Showing papers by "Andrea Z. LaCroix published in 2012"
TL;DR: In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, this paper observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples.
Abstract: In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
496 citations
TL;DR: This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
Abstract: Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
249 citations
Fred Hutchinson Cancer Research Center1, University of Washington2, University of Southern California3, University Health Network4, Ottawa Hospital Research Institute5, Ontario Institute for Cancer Research6, Translational Genomics Research Institute7, Harvard University8, University of Chicago9, University of Michigan10, German Cancer Research Center11, Memorial University of Newfoundland12, Ohio State University13, Kaiser Permanente14, New York University15, National Institutes of Health16, University of Pittsburgh17, University of Nantes18, University of Utah19, University of Melbourne20, University of Hawaii at Manoa21, Mayo Clinic22, University of Toronto23
TL;DR: The study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer and selected the most statistically significant single nucleotide polymorphisms for replication using ten independent studies.
Abstract: Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.
200 citations
University of Washington1, German Cancer Research Center2, University of Utah3, Translational Genomics Research Institute4, Harvard University5, Boston University6, University Health Network7, University of Southern California8, University of Chicago9, University of Nantes10, Ottawa Hospital Research Institute11, Ohio State University12, University of Pittsburgh13, National Institutes of Health14, New York University15, Kaiser Permanente16, Massey University17, University of Toronto18
TL;DR: Overall, the association of most CRC susceptibility loci identified in initial GWAS seems to be invariant to the other risk factors considered; however, the results suggest potential modification of the rs16892766 effect by vegetable consumption.
Abstract: Genome-wide association studies (GWAS) have identified more than a dozen loci associated with colorectal cancer (CRC) risk. Here, we examined potential effect-modification between single-nucleotide polymorphisms (SNP) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23), rs6983267 at 8q24 (MYC), rs10795668 at 10p14 (FLJ3802842), rs3802842 at 11q23 (LOC120376), rs4444235 at 14q22.2 (BMP4), rs4779584 at 15q13 (GREM1), rs9929218 at 16q22.1 (CDH1), rs4939827 at 18q21 (SMAD7), rs10411210 at 19q13.1 (RHPN2), and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/nonsteroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal P(interaction) = 1.3 × 10(-4); adjusted P = 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS seems to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption.
148 citations
University of Massachusetts Medical School1, University of Alabama at Birmingham2, McMaster University3, Katholieke Universiteit Leuven4, University of Lyon5, Cambridge University Hospitals NHS Foundation Trust6, University of Southampton7, Autonomous University of Barcelona8, University of Pittsburgh9, Fred Hutchinson Cancer Research Center10, VU University Medical Center11, University of Verona12, Paris Descartes University13, Royal North Shore Hospital14, Cedars-Sinai Medical Center15, Columbia University Medical Center16, University of Cincinnati17
TL;DR: It is suggested that a broad range of prior fracture sites are associated with an increased risk of incident fractures, with important implications for clinical assessments and risk model development.
Abstract: Previous fractures of the hip, spine, or wrist are well-recognized predictors of future fracture, but the role of other fracture sites is less clear. We sought to assess the relationship between prior fracture at 10 skeletal locations and incident fracture. The Global Longitudinal Study of Osteoporosis in Women (GLOW) is an observational cohort study being conducted in 17 physician practices in 10 countries. Women aged ≥55 years answered questionnaires at baseline and at 1 and/or 2 years (fractures in previous year). Of 60,393 women enrolled, follow-up data were available for 51,762. Of these, 17.6%, 4.0%, and 1.6% had suffered 1, 2, or ≥3 fractures, respectively, since age 45 years. During the first 2 years of follow-up, 3149 women suffered 3683 incident fractures. Compared with women with no previous fractures, women with 1, 2, or ≥3 prior fractures were 1.8-, 3.0-, and 4.8-fold more likely to have any incident fracture; those with ≥3 prior fractures were 9.1-fold more likely to sustain a new vertebral fracture. Nine of 10 prior fracture locations were associated with an incident fracture. The strongest predictors of incident spine and hip fractures were prior spine fracture (hazard ratio [HR] = 7.3) and hip (HR = 3.5). Prior rib fractures were associated with a 2.3-fold risk of subsequent vertebral fracture, and previous upper leg fracture predicted a 2.2-fold increased risk of hip fracture. Women with a history of ankle fracture were at 1.8-fold risk of future fracture of a weight-bearing bone. Our findings suggest that a broad range of prior fracture sites are associated with an increased risk of incident fractures, with important implications for clinical assessments and risk model development.
