analysis of individual-level data from 15 prospective cohort studies. Setting: The international Premenopausal Breast Cancer Collaborative Group. Participants: Women younger than 55 years. Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression. Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns. Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited. Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women. Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

8.
Reprod Toxicol ; 84: 32-38, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30594671

RESUMO

BACKGROUND: Animal studies suggest that prenatal exposure to diethylstilbestrol (DES) causes epigenetic alterations in primordial germ cells that affect the next generation, but human studies are sparse. METHODS: We assessed hormonally mediated outcomes in third generation women whose mothers were prenatally DES-exposed and unexposed. RESULTS: Compared to the unexposed, DES-exposed third generation women had an increased risk of irregular menses and amenorrhea; the respective prevalence ratios and 95% confidence intervals (CI) in follow-up data were 1.32 (95% CI: 1.10, 1.60) and 1.26 (95% CI: 1.06, 1.49); associations were more apparent in third generation women whose prenatally DES-exposed mothers were affected by vaginal epithelial changes. The follow-up data also indicated an association with preterm delivery (relative risk (RR): 1.54; 95% CI: 1.35, 1.75). CONCLUSION: DES third generation women may have an increased risk of irregular menstrual cycles, amenorrhea, and preterm delivery, consistent with inter-generational effects of endocrine disrupting chemical exposure in humans.


Assuntos
Dietilestilbestrol/toxicidade , Disruptores Endócrinos/toxicidade , Distúrbios Menstruais/epidemiologia , Nascimento Prematuro/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Feminino , Humanos , Troca Materno-Fetal , Mães , National Cancer Institute (U.S.) , Gravidez , Reprodução , Risco , Estados Unidos , Adulto Jovem
9.
Artigo em Inglês | MEDLINE | ID: mdl-30498869

RESUMO

PURPOSE: The purpose of the study was to investigate the association between pre- or perinatal factors and breast cancer risk among African American women. METHODS: Participants in the Black Women's Health Study, a prospective cohort of 59,000 African American women, reported birth weight, preterm birth, twin or triplet status, maternal age at birth, birth order, and having been breastfed during infancy at various times during follow-up from 1997 to 2015. Numbers of incident cases ranged from 312 for breastfed analyses to 1,583 for twin or triplet analyses. Using multivariable Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between each factor and breast cancer risk overall and by estrogen receptor (ER) status. RESULTS: Compared to birth weights of 5 lbs. 8 oz.-8 lbs. 13 oz., low (< 5 lbs. 8 oz.) and high (> 8 lbs. 13 oz.) birth weights were associated with increased breast cancer risk; HRs (95% CI) were 1.19 (0.98-1.44) and 1.26 (0.97-1.63), respectively. Associations were similar by ER status. Having been born to a mother aged ≥ 35 years versus < 20 years was associated with risk of ER+ (HR 1.59, 95% CI 1.10-2.29), but not ER- breast cancer. Other perinatal factors were not associated with breast cancer. CONCLUSION: African American women with a low or high birth weight or born to older mothers may have increased breast cancer risk. Trends towards delayed child birth and higher birth weights, coupled with disproportionately high rates of low birth weight among African Americans, may contribute to increases in breast cancer incidence.

10.
Ann Behav Med ; 52(12): 989-998, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30418522

RESUMO

Background: The few studies of the relationship between religion and/or spirituality (R/S) and hypertension are conflicting. We hypothesized that R/S may reduce the risk of hypertension by buffering adverse physiological effects of stress. Methods: We prospectively assessed the association of R/S with hypertension within the Black Women's Health Study (BWHS), a cohort study initiated in 1995 that follows participants through biennial questionnaires. The 2005 questionnaire included four R/S questions: (i) extent to which one's R/S is involved in coping with stressful situations, (ii) self-identification as a religious/spiritual person, (iii) frequency of attending religious services, and (iv) frequency of prayer. Incidence rate ratios (IRRs) and 95% confidence intervals were calculated for each R/S variable in relation to incident hypertension using Cox proportional hazards regression models, controlling for demographics, known hypertension risk factors, psychosocial factors, and other R/S variables. Results: During 2005-2013, 5,194 incident cases of hypertension were identified. High involvement of R/S in coping with stressful events compared with no involvement was associated with reduced risk of hypertension (IRR: 0.87; 95% CI: 0.75, 1.00). The association was strongest among women reporting greater levels of perceived stress (IRR: 0.77; 95% CI: 0.61, 0.98; p interaction = .01). More frequent prayer was associated with increased risk of hypertension (IRR: 1.12; 95% CI: 0.99, 1.27). No association was observed for the other R/S measures. Conclusion: R/S coping was associated with decreased risk of hypertension in African American women, especially among those reporting higher levels of stress. Further research is needed to understand the mechanistic pathways through which R/S coping may affect health.

