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1.  Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis 
Wormser, David | Angelantonio, Emanuele Di | Kaptoge, Stephen | Wood, Angela M | Gao, Pei | Sun, Qi | Walldius, Göran | Selmer, Randi | Verschuren, WM Monique | Bueno-de-Mesquita, H Bas | Engström, Gunnar | Ridker, Paul M | Njølstad, Inger | Iso, Hiroyasu | Holme, Ingar | Giampaoli, Simona | Tunstall-Pedoe, Hugh | Gaziano, J Michael | Brunner, Eric | Kee, Frank | Tosetto, Alberto | Meisinger, Christa | Brenner, Hermann | Ducimetiere, Pierre | Whincup, Peter H | Tipping, Robert W | Ford, Ian | Cremer, Peter | Hofman, Albert | Wilhelmsen, Lars | Clarke, Robert | de Boer, Ian H | Jukema, J Wouter | Ibañez, Alejandro Marín | Lawlor, Debbie A | D'Agostino, Ralph B | Rodriguez, Beatriz | Casiglia, Edoardo | Stehouwer, Coen DA | Simons, Leon A | Nietert, Paul J | Barrett-Connor, Elizabeth | Panagiotakos, Demosthenes B | Björkelund, Cecilia | Strandberg, Timo E | Wassertheil-Smoller, Sylvia | Blazer, Dan G | Meade, Tom W | Welin, Lennart | Svärdsudd, Kurt | Woodward, Mark | Nissinen, Aulikki | Kromhout, Daan | Jørgensen, Torben | Tilvis, Reijo S | Guralnik, Jack M | Rosengren, Annika | Taylor, James O | Kiechl, Stefan | Dagenais, Gilles R | Gerry, F | Fowkes, R | Wallace, Robert B | Khaw, Kay-Tee | Shaffer, Jonathan A | Visser, Marjolein | Kauhanen, Jussi | Salonen, Jukka T | Gallacher, John | Ben-Shlomo, Yoav | Kitamura, Akihiko | Sundström, Johan | Wennberg, Patrik | Kiyohara, Yutaka | Daimon, Makoto | de la Cámara, Agustin Gómez | Cooper, Jackie A | Onat, Altan | Devereux, Richard | Mukamal, Kenneth J | Dankner, Rachel | Knuiman, Matthew W | Crespo, Carlos J | Gansevoort, Ron T | Goldbourt, Uri | Nordestgaard, Børge G | Shaw, Jonathan E | Mussolino, Michael | Nakagawa, Hidaeki | Fletcher, Astrid | Kuller, Lewis H | Gillum, Richard F | Gudnason, Vilmundur | Assmann, Gerd | Wald, Nicholas | Jousilahti, Pekka R | Greenland, Philip | Trevisan, Maurizio | Ulmer, Hanno | Butterworth, Adam S | Folsom, Aaron R | Davey-Smith, George | Hu, Frank B | Danesh, John | Tipping, Robert W | Ford, Charles E | Simpson, Lara M | Walldius, Göran | Jungner, Ingmar | Folsom, Aaron R | Demerath, Ellen W | Franceschini, Nora | Lutsey, Pamela L | Panagiotakos, Demosthenes B | Pitsavos, Christos | Chrysohoou, Christina | Stefanadis, Christodoulos | Shaw, Jonathan E | Atkins, Robert | Zimmet, Paul Z | Barr, Elizabeth LM | Knuiman, Matthew W | Whincup, Peter H | Wannamethee, S Goya | Morris, Richard W | Willeit, Johann | Kiechl, Stefan | Weger, Siegfried | Oberhollenzer, Friedrich | Wald, Nicholas | Ebrahim, Shah | Lawlor, Debbie A | Gallacher, John | Ben-Shlomo, Yoav | Yarnell, John WG | Casiglia, Edoardo | Tikhonoff, Valérie | Greenland, Philip | Shay, Christina M | Garside, Daniel B | Nietert, Paul J | Sutherland, Susan E | Bachman, David L | Keil, Julian E | de Boer, Ian H | Kizer, Jorge R | Psaty, Bruce M | Mukamal, Kenneth J | Nordestgaard, Børge G | Tybjærg-Hansen, Anne | Jensen, Gorm B | Schnohr, Peter | Giampaoli, Simona | Palmieri, Luigi | Panico, Salvatore | Pilotto, Lorenza | Vanuzzo, Diego | de la Cámara, Agustin Gómez | Simons, Leon A | Simons, Judith | McCallum, John | Friedlander, Yechiel | Gerry, F | Fowkes, R | Price, Jackie F | Lee, Amanda J | Taylor, James O | Guralnik, Jack M | Phillips, Caroline L | Wallace, Robert B | Kohout, Frank J | Cornoni-Huntley, Joan C | Guralnik, Jack M | Blazer, Dan G | Guralnik, Jack M | Phillips, Caroline L | Phillips, Caroline L | Guralnik, Jack M | Khaw, Kay-Tee | Wareham, Nicholas J | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Rothenbacher, Dietrich | Wennberg, Patrik | Jansson, Jan-Håkan | Nissinen, Aulikki | Donfrancesco, Chiara | Giampaoli, Simona | Woodward, Mark | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | D'Agostino, Ralph B | Vasan, Ramachandran S | Fox, Caroline S | Pencina, Michael J | Daimon, Makoto | Oizumi, Toshihide | Kayama, Takamasa | Kato, Takeo | Bladbjerg, Else-Marie | Jørgensen, Torben | Møller, Lars | Jespersen, Jørgen | Dankner, Rachel | Chetrit, Angela | Lubin, Flora | Svärdsudd, Kurt | Eriksson, Henry | Welin, Lennart | Lappas, Georgios | Rosengren, Annika | Lappas, Georgios | Welin, Lennart | Svärdsudd, Kurt | Eriksson, Henry | Lappas, Georgios | Bengtsson, Calle | Lissner, Lauren | Björkelund, Cecilia | Cremer, Peter | Nagel, Dorothea | Strandberg, Timo E | Salomaa, Veikko | Tilvis, Reijo S | Miettinen, Tatu A | Tilvis, Reijo S | Strandberg, Timo E | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Rodriguez, Beatriz | Dekker, Jacqueline M | Nijpels, Giel | Stehouwer, Coen DA | Hu, Frank B | Sun, Qi | Rimm, Eric B | Willett, Walter C | Iso, Hiroyasu | Kitamura, Akihiko | Yamagishi, Kazumasa | Noda, Hiroyuki | Goldbourt, Uri | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | Kauhanen, Jussi | Salonen, Jukka T | Kurl, Sudhir | Tuomainen, Tomi-Pekka | Poppelaars, Jan L | Deeg, Dorly JH | Visser, Marjolein | Meade, Tom W | De Stavola, Bianca Lucia | Hedblad, Bo | Nilsson, Peter | Engström, Gunnar | Verschuren, WM Monique | Blokstra, Anneke | de Boer, Ian H | Shea, Steven J | Meisinger, Christa | Thorand, Barbara | Koenig, Wolfgang | Döring, Angela | Verschuren, WM Monique | Blokstra, Anneke | Bueno-de-Mesquita, H Bas | Wilhelmsen, Lars | Rosengren, Annika | Lappas, Georgios | Fletcher, Astrid | Nitsch, Dorothea | Kuller, Lewis H | Grandits, Greg | Tverdal, Aage | Selmer, Randi | Nystad, Wenche | Mussolino, Michael | Gillum, Richard F | Hu, Frank B | Sun, Qi | Manson, JoAnn E | Rimm, Eric B | Hankinson, Susan E | Meade, Tom W | De Stavola, Bianca Lucia | Cooper, Jackie A | Bauer, Kenneth A | Davidson, Karina W | Kirkland, Susan | Shaffer, Jonathan A | Shimbo, Daichi | Kitamura, Akihiko | Iso, Hiroyasu | Sato, Shinichi | Holme, Ingar | Selmer, Randi | Tverdal, Aage | Nystad, Wenche | Nakagawa, Hidaeki | Miura, Katsuyuki | Sakurai, Masaru | Ducimetiere, Pierre | Jouven, Xavier | Bakker, Stephan JL | Gansevoort, Ron T | van der Harst, Pim | Hillege, Hans L | Crespo, Carlos J | Garcia-Palmieri, Mario R | Kee, Frank | Amouyel, Philippe | Arveiler, Dominique | Ferrières, Jean | Schulte, Helmut | Assmann, Gerd | Jukema, J Wouter | de Craen, Anton JM | Sattar, Naveed | Stott, David J | Cantin, Bernard | Lamarche, Benoît | Després, Jean-Pierre | Dagenais, Gilles R | Barrett-Connor, Elizabeth | Bergstrom, Jaclyn | Bettencourt, Richele R | Buisson, Catherine | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Trevisan, Maurizio | Hofman, Albert | Ikram, M Arfan | Tiemeier, Henning | Witteman, Jacqueline CM | Tunstall-Pedoe, Hugh | Tavendale, Roger | Lowe, Gordon DO | Woodward, Mark | Devereux, Richard | Yeh, Jeun-Liang | Ali, Tauqeer | Calhoun, Darren | Ben-Shlomo, Yoav | Davey-Smith, George | Onat, Altan | Can, Günay | Nakagawa, Hidaeki | Sakurai, Masaru | Nakamura, Koshi | Morikawa, Yuko | Njølstad, Inger | Mathiesen, Ellisiv B | Løchen, Maja-Lisa | Wilsgaard, Tom | Sundström, Johan | Ingelsson, Erik | Michaëlsson, Karl | Cederholm, Tommy | Gaziano, J Michael | Buring, Julie | Ridker, Paul M | Gaziano, J Michael | Ridker, Paul M | Ulmer, Hanno | Diem, Günter | Concin, Hans | Rodeghiero, Francesco | Tosetto, Alberto | Wassertheil-Smoller, Sylvia | Manson, JoAnn E | Marmot, Michael | Clarke, Robert | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimaki, Mika | Ridker, Paul M | Buring, Julie | Ford, Ian | Robertson, Michele | Ibañez, Alejandro Marín | Feskens, Edith | Geleijnse, Johanna M | Kromhout, Daan | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S | Angelantonio, Emanuele Di | Franco, Oscar H | Gao, Pei | Gobin, Reeta | Haycock, Philip | Kaptoge, Stephen | Seshasai, Sreenivasa R Kondapally | Lewington, Sarah | Pennells, Lisa | Rapsomaniki, Eleni | Sarwar, Nadeem | Thompson, Alexander | Thompson, Simon G | Walker, Matthew | Watson, Sarah | White, Ian R | Wood, Angela M | Wormser, David | Zhao, Xiaohui | Danesh, John
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
doi:10.1093/ije/dys086
PMCID: PMC3465767  PMID: 22825588
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
2.  Does CHA2DS2-VASc Improve Stroke Risk Stratification in Postmenopausal Women with Atrial Fibrillation? 
The American journal of medicine  2013;126(12):10.1016/j.amjmed.2013.05.023.
Background
Risk stratification of atrial fibrillation patients with a CHADS2 score of < 2 remains imprecise, particularly in women. Our objectives were to validate the CHADS2 and CHA2DS2-VASc stroke risk scores in a healthy cohort of American women with atrial fibrillation and to determine whether CHA2DS2-VASc further risk stratifies individuals with a CHADS2 score of < 2.
Methods
We identified a cohort of 5,981 women with atrial fibrillation not on warfarin at baseline (mean age 65.9±7.2 years) enrolled in the Women's Health Initiative and followed for a median of 11.8 years. Univariate and multivariate proportional hazards analyses were used to examine these two risk scores with main outcome measures being annualized event rates of ischemic stroke or transient ischemic attack stratified by risk score.
Results
Annualized stroke/ transient ischemic attack rates ranged from 0.36-2.43% with increasing CHADS2 score (0-4+) (hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.45-1.71 for each 1 point increase) and 0.20-2.02% with increasing CHA2DS2-VASc score (1-6+) (HR 1.50, 95% CI 1.41-1.60 for each 1 point increase). CHA2DS2-VASc had a higher c statistic than CHADS2: 0.67 (95% CI 0.65-0.69) vs. 0.65 (95% CI 0.62-0.67), p < 0.01. For CHADS2 scores < 2, stroke risk almost doubled with every additional CHA2DS2-VASc point.