142 citations
Victoria University of Wellington1, Southampton General Hospital2, University of Cambridge3, University of Massachusetts Medical School4, Columbia University Medical Center5, St. Joseph Hospital6, Katholieke Universiteit Leuven7, University of Lyon8, Autonomous University of Barcelona9, Fred Hutchinson Cancer Research Center10, VU University Medical Center11, University of Verona12, Paris Descartes University13, University of Alabama at Birmingham14, Royal North Shore Hospital15, Cedars-Sinai Medical Center16, University of Cincinnati17, University of Pittsburgh18, University of Oxford19
TL;DR: Addition of co-morbidity index to FRAX risk factors improved fracture prediction, and Parkinson's disease carried a particularly high risk of fracture; and increasing co- Morbidity Index was associated with increasing fracture risk.
129 citations
TL;DR: To examine the associations between depressive symptoms, antidepressant use, and duration of use with incident frailty 3 years later in nonfrail women aged 65 and older, the aim was to establish a baseline level of baseline depression and establish an apples-to- apples relationship.
Abstract: Objectives
To examine the associations of depressive symptoms, antidepressant use, and duration of use with incident frailty three years later in nonfrail women ≥ age 65.
119 citations
TL;DR: Sedentary time was strongly associated with diminished physical function and most pronounced among older women and those reporting the greatest sedentary time, and maintaining physical function with age may be improved by pairing messages to limit sedentary activities with those promoting recommended levels of physical activity.
Abstract: Sedentary behavior is associated with deleterious health outcomes. This study evaluated the association between sedentary time and physical function among postmenopausal women in the Women's Health Initiative Observational Study. Data for this prospective cohort study were collected between 1993-1998 (enrollment) and 2009, with an average of 12.3 follow-up years. Analyses included 61,609 women (aged 50-79 years at baseline). Sedentary time was estimated by questionnaire; physical function was measured using the RAND SF-36 physical function scale. Mixed-model analysis of repeated measures was used to estimate the relationship of sedentary time exposures and changes in physical function adjusting for relevant covariates. Compared to women reporting sedentary time of ≤6 hours/day, those with greater amounts of sedentary time (>6-8 hours/day, >8-11 hours/day, >11 hours/day) reported lower physical function between baseline and follow up (coefficient = -0.78, CI = -0.98, -0.57, -1.48, CI = -1.71, -1.25, -3.13, and CI = -3.36, -2.89, respectively P < 0.001). Sedentary time was strongly associated with diminished physical function and most pronounced among older women and those reporting the greatest sedentary time. Maintaining physical function with age may be improved by pairing messages to limit sedentary activities with those promoting recommended levels of physical activity.
107 citations
University of Texas MD Anderson Cancer Center1, National Institutes of Health2, Yale University3, Memorial Sloan Kettering Cancer Center4, Fred Hutchinson Cancer Research Center5, Harvard University6, Brigham and Women's Hospital7, Baylor College of Medicine8, Silver Spring Networks9, New York University10, Utrecht University11, University of Toronto12, University of Minnesota13, University of California, San Francisco14, American Cancer Society15, Johns Hopkins University16, Johns Hopkins University School of Medicine17, Group Health Cooperative18, Mayo Clinic19, Vanderbilt University20, Albert Einstein College of Medicine21, Institut Gustave Roussy22, German Cancer Research Center23, University of California, Irvine24, Science Applications International Corporation25, Cancer Care Ontario26, Umeå University27, International Agency for Research on Cancer28, University of Cambridge29, Imperial College London30, Academy of Athens31
TL;DR: The results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.
