Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect.

NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: The Liver Cancer Pooling Project.

Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence.

Plasma Inflammatory Markers and the Risk of Developing Hypertension in Men.

Background: Several cross-sectional, but few prospective, studies suggest that inflammation may be involved in the development of hypertension. We examined markers of inflammation-high-sensitivity C-reactive protein, interleukin-6, and soluble intercellular adhesion molecule-1-and a marker of fibrinolysis, D-dimer, for their associations with incident hypertension in the Physicians' Health Study.

Methods And Results: Baseline blood values and information on hypertension-related risk factors were collected in 1982.

Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies.

Background: Body mass index (BMI), a measure of obesity typically assessed in middle age or later, is known to be positively associated with pancreatic cancer. However, little evidence exists regarding the influence of central adiposity, a high BMI during early adulthood, and weight gain after early adulthood on pancreatic cancer risk.

Design: We conducted a pooled analysis of individual-level data from 20 prospective cohort studies in the National Cancer Institute BMI and Mortality Cohort Consortium to examine the association of pancreatic cancer mortality with measures of central adiposity (e.

Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies.

Background: Breast cancer aetiology may differ by estrogen receptor (ER) status. Associations of alcohol and folate intakes with risk of breast cancer defined by ER status were examined in pooled analyses of the primary data from 20 cohorts.

Methods: During a maximum of 6-18 years of follow-up of 1 089 273 women, 21 624 ER+ and 5113 ER- breast cancers were identified.

Rare coding variants and X-linked loci associated with age at menarche.

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.

Coffee Consumption and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma by Sex: The Liver Cancer Pooling Project.

Background: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer.

Anthropometry and head and neck cancer:a pooled analysis of cohort data.

Background: Associations between anthropometry and head and neck cancer (HNC) risk are inconsistent. We aimed to evaluate these associations while minimizing biases found in previous studies.

Methods: We pooled data from 1,941,300 participants, including 3760 cases, in 20 cohort studies and used multivariable-adjusted Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of anthropometric measures with HNC risk overall and stratified by smoking status.

Plasma C-reactive protein and risk of breast cancer in two prospective studies and a meta-analysis.

Background: C-reactive protein (CRP) has been evaluated as a risk factor for breast cancer in epidemiologic studies. However, results from prospective studies are inconsistent.

Methods: We evaluated the association using prediagnostic blood samples in a case-control study nested within the Nurses' Health Study (NHS) and the full cohort of the Women's Health Study (WHS).

Within-team Patterns of Communication and Referral in Multimodal Treatment of Chronic Low Back Pain Patients by an Integrative Care Team.

Background: Nonspecific chronic low back pain (CLBP) is a highly prevalent and costly public health problem with few treatment options that provide consistent and greater than modest benefits. Treatment of CLBP is shifting from unimodal to multimodal and multidisciplinary approaches, including biopsychosocially-based complementary and integrative care. Multidisciplinary approaches require unique levels of communication and coordination amongst clinicians; however, to date few studies have evaluated patterns of communication and decision making amongst clinicians collaborating in the care of challenging patients with CLBP.

Association between plasma adiponectin levels and colorectal cancer risk in women.

Background: Adiponectin, an adipocyte-secreted hormone, has insulin-sensitizing characteristics. It remains unclear whether adiponectin may influence colorectal cancer development.

Methods: To determine whether prediagnostic levels of adiponectin were associated with risk of incident colorectal cancer in the Women's Health Study, we conducted a nested case-control study of 275 colorectal cancer cases and 275 matched controls.

TERT gene harbors multiple variants associated with pancreatic cancer susceptibility.

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681.

Higher Intake of Fruit, but Not Vegetables or Fiber, at Baseline Is Associated with Lower Risk of Becoming Overweight or Obese in Middle-Aged and Older Women of Normal BMI at Baseline.

Background: Fruit, vegetable, and dietary fiber intake have been associated with lower risk of cardiovascular disease (CVD); however, little is known about their role in obesity prevention.

Objective: Our goal was to investigate whether intake of fruits, vegetables, and dietary fiber is associated with weight change and the risk of becoming overweight and obese.