Conclusions
Although both CHADS2, and CHA2DS2-VASc are predictive of stroke risk in post-menopausal women with atrial fibrillation, CHA2DS2-VASc further risk-stratifies patients with a CHADS2 score < 2.
doi:10.1016/j.amjmed.2013.05.023
PMCID: PMC3883047  PMID: 24139523
atrial fibrillation; CHADS2; CHA2DS2-VASc; stroke; women
3.  Insulin, Insulin-like Growth Factor-I, Endogenous Estradiol, and Risk of Colorectal Cancer in Postmenopausal Women 
Cancer research  2008;68(1):329-337.
Obesity is a risk factor for colorectal cancer, and hyperinsulinemia, a common condition in obese patients, may underlie this relationship. Insulin, in addition to its metabolic effects, has promitotic and antiapoptotic activity that may be tumorigenic. Insulin-like growth factor (IGF)-I, a related hormone, shares sequence homology with insulin, and has even stronger mitogenic effects. However, few prospective colorectal cancer studies directly measured fasting insulin, and none evaluated free IGF-I, or endogenous estradiol, a potential cofactor in postmenopausal women. Therefore, we conducted a case-cohort investigation of colorectal cancer among nondiabetic subjects enrolled in the Women’s Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. Fasting baseline serum specimens from all incident colorectal cancer cases (n = 438) and a random subcohort (n = 816) of Women’s Health Initiative Observational Study subjects were tested for insulin, glucose, total IGF-I, free IGF-I, IGF binding protein-3, and estradiol. Comparing extreme quartiles, insulin [hazard ratio (HR)q4–q1, 1.73; 95% confidence interval (CI), 1.16–2.57; ptrend = 0.005], waist circumference (HRq4–q1, 1.82; 95% CI, 1.22–2.70; ptrend = 0.001), and free IGF-I (HRq4–q1, 1.35; 95% CI, 0.92–1.98; Ptrend = 0.05) were each associated with colorectal cancer incidence in multivariate models. However, these associations each became nonsignificant when adjusted for one another. Endogenous estradiol levels, in contrast, were positively associated with risk of colorectal cancer (HR comparing high versus low levels, 1.53; 95% CI, 1.05–2.22), even after control for insulin, free IGF-I, and waist circumference. These data suggest the existence of at least two independent biological pathways that are related to colorectal cancer: one that involves endogenous estradiol, and a second pathway broadly associated with obesity, hyperinsulinemia, and free IGF-I.
doi:10.1158/0008-5472.CAN-07-2946
PMCID: PMC4225702  PMID: 18172327
4.  The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases 
IMPORTANCE
Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
OBJECTIVE
To provide a comprehensive, integrated overview of findings from the two Women’s Health Initiative (WHI) hormone therapy (HT) trials with extended post-intervention follow up.
DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS
27,347 postmenopausal women, age 50–79 years, were enrolled at 40 US centers. Interventions were conjugated equine estrogens (CEE, 0.625 mg/day) with medroxyprogesterone acetate (MPA, 2.5 mg/day) for women with an intact uterus (N = 16,608) and CEE alone for women with hysterectomy (N= 10,739), or their placebos. Intervention continued for 5.6 and 7.2 years (median), respectively, with cumulative follow-up of 13 years through September 30, 2010.
MAIN OUTCOMES AND MEASURES
The primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and deaths. Secondary and quality-of-life outcomes were also assessed.