Abstract: Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS) Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan) We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 005), ie pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 20 × 10(-6), 16 × 10(-5), 00019, 0019 and 0023, respectively) After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 83 × 10(-5)), whereas the others did not The most significant genes (P < 001) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for Hpylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer
105 citations
TL;DR: Elevated levels of inflammatory markers for all three cytokine‐soluble receptors were associated with an increased risk of hip fractures in older women, and future clinical trials should test whether interventions to decrease inflammatory marker levels reduces hip fractures.
Abstract: Cytokines play a major role in bone remodeling in vitro and in animal models, with evidence supporting the involvement of inflammatory markers in the pathogenesis of osteoporosis. However, less is known about the longitudinal association of inflammatory markers with hip fracture. We tested whether high receptor levels of proinflammatory cytokines are associated with an increased risk of hip fracture in older women. We used a nested case-control study design from the Women's Health Initiative Observational Study (WHI-OS) and selected 400 cases with physician-adjudicated incident hip fractures and 400 controls matched on age, race, and date of blood draw. Participants were chosen from 39,795 postmenopausal women without previous hip fractures, not using estrogens or other bone-active therapies. Incident hip fractures (median follow-up 7.1 years) were verified by review of radiographs and confirmed by blinded central adjudicators. Hip fractures with a pathological cause were excluded. In multivariable models, the risk of hip fracture for subjects with the highest levels of inflammatory markers (quartile 4) compared with those with lower levels (quartiles 1, 2, and 3) was 1.43 (95% confidence interval [CI], 0.98-2.07) for interleukin-6 (IL-6) soluble receptor (SR), 1.40 (95% CI, 0.97-2.03) for tumor necrosis factor (TNF) SR1, and 1.56 (95% CI, 1.09-2.22) for TNF SR2. In subjects with all three markers in the highest quartile, the risk ratio of fracture was 2.76 (95% CI, 1.22-6.25) in comparison with subjects with 0 or 1 elevated marker(s) (p trend = 0.018). Elevated levels of inflammatory markers for all three cytokine-soluble receptors were associated with an increased risk of hip fractures in older women. Future clinical trials should test whether interventions to decrease inflammatory marker levels reduces hip fractures.
104 citations
Paris Descartes University1, University of Massachusetts Medical School2, St. Joseph Hospital3, University of Lyon4, University of Cambridge5, University of Southampton6, Autonomous University of Barcelona7, University of Pittsburgh8, Fred Hutchinson Cancer Research Center9, VU University Medical Center10, University of Verona11, University of Alabama at Birmingham12, Royal North Shore Hospital13, Cedars-Sinai Medical Center14, Columbia University Medical Center15, University of Cincinnati16, Katholieke Universiteit Leuven17
TL;DR: This prospective study shows that NHNV fractures have a detrimental effect on HRQL, and efforts to optimize the care of osteoporosis patients should include the prevention ofNHNV fractures.
Abstract: Among 50,461 postmenopausal women, 1,822 fractures occurred (57% minor non-hip, non-vertebral [NHNV], 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D, followed by major NHNV and hip fractures. Decreases in physical function and health status were greatest for spine or hip fractures. There is growing evidence that NHNV fractures result in substantial morbidity and healthcare costs. The aim of this prospective study was to assess the effect of these NHNV fractures on quality of life. We analyzed the 1-year incidences of hip, spine, major NHNV (pelvis/leg, shoulder/arm) and minor NHNV (wrist/hand, ankle/foot, rib/clavicle) fractures among women from the Global Longitudinal study of Osteoporosis in Women (GLOW). Health-related quality of life (HRQL) was analyzed using the EuroQol EQ-5D tool and the SF-36 health survey. Among 50,461 women analyzed, there were 1,822 fractures (57% minor NHNV, 26% major NHNV, 10% spine, 7% hip) over 1 year. Spine fractures had the greatest detrimental effect on EQ-5D summary scores, followed by major NHNV and hip fractures. The number of women with mobility problems increased most for those with major NHNV and spine fractures (both +8%); spine fractures were associated with the largest increases in problems with self care (+11%), activities (+14%), and pain/discomfort (+12%). Decreases in physical function and health status were greatest for those with spine or hip fractures. Multivariable modeling found that EQ-5D reduction was greatest for spine fractures, followed by hip and major/minor NHNV. Statistically significant reductions in SF-36 physical function were found for spine fractures, and were borderline significant for major NHNV fractures. This prospective study shows that NHNV fractures have a detrimental effect on HRQL. Efforts to optimize the care of osteoporosis patients should include the prevention of NHNV fractures.