11.
Am J Gastroenterol ; 113(10): 1494-1505, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30177781

RESUMO

OBJECTIVE: Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature. DESIGN: For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n = 414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017. RESULTS: In the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR) = 1.62, 95% Confidence Interval (CI): 1.24-2.12] and an 81% (HR = 1.81, 95% CI: 1.33-2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR) = 1.49, 95% CI: 1.32-1.70; n = 4 studies; I2 = 0%]. Diabetes was associated with a 53% increased ICC risk (RR = 1.53, 95% CI: 1.31-1.78; n = 6 studies). While we noted heterogeneity between studies (I2 = 67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n = 9) were mostly consistent, but these studies are potentially subject to reverse causation. CONCLUSIONS: These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.

12.
J Hum Genet ; 63(11): 1109-1117, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30135545

RESUMO

African American women are disproportionately affected by type 2 diabetes. Genetic factors may explain part of the excess risk. More than 100 genetic variants have been associated with risk of type 2 diabetes, but most studies have been conducted in white populations. Two genome-wide association studies (GWAS) in African Americans have identified three novel genetic variants only. We conducted admixture mapping using 2918 ancestral informative markers in 2632 cases of type 2 diabetes, and 2596 controls nested in the ongoing Black Women's Health Study cohort, with the goal of identifying genomic loci with local African ancestry associated with type 2 diabetes. In addition, we performed replication analysis of 71 previously identified index SNPs, and fine-mapped those genetic loci to identify better or new genetic variants associated with type 2 diabetes in African Americans. We found that individual African ancestry was associated with higher risk of type 2 diabetes. In addition, we identified two genomic regions, 3q26 and 12q23, with excess of African ancestry associated with higher risk of type 2 diabetes. Lastly, we replicated 8 out of 71 index SNPs from previous GWAS, including, for the first time in African Americans, the X-linked rs5945326 SNP near the DUSP9 gene. In addition, our fine-mapping efforts suggest independent signals at five loci. Our detailed analysis identified two genomic regions associated with risk of type 2 diabetes, and showed that many genetic risk variants are shared across ancestries.

13.
Hum Genet ; 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30006737

RESUMO

Several genome-wide association studies (GWAS) have identified genetic variants associated with birth weight. To date, however, most GWAS of birth weight have focused primarily on European ancestry samples even though prevalence of low birth weight is higher among African-Americans. We conducted admixture mapping using 2918 ancestral informative markers in 2596 participants of the Black Women's Health Study, with the goal of identifying novel genomic regions where local African ancestry is associated with birth weight. In addition, we performed a replication analysis of 11 previously identified index single nucleotide polymorphisms (SNPs), and fine-mapped those genetic loci to identify better or new genetic variants associated with birth weight in African-Americans. We found that high African ancestry at 12q14 was associated with low birth weight, and we identified multiple independent birth weight-lowering variants in this genomic region. We replicated the association of a previous GWAS SNP in ADRB1 and our fine-mapping efforts suggested the presence of new birth weight-associated variants in ADRB1, HMGA2, and SLC2A4. Further studies are needed to determine whether birth weight-associated loci can in part explain race-associated birth weight disparities.