RESULTS
During the intervention phase for CEE+MPA, the hazard ratio (HR) for CHD was 1.18 (95% confidence interval [CI] 0.95–1.45) and overall risks outweighed benefits, with increases in invasive breast cancer, stroke, pulmonary embolism, and the global index. Other risks included increased dementia (in women >65 years), gallbladder disease, and urinary incontinence, while benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Post-intervention, most risks and benefits dissipated, although some elevation in breast cancer risk persisted (cumulative hazard ratio [HR] =1.28; 95% confidence interval, 1.11–1.48). During intervention for CEE alone, risks and benefits were more balanced, with a HR for CHD of 0.94 (0.78–1.14), increased stroke and venous thrombosis, decreased hip fractures and diabetes, and over cumulative follow-up, decreased breast cancer (HR=0.79 [0.65–0.97]). Neither regimen affected all-cause mortality. With CEE, younger women (50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P values for trend by age <0.05), but not for stroke and venous thrombosis. Absolute risks of adverse events (measured by the global index) per 10,000 women per year on CEE+MPA ranged from 12 excess cases for age 50–59 to 38 for age 70–79 and, for CEE, from 19 fewer cases for age 50–59 to 51 excess cases for age 70–79. Results for quality of life outcomes in both trials were mixed.
CONCLUSIONS AND RELEVANCE
Menopausal hormone therapy has a complex pattern of risks and benefits. While appropriate for symptom management in some women, its use for chronic disease prevention is not supported by the WHI randomized trials.
TRIAL REGISTRATION
clinical trials.gov Identifier: NCT00000611
doi:10.1001/jama.2013.278040
PMCID: PMC3963523  PMID: 24084921
5.  Stroke Genetics Network (SiGN) Study: Design and rationale for a genome-wide association study of ischemic stroke subtypes 
Background and Purpose
Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The NINDS Stroke Genetics Network (SiGN) contributes substantially to meta-analyses that focus on specific subtypes of stroke.
Methods
The NINDS Stroke Genetics Network (SiGN) includes ischemic stroke cases from 24 Genetic Research Centers (GRCs), 13 from the US and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the web-based Causative Classification of Stroke (CCS) system, with data entered by trained and certified adjudicators at participating GRCs. Through the Center for Inherited Diseases Research (CIDR), SiGN plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide SNP arrays, and add to these another 4,253 previously genotyped cases for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. CIDR-generated genotypes and corresponding phenotypic data will be shared with the scientific community through dbGaP, and brain MRI studies will be centrally archived.
Conclusions
The SiGN consortium, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
doi:10.1161/STROKEAHA.113.001857
PMCID: PMC4056331  PMID: 24021684
ischemic stroke; genetics; genomics
6.  Pre-Stroke Factors Associated with Post-Stroke Mortality and Recovery in Older Women in the Women’s Health Initiative 
Objectives
We sought to examine pre-stroke lifestyle factorsassociated with post-stroke mortalityand recovery in older women.
Design
Longitudinal prospective cohort study.
Setting
The Women’s Health Initiative (clinical trials and observational study), 40 clinical centers in the U.S.
Participants
WHI participants, women aged 50–79, who were stroke-free at baseline 1993–1998, with incident stroke prior to 2005.
Measurements
Participants were followed for mortality through 2010. Pre-stroke characteristics were from the most proximal examination before the stroke event. Annual follow-up for clinical events ascertained hospitalization for stroke which was subsequently physician-adjudicated with medical records. Multivariable regression models analyzed factors associated with post-stroke mortality and post-stroke recovery at hospital discharge (post-stroke Glasgow score), adjusting for stroke type.
Results
Of 3,173 women with incident stroke, 1,111 (35%) died. Overweight and obese BMI pre-stroke was associated with reduced post-stroke mortality (vs. normal BMI, obese BMI hazards ratio, HR=0.69, 95% confidence interval (CI)=0.53–0.88; overweight BMI: HR=0.72, 95%CI=0.58–0.90); underweight pre-stroke BMI had borderline increased post-stroke mortality (HR=2.02, 95%CI=0.98–4.16).Other pre-stroke factors associated with post-stroke mortality included diabetes (HR=1.28, 95%CI=1.01–1.64), current smoking (vs. nonsmoker, hazard ratio (HR)=2.13, 95%CI=1.53–3.00), physical inactivity (vs. >150 minutes exercise/week, HR=1.39, 95%CI=1.09–1.78) and lowest physical function quartile (vs. highest, HR=1.54, 95%CI=1.18–2.02). Pre-stroke diabetes was associated with reduced odds of good recovery post-stroke (odds ratio (OR)= 0.60, 95%CI= 0.44–0.82). Current hormone use pre-stroke was associated with increased odds of moderate vs. severe disability post-stroke (OR=1.29, 95%CI=1.00–1.66).