TL;DR: In this paper, the effect of escitalopram on insomnia and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flashes was evaluated in a randomized, blinded, multicenter, placebo-controlled parallel-group 8-week trial with 205 women.
Abstract: Objective: The aim of this study was to determine the effect of escitalopram on insomnia symptoms and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flashes. Methods: A randomized, blinded, multicenter, placebo-controlled parallel-group 8-week trial with 205 women (95 African American, 102 white, 8 other) was conducted between July 2009 and June 2010. The participants received escitalopram (10-20 mg/d) or placebo. Insomnia symptoms (Insomnia Severity Index [ISI]) and subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]) at weeks 4 and 8 were the prespecified secondary outcomes. A total of 199 women (97%) provided ISI data, and 194 (95%) women provided PSQI data at follow-up. Results: At baseline, mean hot flash frequency was 9.78 per day (SD, 5.60), mean ISI was 11.4 (SD, 6.3), and mean PSQI was 8.0 (SD, 3.7). Treatment with escitalopram reduced ISI at week 8 (mean difference, j2.00; 95% CI, j3.43 to j0.57; P G 0.001 overall treatment effect), with mean differences of j4.73 (95% CI, j5.72 to j3.75) in the escitalopram group and j2.73 (95% CI, j3.78 to j1.69) in the placebo group. The reduction in PSQI was greater in the escitalopram than in the placebo group at week 8 (mean difference, j1.31; 95% CI, j2.14 to j0.49; P G 0.001 overall treatment effect). Clinical improvement in insomnia symptoms and subjective sleep quality (Q50% decreases in ISI and PSQI from baseline) was observed more frequently in the escitalopram group than in the placebo group (ISI, 50.0% vs 35.4%, P = 0.04; PSQI, 29.6% vs 19.2%, P = 0.09). Conclusions: Among healthy perimenopausal and postmenopausal women with hot flashes, escitalopram at 10 to 20 mg/day compared with placebo reduced insomnia symptoms and improved subjective sleep quality at 8 weeks of follow-up.
University of Pittsburgh1, University of Massachusetts Medical School2, University of Verona3, Katholieke Universiteit Leuven4, Fred Hutchinson Cancer Research Center5, VU University Medical Center6, University of California, Los Angeles7, Columbia University Medical Center8, University of Cincinnati9
TL;DR: To determine the proportion of untreated women who reported receiving treatment after incident fracture and to identify factors that predict treatment across an international spectrum of individuals.
Abstract: Osteoporosis is a common and costly problem. Approximately half of women aged 50 and older will sustain a fragility fracture, and the greatest morbidity occurs in those aged 65 and older.1 Mortality can reach 20% for a hip or vertebral fracture within the first year and continues to rise for up to 10 years.2–4 Medications are available to reduce the risk of fractures.5–8 Oral, intravenous, inhaled, and subcutaneous medications reduce the risk of vertebral fractures 50% or more,5,6 and some medications also substantially reduce the risk of nonvertebral and hip fractures.5,6
Despite the availability of a variety of medications, few recent data are available on factors that determine whether individuals with new fragility fractures are treated. Previous studies suggest that fewer than 5% of individuals admitted to hospital with hip fracture leave the hospital with a diagnosis of osteoporosis and that fewer than 1% are treated.9 Similar studies have documented poor treatment rates in individuals with vertebral fractures. Data from the National Health and Nutrition Examination Survey (NHANES) suggest that fewer than 14% of women with a diagnosis of osteoporosis are treated with an antiresorptive medication and that the number of risk factors for fracture does not alter rates of medication use.10 Previous studies have focused on a single community or country, often under the umbrella of a national or insurance-based health care environment. Such local or national health environments may limit or support osteoporosis medication use. Global data are needed to better identify barriers to treatment across a range of practices, regions, and healthcare systems. Such data with differing healthcare costs, guidelines, reimbursements, and access to care may clarify obstacles to treatment after a fracture.