14.
Cancer Epidemiol Biomarkers Prev ; 27(10): 1208-1213, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30049842

RESUMO

Background: Prenatal diethylstilbestrol (DES) exposure is associated with adverse reproductive outcomes and cancer of the breast and vagina/cervix in adult women. DES effects on estrogen metabolism have been hypothesized, but reproductive hormone concentrations and metabolic pathways have not been comprehensively described.Methods: Blood samples were provided by 60 postmenopausal women (40 exposed and 20 unexposed) who were participants in the NCI Combined DES Cohort Study, had never used hormone supplements or been diagnosed with cancer, had responded to the most recent cohort study questionnaire, and lived within driving distance of Boston University Medical School (Boston, MA). Parent estrogens and their metabolites were measured by high-performance liquid chromatography-tandem mass spectrometry. Age-adjusted percent changes in geometric means and associated 95% confidence intervals (CIs) between the exposed and unexposed were calculated.Results: Concentrations of total estrogens (15.3%; CI, -4.1-38.5) and parent estrogens (27.1%; CI, -8.2-76.1) were slightly higher in the DES-exposed than unexposed. Ratios of path2:parent estrogens (-36.5%; CI, -53.0 to -14.3) and path2:path16 (-28.8%; CI, -47.3-3.7) were lower in the DES exposed. These associations persisted with adjustment for total estrogen, years since menopause, body mass index, parity, and recent alcohol intake.Conclusions: These preliminary data suggest that postmenopausal women who were prenatally DES exposed may have relatively less 2 than 16 pathway estrogen metabolism compared with unexposed women.Impact: Lower 2 pathway metabolism has been associated with increased postmenopausal breast cancer risk and could potentially offer a partial explanation for the modest increased risk observed for prenatally DES-exposed women. Cancer Epidemiol Biomarkers Prev; 27(10); 1208-13. ©2018 AACR.

15.
Breast Cancer Res ; 20(1): 45, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29871690

RESUMO

BACKGROUND: MicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor subtype among African-American (AA) women. METHODS: Under the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC in AA women were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8350 women: 3663 cases and 4687 controls. The primary miRNA sequence was identified for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets. Association analysis was conducted using logistic regression for BC status overall and by tumor subtype. RESULTS: A novel BC signal was localized to an 8.6-kb region of 17q25.3 by four SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and remained statistically significant after multiple test correction (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.26-1.65; p = 3.15 × 10-7; false discovery rate (FDR) = 0.03). These SNPs reside in a genomic location that includes both the predicted primary transcript of the noncoding miRNA gene MIR3065 and the first intron of the gene for brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2). Furthermore, miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1 were the strongest signals for hormone receptor, luminal versus basal-like, and HER2 enrichment status, respectively. A second phase of genotyping (1397 BC cases, 2418 controls) that included two SNPs in the 8.6-kb region was used for validation and meta-analysis. While neither rs4969239 nor rs9913477 was validated, when meta-analyzed with the original dataset their association with BC remained directionally consistent (OR = 1.29, 95% CI = 1.16-1.44 (p = 4.18 × 10-6) and OR = 1.33, 95% CI = 1.17-1.51 (p = 1.6 × 10-5), respectively). CONCLUSION: Germline genetic variation indicates that MIR3065 may play an important role in BC development and heterogeneity among AA women. Further investigation to determine the potential functional effects of these SNPs is warranted. This study contributes to our understanding of BC risk in AA women and highlights the complexity in evaluating variation in gene-dense regions of the human genome.

16.
PLoS Genet ; 14(6): e1007368, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29879116

RESUMO

Selection pressure due to exposure to infectious pathogens endemic to Africa may explain distinct genetic variations in immune response genes. However, the impact of those genetic variations on human immunity remains understudied, especially within the context of modern lifestyles and living environments, which are drastically different from early humans in sub Saharan Africa. There are few data on population differences in constitutional immune environment, where genetic ancestry and environment are likely two primary sources of variation. In a study integrating genetic, molecular and epidemiologic data, we examined population differences in plasma levels of 14 cytokines involved in innate and adaptive immunity, including those implicated in chronic inflammation, and possible contributing factors to such differences, in 914 AA and 855 EA women. We observed significant differences in 7 cytokines, including higher plasma levels of CCL2, CCL11, IL4 and IL10 in EAs and higher levels of IL1RA and IFNα2 in AAs. Analyses of a wide range of demographic and lifestyle factors showed significant impact, with age, education level, obesity, smoking, and alcohol intake, accounting for some, but not all, observed population differences for the cytokines examined. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with percent of African ancestry among AAs. Through admixture mapping, the signal was pinpointed to local ancestry at 1q23, with fine-mapping analysis refined to the Duffy-null allele of rs2814778. In AA women, this variant was a major determinant of systemic levels of CCL2 (p = 1.1e-58) and CCL11 (p = 2.2e-110), accounting for 19% and 40% of the phenotypic variance, respectively. Our data reveal strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. The substantial immune differences by ancestry may have broad implications to health disparities between AA and EA populations.