Conclusion
Potentially modifiable factors pre-stroke, including smoking, diabetes and underweight BMI, were associated with increased post-stroke mortality in older women. Pre-stroke overweight or obese BMI and physical activity were associated with reduced post-stroke mortality in older women.
doi:10.1111/jgs.12361
PMCID: PMC3743941  PMID: 23869842
stroke; mortality; women; BMI; recovery; diabetes
7.  Circulating Soluble Cytokine Receptors and Colorectal Cancer Risk 
Background
Soluble cytokine receptors and receptor antagonist of proinflammatory cytokines can modify cytokine signaling and may affect cancer risk.
Methods
In a case-cohort study nested within the Women’s Health Initiative cohort of postmenopausal women, we assessed the associations of plasma levels of IL-1 receptor antagonist (IL-1Ra) and the soluble receptors of IL-1 (sIL-1R2), IL-6 (sIL-6R and sgp130), and TNF (sTNFR1 and sTNFR2) with risk of colorectal cancer in 433 cases and 821 subcohort subjects. Baseline levels of estradiol, insulin, leptin, IL-6, and TNF-α measured previously were also available for data analysis.
Results
After adjusting for significant covariates – including age, race, smoking, colonoscopy history, waist circumference, and levels of estrogen, insulin, and leptin – relatively high levels of sIL-6R and sIL-1R2 were associated with reduced colorectal cancer risk [hazard ratios comparing extreme quartiles (HRQ4-Q1) for sIL-6R = 0.56, 95% CI = 0.38–0.83; HRQ4-Q1 for sIL-1R2 = 0.44, 95% CI = 0.29–0.67]. The associations with IL-1Ra, sgp130, sTNFR1, and sTNFR2 were null. The inverse association of sIL-1R2 with colorectal cancer risk persisted in cases diagnosed ≤5 and >5 years from baseline blood draw; the association with sIL-6R, however, was not evident in the latter group, possibly indicating that relatively low levels of sIL-6R in cases might be due to undiagnosed cancer at the time of blood draw.
Conclusions
High circulating levels of sIL-1R2 may be protective against colorectal carcinogenesis and/or be a marker of reduced risk for the disease.
Impact
sIL-1R2 has potential to be a chemopreventive and/or immunotherapeutic agent in inflammation-related diseases.
doi:10.1158/1055-9965.EPI-13-0545
PMCID: PMC3947182  PMID: 24192010
soluble cytokine receptor; receptor antagonist; colorectal cancer; IL-1; IL-6; TNF
8.  Resistin, but not Adiponectin and Leptin, is Associated with the Risk of Ischemic Stroke Among Postmenopausal Women: Results from the Women’s Health Initiative 
Background
Adipose tissue is considered an endocrine organ that secretes adipokines which possibly mediate the effects of obesity on risk of cardiovascular disease. However, there are yet limited prospective data on the association between circulating adipokine levels and risk of ischemic stroke. We aimed to examine the associations of three adipokines (adiponectin, leptin and resistin) with risk of ischemic stroke.
Methods and Results
We conducted a prospective nested case-control study (972 stroke cases and 972 matched controls) within the Women’s Health Initiative Observational Study cohort. The controls were matched to cases on age, race/ethnicity, date of study enrollment and follow-up time. Adipokine levels were associated with established stroke risk factors, such as obesity and systolic blood pressure. Adjusted for body mass index, the odds ratios (OR) for incident ischemic stroke comparing the highest (Q4) to the lowest quartile (Q1) were 0.81 (95% confidence intervals [CI]: 0.61–1.08; p-trend: 0.068) for adiponectin, 1.15 (95% CI: 0.83–1.59; p-trend: 0.523) for leptin, and 1.57 (95% CI: 1.18–2.08; p-trend: 0.002) for resistin. The association for resistin remained significant even after accounting for established stroke risk factors (OR: 1.39; 95% CI: 1.01–1.90; p-trend: 0.036). Further adjustment for markers for inflammation, angiogenesis, and endothelial function also did not affect our results.