The Global Longitudinal Study of Osteoporosis in Women (GLOW) is a multinational, observational, prospective study designed to provide information on patterns of management of fracture and fracture risk in women aged 55 and older, with an oversampling of elderly women over a 5-year period on an international basis. The goals of the present study were to determine the proportion of women not receiving therapy at baseline who suffered an incident fracture and were receiving treatment at 1-year follow-up and to understand the factors that predict treatment. To examine this, GLOW participants who had sustained a fragility fracture during their first year of follow-up were surveyed.
TL;DR: A prominent role for B-cell activation among postmenopausal women in the etiology of B- cell NHL and/or in processes reflective of early disease development as early as 9 years before diagnosis is indicated.
Abstract: B-cell activation biomarkers have been associated with increased risk of non-Hodgkin lymphoma (NHL) in HIV-infected populations. However, whether a similar association may exist in general populations has not been established. We conducted a case-control study within the Women's Health Initiative Observational Study cohort to measure the B-cell activation biomarkers sCD23, sCD27, sCD30, sCD44, and CXCL13 in serum samples collected an average of 6 years before NHL diagnosis in 491 cases and 491 controls. Using logistic regression to estimate odds ratios, we observed strong associations between NHL and markers for all B-cell NHL and for major subtypes. Women with marker levels in the highest-versus-lowest quartile categories of CD23, CD27, CD30, or CXCL13 were at 2.8- to 5.5-fold increased risk of B-NHL. In addition, there were significant trends of risk with increasing levels of these markers present. Associations were strongest for cases with shortest lag times between blood draw and diagnosis (<3 years). However, there were also significant associations for cases with the longest prediagnostic lag (9 to 13 years). Taken together, our findings indicate a prominent role for B-cell activation among postmenopausal women in the etiology of B-cell NHL and/or in processes reflective of early disease development as early as 9 years before diagnosis.
University of Pennsylvania1, Utrecht University2, University of Amsterdam3, University of Western Ontario4, University of Virginia5, Johns Hopkins University6, Washington University in St. Louis7, Baylor College of Medicine8, Jackson State University9, Cedars-Sinai Medical Center10, National Institutes of Health11, Boston University12, University of Vermont13, Translational Genomics Research Institute14, Medical University of South Carolina15, University of Texas Health Science Center at Houston16, University of Alabama at Birmingham17, University of Pittsburgh18, Fred Hutchinson Cancer Research Center19, Wake Forest University20, Northwestern University21, Harvard University22, United States Department of Agriculture23, Icahn School of Medicine at Mount Sinai24, Broad Institute25, University of Minnesota26, McMaster University27, Group Health Cooperative28, University College London29, University of Mississippi30
TL;DR: Differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.
Abstract: Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.
TL;DR: The results suggest depression, nonpain physical symptoms, obesity, and possibly opioid treatment are associated with worse long-term pain outcomes in this population of postmenopausal women.
TL;DR: Substantial differences in risk profiles exist among the 10 bones considered, and why model discrimination using clinical risk factors is generally better in hip fracture models than in models that combine hip with other bones is understood.