Methods: We studied 18,146 women aged ≥45 y from the Women's Health Study free of CVD and cancer with an initial body mass index (BMI) of 18.

Headache, migraine and risk of brain tumors in women: prospective cohort study.

Background: While headache is a common symptom among brain tumors patients, often patients with common headache have concerns of being at risk for developing brain tumors. We aimed to disprove that migraine or headache in general is associated with increased risk of developing brain tumors.

Methods: Prospective study among 39,534 middle-aged women, free of any cancer, and who provided information on headache history at baseline.

Novel protein glycan side-chain biomarker and risk of incident type 2 diabetes mellitus.

Objectives: Enzymatically glycosylated proteins partake in multiple biological processes, including glucose transport and inflammation. We hypothesized that a novel biomarker (GlycA) of N-acetyl methyl groups originating mainly from N-acetylglucosamine moieties of acute-phase glycoproteins is related to incident type 2 diabetes mellitus and compared it with high-sensitivity C-reactive protein.

Approach And Results: In 26,508 initially healthy women free of diabetes mellitus, baseline GlycA and high-sensitivity C-reactive protein were quantified by nuclear magnetic resonance spectroscopy and immunoturbidimetry, respectively.

Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data.

We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 × 10(-11) ), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls).

A prospective study of erythrocyte polyunsaturated fatty acid, weight gain, and risk of becoming overweight or obese in middle-aged and older women.

Purpose: ω3 and ω6 fatty acids (FA) may have divergent effects on the development of obesity. We examined the association of baseline erythrocyte ω3 and ω6 FA composition with body weight change and the risk of becoming overweight or obese in the Women's Health Study (WHS) participants.

Methods: We identified 534 women who had baseline erythrocyte FA measured and a baseline body mass index (BMI) of 18.

Circulating Vitamin D Levels and Risk of Colorectal Cancer in Women.

Observational data on the association between circulating 25(OH)D and colorectal cancer risk are limited in women. To determine whether prediagnostic levels of 25(OH)D were associated with risk of incident colorectal cancer in the Women's Health Study (WHS), we conducted a nested case-control study using 274 colorectal cases and 274 controls. Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw.

Prospective study of plasma homocysteine level and risk of age-related macular degeneration in women.

Purpose: Prospective data to examine the association of homocysteine with age-related macular degeneration (AMD) are limited. We examined the prospective relation of plasma homocysteine level and AMD in a large cohort of apparently healthy women.

Methods: We evaluated the relationship between baseline levels of plasma homocysteine and incident AMD among 27,479 female health professionals aged 40 years or older.

Interrelationship Between Alcohol Intake and Endogenous Sex-Steroid Hormones on Diabetes Risk in Postmenopausal Women.

Objective: We examined whether circulating concentrations of sex hormones, including estradiol, testosterone, sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEAS), were associated with alcohol intake or mediated the alcohol-type 2 diabetes (T2D) association.

Methods: Among women not using hormone replacement therapy and free of baseline cardiovascular disease, cancer, and diabetes in the Women's Health Study, 359 incident cases of T2D and 359 matched controls were chosen during 10 years of follow-up.

Results: Frequent alcohol intake (≥1 drink/day) was positively and significantly associated with higher plasma estradiol concentrations in an age-adjusted model (β = 0.

Characterization of large structural genetic mosaicism in human autosomes.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals.

Reproductive factors, exogenous hormone use and risk of hepatocellular carcinoma among US women: results from the Liver Cancer Pooling Project.

Background: Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic.

VITAL-Bone Health: rationale and design of two ancillary studies evaluating the effects of vitamin D and/or omega-3 fatty acid supplements on incident fractures and bone health outcomes in the VITamin D and OmegA-3 TriaL (VITAL).

Rationale: Although vitamin D is widely used to promote skeletal health, definitive data on benefits and risks of supplemental vitamin D alone on bone are lacking. Results from large, randomized controlled trials in the general population are sparse. Data on the effects of supplemental omega-3 fatty acids (FAs) on bone are also limited.