Conclusions
Circulating levels of resistin, but not those of adiponectin or leptin, are associated with an increased risk of incident ischemic stroke in postmenopausal women, independent of obesity and other CVD risk factors.
doi:10.1161/STROKEAHA.110.607853
PMCID: PMC4059356  PMID: 21546486
stroke; adipokines; women
9.  Improvement in Stroke Risk Prediction: Role of c-reactive protein (CRP) and Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) in the Women’s Health Initiative 
Background and Purpose
Classification of risk of ischemic stroke is important for medical care and public health reasons. Whether addition of biomarkers adds to predictive power of the Framingham Stroke Risk or other traditional risk factors has not been studied in older women.
Methods
The Hormones and Biomarkers Predicting Stroke (HaBPS) Study is a case-control study of blood biomarkers assayed in 972 ischemic stroke cases and 972 controls, nested in the Women’s Health Initiative Observational Study of 93,676 postmenopausal women followed for an average of 8 years. We evaluated additive predictive value of two commercially available biomarkers: c-reactive protein (CRP) and Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) to determine if they added to risk prediction by the Framingham Stroke Risk Score (FSRS) or by traditional risk factors (TRF) which included lipids and other variables not included in the FSRS. As measures of additive predictive value, we used the c-statistic, Net Reclassification Improvement (NRI), category-less NRI, and Integrated Discrimination Improvement Index (IDI).
Results
Addition of CRP to Framingham risk models or additional traditional risk factors overall modestly improved prediction of ischemic stroke and resulted in overall NRI of 6.3%, (case NRI=3.9%, control NRI=2.4%) .In particular, hs-CRP was useful in prediction of cardioembolic strokes (NRI=12.0%; 95%CI: 4.3-19.6%) and in strokes occurring in less than 3 years (NRI=7.9%, 95%CI: 0.8-14.9%). Lp-PLA2 was useful in risk prediction of large artery strokes (NRI=19.8%, 95%CI: 7.4 -32.1%) and in early strokes (NRI=5.8%, 95%CI: 0.4-11.2%).
Conclusions
CRP and Lp-PLA2 can improve prediction of certain subtypes of ischemic stroke in older women, over the Framingham stroke risk model and traditional risk factors, and may help to guide surveillance and treatment of women at risk.
doi:10.1111/j.1747-4949.2012.00860.x
PMCID: PMC3556354  PMID: 23088183
10.  Stroke in women 
Aims
The aim of this article is to provide an overview of stroke in women and describe modifiable and non-modifiable risk factors for stroke.
Data synthesis
Data supporting this article come from the National Center for Health Statistics, from American Heart Association publications, and from some of the large, multicenter trials and observational studies that inform guidelines for prevention of stroke. These data indicate that stroke is the third leading cause of death in women, that risk for stroke rises rapidly with age, and that the strongest risk factors for stroke are high blood pressure and atrial fibrillation, as well as diabetes and smoking. Risk rises rapidly when two or more risk factors are present. Hormone therapy in postmenopausal women increases risk of ischemic, but not hemorrhagic stroke, by 40–50%. Biomarkers of inflammation are associated with stroke risk. Other risk factors include certain lipids, physical inactivity, and low potassium diets. Although there has been improvement in the past decade, control of hypertension is inadequate in older women and many strokes could be prevented by better treatment of hypertension.
Conclusion
Death and disability from stroke can be reduced with modification, treatment, and better control of risk factors like hypertension, diabetes and atrial fibrillation.
doi:10.1016/j.numecd.2010.02.017
PMCID: PMC3993990  PMID: 20605084
Stroke in women; Ischemic stroke; Hemorrhagic stroke; Hormone therapy; Risk factors for stroke
11.  Hepatocyte Growth Factor and the Risk of Developing Ischemic Stroke Among Postmenopausal Women: Results from the Women’s Health Initiative 
Background
Hepatocyte growth factor (HGF) is a potent angiogenic factor and may play a role in the development and progression of atherosclerotic lesions, the underlying mechanism of cardiovascular disease. However, there have been no prospective studies examining the relationship between HGF levels and risk of stroke.