Abstract: The purposes of this study were to examine fracture risk profiles at specific bone sites, and to understand why model discrimination using clinical risk factors is generally better in hip fracture models than in models that combine hip with other bones. Using 3-year data from the GLOW study (54,229 women with more than 4400 total fractures), we present Cox regression model results for 10 individual fracture sites, for both any and first-time fracture, among women aged ≥55 years. Advanced age is the strongest risk factor in hip (hazard ratio [HR] = 2.3 per 10-year increase), pelvis (HR = 1.8), upper leg (HR = 1.8), and clavicle (HR = 1.7) models. Age has a weaker association with wrist (HR = 1.1), rib (HR = 1.2), lower leg (not statistically significant), and ankle (HR = 0.81) fractures. Greater weight is associated with reduced risk for hip, pelvis, spine, and wrist, but higher risk for first lower leg and ankle fractures. Prior fracture of the same bone, although significant in nine of 10 models, is most strongly associated with spine (HR = 6.6) and rib (HR = 4.8) fractures. Past falls are important in all but spine models. Model c indices are ≥0.71 for hip, pelvis, upper leg, spine, clavicle, and rib, but ≤0.66 for upper arm/shoulder, lower leg, wrist, and ankle fractures. The c index for combining hip, spine, upper arm, and wrist (major fracture) is 0.67. First-time fracture models have c indices ranging from 0.59 for wrist to 0.78 for hip and pelvis. The c index for first-time major fracture is 0.63. In conclusion, substantial differences in risk profiles exist among the 10 bones considered.
TL;DR: To examine associations between angiotensin‐converting enzyme (ACE) inhibitor and statin medications and baseline and mean annual change in physical performance measures and muscle strength in older women, a large number of patients were prescribed statins.
Abstract: Objectives: To examine associations between angiotensin-converting enzyme (ACE) inhibitor and statin medications and baseline and mean annual change in physical performance measures and muscle strength in older women.
Design: Prospective cohort study.
Participants: Participants from the Women's Health Initiative Clinical Trials aged 65 to 79 at baseline who had physical performance measures, self-report of health insurance, and no prior history of stroke or congestive heart failure were included (N = 5,777). Women were recruited between 1993 and 1998.
Measurements: Medication use was ascertained through a baseline inventory. Physical performance measures (timed 6-m walk, repeated chair stands in 15 seconds) and grip strength were assessed at baseline and follow-up Years 1, 3, and 6. Multivariable-adjusted linear repeated-measures models were adjusted for demographic and health characteristics.
Results: ACE inhibitor use was associated with lower mean grip strength at baseline (22.40 kg, 95% confidence interval (CI) = 21.89�22.91 vs 23.18 kg, 95% CI 23.02�23.34; P = .005) and greater mean annual change in number of chair stands (-0.182, 95% CI -0.217 to -0.147 vs -0.145, 95% CI -0.156 to -0.133; P = .05) than nonuse. Statin use was not significantly associated with baseline measures or mean annual change for any outcome. A subgroup analysis suggested that statin use was associated with less mean annual change in chair stands (P = .006) in the oldest women.
Conclusion: These results do not support an association between statin or ACE inhibitor use and slower decline in physical performance or muscle strength and thus do not support the use of these medications for preserving functional status in older adults.
TL;DR: Treatment with escitalopram 10-20mg/day in healthy women with vasomotor symptoms significantly improved menopause-related quality of life and pain.
TL;DR: In this article, the effect of escitalopram (10-20 mg/d) versus placebo for reducing hot flash interference in daily life and understand correlates and predictors of reductions in hot flash interferences, a key measure of quality of life.
TL;DR: Postmenopausal White women with mild renal dysfunction are at increased risk of nonvertebral fracture, and effects of renal function on chronic inflammation may mediate this association.
Abstract: Summary
To examine the association between renal function and fracture in multiethnic women, we studied postmenopausal women enrolled in the Women’s Health Initiative. Postmenopausal White women with mild renal dysfunction were at increased risk of nonvertebral fracture; this association was at least partially explained by effects of renal dysfunction on chronic inflammation. Reduced renal function appeared to increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups.
TL;DR: The modest discriminatory accuracy of the BCRAT for Hispanic women might improve by using risk factor relative risks specific to Hispanic women by using risks from non-Hispanic white women.