Assuntos
Adaptação Biológica/genética , Citocinas/genética , Regulação da Expressão Gênica , Variação Genética , Seleção Genética , Imunidade Adaptativa/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Alelos , Evolução Biológica , Citocinas/sangue , Sistema do Grupo Sanguíneo Duffy/genética , Meio Ambiente , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Disparidades nos Níveis de Saúde , Voluntários Saudáveis , Humanos , Imunidade Inata/genética , Pessoa de Meia-Idade
17.
JAMA Oncol ; 4(11): e181771, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931120

RESUMO

Importance: The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation. Objective: To investigate the association of BMI with premenopausal breast cancer risk, in particular by age at BMI, attained age, risk factors for breast cancer, and tumor characteristics. Design, Setting, and Participants: This multicenter analysis used pooled individual-level data from 758 592 premenopausal women from 19 prospective cohorts to estimate hazard ratios (HRs) of premenopausal breast cancer in association with BMI from ages 18 through 54 years using Cox proportional hazards regression analysis. Median follow-up was 9.3 years (interquartile range, 4.9-13.5 years) per participant, with 13 082 incident cases of breast cancer. Participants were recruited from January 1, 1963, through December 31, 2013, and data were analyzed from September 1, 2013, through December 31, 2017. Exposures: Body mass index at ages 18 to 24, 25 to 34, 35 to 44, and 45 to 54 years. Main Outcomes and Measures: Invasive or in situ premenopausal breast cancer. Results: Among the 758 592 premenopausal women (median age, 40.6 years; interquartile range, 35.2-45.5 years) included in the analysis, inverse linear associations of BMI with breast cancer risk were found that were stronger for BMI at ages 18 to 24 years (HR per 5 kg/m2 [5.0-U] difference, 0.77; 95% CI, 0.73-0.80) than for BMI at ages 45 to 54 years (HR per 5.0-U difference, 0.88; 95% CI, 0.86-0.91). The inverse associations were observed even among nonoverweight women. There was a 4.2-fold risk gradient between the highest and lowest BMI categories (BMI≥35.0 vs <17.0) at ages 18 to 24 years (HR, 0.24; 95% CI, 0.14-0.40). Hazard ratios did not appreciably vary by attained age or between strata of other breast cancer risk factors. Associations were stronger for estrogen receptor-positive and/or progesterone receptor-positive than for hormone receptor-negative breast cancer for BMI at every age group (eg, for BMI at age 18 to 24 years: HR per 5.0-U difference for estrogen receptor-positive and progesterone receptor-positive tumors, 0.76 [95% CI, 0.70-0.81] vs hormone receptor-negative tumors, 0.85 [95% CI: 0.76-0.95]); BMI at ages 25 to 54 years was not consistently associated with triple-negative or hormone receptor-negative breast cancer overall. Conclusions and Relevance: The results of this study suggest that increased adiposity is associated with a reduced risk of premenopausal breast cancer at a greater magnitude than previously shown and across the entire distribution of BMI. The strongest associations of risk were observed for BMI in early adulthood. Understanding the biological mechanisms underlying these associations could have important preventive potential.

18.
PLoS One ; 13(5): e0196755, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29738558

RESUMO

Obesity-driven Type 2 diabetes (T2D) is a systemic inflammatory condition associated with cardiovascular disease. However, plasma cytokines and tissue inflammation that discriminate T2D risk in African American women with obese phenotypes are not well understood. We analyzed 64 circulating cytokines and chemokines in plasma of 120 African American women enrolled in the Black Women's Health Study. We used regression analysis to identify cytokines and chemokines associated with obesity, co-morbid T2D and hypertension, and compared results to obese women without these co-morbidities, as well as to lean women without the co-morbidities. We then used hierarchical clustering to generate inflammation signatures by combining the effects of identified cytokines and chemokines and summarized the signatures using an inflammation score. The analyses revealed six distinct signatures of sixteen cytokines/chemokines (P = 0.05) that differed significantly by prevalence of T2D (P = 0.004), obesity (P = 0.0231) and overall inflammation score (P < E-12). Signatures were validated in two independent cohorts of African American women with obesity: thirty nine subjects with no metabolic complications or with T2D and hypertension; and thirteen breast reduction surgical patients. The signatures in the validation cohorts closely resembled the distributions in the discovery cohort. We find that blood-based cytokine profiles usefully associate inflammation with T2D risks in vulnerable subjects, and should be combined with metabolism and obesity counselling for personalized risk assessment.