Abstract: For Hispanic women, the Breast Cancer Risk Assessment Tool (BCRAT; “Gail Model”) combines 1990–1996 breast cancer incidence for Hispanic women with relative risks for breast cancer risk factors from non-Hispanic white (NHW) women. BCRAT risk projections have never been comprehensively evaluated for Hispanic women. We compared the relative risks and calibration of BCRAT risk projections for 6,353 Hispanic to 128,976 NHW postmenopausal participants aged 50 and older in the Women’s Health Initiative (WHI). Calibration was assessed by the ratio of the number of breast cancers observed with that expected by the BCRAT (O/E). We re-evaluated calibration for an updated BCRAT that combined BCRAT relative risks with 1993–2007 breast cancer incidence that is contemporaneous with the WHI. Cox regression was used to estimate relative risks. Discriminatory accuracy was assessed using the concordance statistic (AUC). In the WHI Main Study, the BCRAT underestimated the number of breast cancers by 18% in both Hispanics (O/E = 1.18, P = 0.06) and NHWs (O/E = 1.18, P < 0.001). Updating the BCRAT improved calibration for Hispanic women (O/E = 1.08, P = 0.4) and NHW women (O/E = 0.98, P = 0.2). For Hispanic women, relative risks for number of breast biopsies (1.71 vs. 1.27, P = 0.03) and age at first birth (0.97 vs. 1.24, P = 0.02) differed between the WHI and BCRAT. The AUC was higher for Hispanic women than NHW women (0.63 vs. 0.58, P = 0.03). Updating the BCRAT with contemporaneous breast cancer incidence rates improved calibration in the WHI. The modest discriminatory accuracy of the BCRAT for Hispanic women might improve by using risk factor relative risks specific to Hispanic women.
TL;DR: Adjusted for lean body weight, the BMD and bending strength in the femoral neck are significantly lower in insulin-treated diabetic women vs controls, which may represent altered adaptation of bone modeling and explain the higher fracture risk in patients with T2DM.
Abstract: Objective
Women with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD) as compared to women without diabetes. We hypothesized that bone strength is diminished in women with T2DM after accounting for lean body mass, which may contribute to their increased fracture risk.
TL;DR: Physical-Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality.
Abstract: Methods. Data from Women ’ s Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services). Results. We identifi ed a multidimensional phenotype of positive aging that included two factors: Physical – Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical – Social Functioning was the strongest predictor. Each standard deviation of increase in Physical – Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living. Conclusions. Physical – Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical – Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality.
TL;DR: The results suggest that NSAID use is associated with lower CRC mortality among postmenopausal women who use these medications more consistently over time, and support prolongedNSAID use in post menopausal women for the prevention of poor CRC outcomes.
Abstract: Background: Randomized trial evidence shows that nonsteroidal anti-inflammatory drug (NSAID) use, particularly long-term use, reduces the incidence of colorectal neoplasia. Recent data also suggests an inverse association between NSAID use and death due to colorectal cancer (CRC).
Methods: We examined the association between NSAID use and CRC mortality among 160,143 postmenopausal women enrolled in the Women's Health Initiative. Women provided details on medication use at baseline and three years after enrollment. Reported CRC cases were locally confirmed and centrally adjudicated; cause of death was determined according to centralized medical record and death certificate review. Cox regression was used to investigate the association between NSAID use and CRC mortality.
Results: Overall, NSAID use at baseline was not associated with CRC mortality [HR: 0.93; 95% confidence interval (CI) 0.76, 1.14]. However, women who reported NSAID use at both baseline and year 3 experienced reductions in CRC mortality (HR: 0.72; 95% CI 0.54, 0.95) compared with nonusers.
Conclusion: Results suggest that NSAID use is associated with lower CRC mortality among postmenopausal women who use these medications more consistently over time.
Impact: Our results support prolonged NSAID use in postmenopausal women for the prevention of poor CRC outcomes. Cancer Epidemiol Biomarkers Prev; 21(11); 1966–73. ©2012 AACR .
TL;DR: Bone density change was weakly inversely correlated with change in the concentrations of BTMs, which may prove useful in the monitoring of the response to lasofoxifene treatment for women with postmenopausal osteoporosis early in the course of treatment.
TL;DR: Within the WHI-BMD, women with RA group had reduced BMD and structural geometry at baseline, and this reduction was seen at a fixed rate throughout the 9 yr of study.
TL;DR: It is suggested that DMPA use is associated with fat mass in adolescents and that EE dose in OCs is associated for young adult women and baseline body composition was not associated with duration of OC use.
Abstract: Background/Aims Hormonal contraception is a popular contraceptive choice among sexually-active women. Yet its association with body composition in younger women is not well understood. We compared body composition measures by duration of Depo-Provera (DMPA) use and dose and duration of oral contraceptive (OC) use in adolescent and young adult women. Methods Study participants were Group Health Cooperative members. DMPA use (new prevalent or none) was collected in 170 adolescents aged 14-18 years and in 440 women aged 18-39 years. OC use was gathered in 301 adolescents aged 14-18 years and 305 women aged 19-30 years. Among OC users ethinyl estradiol (EE) dose (=30mcg vs. <30mcg) and months of use were also collected. For all participants weight BMI and truncal and total fat and lean mass were estimated using DEXA. Mean differences in baseline body composition by dose and duration of hormone contraception use were compared cross-sectionally using ANOVA. Results Adolescents who were prevalent DMPA users had higher baseline truncal and total fat mass compared to adolescent non-DMPA users. For example baseline mean (SE) total fat mass was 23.3 (1.2) kilograms for prevalent DMPA users but was 19.9 (0.9) kilograms for non-DMPA users (p<0.05). No mean differences in the body composition measures were observed between new DMPA vs. non- DMPA adolescent users or among young women regardless of DMPA use. With OC use baseline BMI and truncal and total fat mass differed by EE dose in young adult women. Baseline mean (SE) total fat mass in kilograms for women using =30mcg EE doses <30mcg EE doses and for non-OC users was 20.8 (0.9) 19.0 (0.9) and 22.2 (0.9) respectively (p=0.02). No differences were noted between EE dose and body composition indices in adolescents. For both adolescents and young women baseline body composition was not associated with duration of OC use. Conclusions Our results suggest that DMPA use is associated with fat mass in adolescents and that EE dose in OCs is associated with fat mass in young adult women. Analysis of follow-up data to determine if these relationships continue to be seen longitudinally is needed.
TL;DR: In women around the menopausal transition, agreement between self-reported OC use and computerized OC prescription fills was moderate for use after age 38 and excellent for OC use within 5 years of the reference date.
Abstract: Background/Aims Self-reported use of oral contraceptives (OCs) may be subject to recall bias. Previous reports comparing self-report OC use and computerized pharmacy data have focused on current use or longer-term use in younger women and have found (adjusted) kappa statistics of 79-85%. The objective of the current analysis was to evaluate the reliability of self-reported OC use obtained from a sample of peri- and early post-menopausal women. Methods Participants were 45-59 year-old women eligible for an ongoing population-based case-control study assessing the association between OC use and incident fractures around the menopausal transition. Cases were all women enrolled in Group Health with an ICD9 osteoporotic fracture code in 2008-2009; age-matched non-fracture controls were randomly selected. Eligible cases and controls (n=535) who reported at interview that they always/usually filled prescriptions at GH pharmacies and agreed to record review were included. Respondents who reported ever using OCs before the reference date (fracture date for cases; randomly assigned dates based on distribution of case dates for controls) were asked for each episode of use their age and length of use. A life events- calendar tool was available to interviewers. Computerized pharmacy information was obtained on OC fills back to 1977. OC use was based on GH pharmacy and First Data Bank OC class key ingredients [e.g. ethinyl estradiol levonorgestrel] and name. OC use was evaluated using >1 fill or >2 fills within a 1-year period. Ever use use since ages 35 38 and 40 and 5 years before reference date were examined. Women were required to be enrolled for the designated time period except for the ever-use category. We calculated kappa (K) the chance-corrected measure of agreement and the prevalence-adjusted bias-adjusted kappa (PABAK). Results The agreement between self-reported OC use and OC fills was highest for more recent use (PABAK=92% for OC use within 5 years of reference date and 55% for use at ages >38). Conclusion In women around the menopausal transition agreement between self-reported OC use and computerized OC prescription fills was moderate for use after age 38 and excellent for OC use within 5 years of the reference date.