Assuntos
Afro-Americanos , Citocinas/sangue , Inflamação/etnologia , Síndrome Metabólica/etnologia , Obesidade/etnologia , Afro-Americanos/estatística & dados numéricos , Biomarcadores , Quimiocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etnologia , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipertensão/sangue , Hipertensão/etnologia , Hipoglicemiantes/uso terapêutico , Inflamação/sangue , Mamoplastia , Síndrome Metabólica/sangue , Metformina/uso terapêutico , Pessoa de Meia-Idade , Obesidade/sangue , Prevalência , Índice de Gravidade de Doença , Magreza/sangue , Magreza/etnologia , Relação Cintura-Quadril
19.
Int J Cancer ; 143(6): 1374-1378, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29658110

RESUMO

In a prospective cohort study of the health effects associated with prenatal Diethylstilbestrol (DES) exposure, DES was associated with an increased breast cancer risk after 40 years of age. It is unknown whether it is associated with greater mammographic density, which strongly predicts breast cancer risk. A cohort of DES-exposed and unexposed women was assembled at the Mayo Clinic in 1975, and followed through 2012 as part of the National Cancer Institute's DES follow-up study. Mammographic density from 3,637 mammograms for 332 (222 DES-exposed, 110 unexposed) women in this cohort screened at the Mayo Clinic, Rochester between 1996 and 2015 was determined clinically using the Breast Imaging Reporting and Data System (BI-RADS). Any effect of prenatal DES exposure on mammographic density was estimated using repeated measures logistic regression. There was no association between prenatal DES exposure and high mammographic density for either premenopausal [Odds ratios (OR) = 0.92 (95% Confidence Interval (CI): 0.50, 1.7] or postmenopausal women (OR = 0.90; 95% CI: 0.54, 1.5). Among premenopausal women, associations differed by body mass index (BMI), with ORs of 1.47 (0.70, 3.1) for women with BMI above the median and 0.53 (0.23, 1.3) for those with BMI below the median (pinteraction = 0.05). Overall, however, prenatal DES exposure was not associated with high mammographic density in this sample of DES Study participants. Consequently, this study does not provide evidence that high mammographic density is involved with the influence of DES on breast cancer risk.

20.
Br J Cancer ; 118(7): 1005-1012, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29520041

RESUMO

BACKGROUND: While tobacco and alcohol are established risk factors for hepatocellular carcinoma (HCC), the most common type of primary liver cancer, it is unknown whether they also increase the risk of intrahepatic cholangiocarcinoma (ICC). Thus, we examined the association between tobacco and alcohol use by primary liver cancer type. METHODS: The Liver Cancer Pooling Project is a consortium of 14 US-based prospective cohort studies that includes data from 1,518,741 individuals (HCC n = 1423, ICC n = 410). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. RESULTS: Current smokers at baseline had an increased risk of HCC (hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.57-2.20) and ICC (HR = 1.47, 95% CI: 1.07-2.02). Among individuals who quit smoking >30 years ago, HCC risk was almost equivalent to never smokers (HR = 1.09, 95% CI: 0.74-1.61). Compared to non-drinkers, heavy alcohol consumption was associated with an 87% increased HCC risk (HR≥7 drinks/day = 1.87, 95% CI: 1.41-2.47) and a 68% increased ICC risk (HR≥5 drinks/day = 1.68, 95% CI: 0.99-2.86). However, light-to-moderate alcohol consumption of <3 drinks/day appeared to be inversely associated with HCC risk (HR>0-<0.5 drinks/day = 0.77, 95% CI: 0.67-0.89; HR>0.5-<1 drinks/day = 0.57, 95% CI: 0.44-0.73; HR1-<3 drinks/day = 0.71, 95% CI: 0.58-0.87), but not ICC. CONCLUSIONS: These findings suggest that, in this relatively healthy population, smoking cessation and light-to-moderate drinking may reduce the risk of HCC.

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