Methods and Results
We conducted a nested case-control study (972 incident stroke cases and 1:1 age- and race-matched controls) to prospectively evaluate the association between plasma HGF and risk of ischemic stroke within the Women’s Health Initiative Observational Study, a cohort of postmenopausal women aged 50–79 years. Baseline HGF levels were correlated positively with body mass index (BMI), systolic blood pressure, low-density lipoprotein cholesterol, insulin resistance, and inflammatory markers such as C-reactive protein, and inversely with high-density lipoprotein cholesterol (all P-values <0.05). Baseline HGF levels were higher among cases than controls (geometric means 601.8 vs. 523.2 pg/mL, p = 0.003). Furthermore, the risk of incident ischemic stroke was significantly greater amongst women in the highest versus lowest quartile of plasma HGF levels (odds ratio [OR] = 1.46; 95% confidence interval [CI]: 1.12–1.91; Ptrend = 0.003), in a conditional logistic regression model that adjusted for BMI. These results were only slightly attenuated after further adjustment for additional stroke risk factors (OR=1.39; 95% CI=1.04–1.85, Ptrend=0.023).
Conclusions
Circulating levels of HGF are associated with an increased risk of incident ischemic stroke, independent of obesity and other risk factors for cardiovascular disease among postmenopausal women aged 50–79 years.
doi:10.1161/STROKEAHA.109.567719
PMCID: PMC3903044  PMID: 20203323
Hepatocyte growth factor; ischemic stroke; women
12.  Low-fat dietary pattern and risk of benign proliferative breast disease: a randomized, controlled dietary modification trial 
Modifiable factors, including diet, might alter breast cancer risk. We used the WHI Dietary Modification (DM) trial to test the effect of the intervention on risk of benign proliferative breast disease, a condition associated with increased risk of and considered to be on the pathway to invasive breast cancer. The WHI DM trial was a randomized, controlled, primary prevention trial conducted in 40 US clinical centers from 1993–2005. 48,835 postmenopausal women, aged 50–79 years, without prior breast cancer, were enrolled. Participants were randomly assigned to the DM intervention group or to the comparison group. The intervention was designed to reduce total dietary fat intake to 20% of total energy intake, and to increase fruit and vegetable intake to ≥5 servings/day and intake of grain products to ≥6 servings/day, but resulted in smaller, albeit significant changes in practice. Participants had biennial mammograms and regular clinical breast exams. We identified women who reported breast biopsies free of cancer, obtained the histologic sections, and subjected them to standardized central review. During follow-up (average, 7.7 years), 570 incident cases of benign proliferative breast disease were ascertained in the intervention group and 793 in the comparison group. The hazard ratio for the association between DM and benign proliferative breast disease was 1.09 (95%CI, 0.98–1.23). Risk varied by levels of baseline total vitamin D intake but it varied little by levels of other baseline variables. These results suggest that a modest reduction in fat intake and increase in fruit, vegetable, and grain intake does not alter the risk of benign proliferative breast disease.
doi:10.1158/1940-6207.CAPR-08-0003
PMCID: PMC3893100  PMID: 19138971
diet; benign proliferative breast disease
13.  A randomized controlled trial of calcium plus vitamin D supplementation and risk of benign proliferative breast disease 
Experimental evidence provides strong support for anti-carcinogenic effects of calcium and vitamin D with respect to breast cancer. Observational epidemiologic data also provide some support for inverse associations with risk. We tested the effect of calcium plus vitamin D supplementation on risk of benign proliferative breast disease, a condition which is associated with increased risk of breast cancer. We used the Women’s Health Initiative randomized controlled trial. The 36,282 participants were randomized either to 500 mg of elemental calcium as calcium carbonate plus 200 IU of vitamin D3 (GlaxoSmithKline) twice daily (n = 18,176) or to placebo (n = 18,106). Regular mammograms and clinical breast exams were performed. We identified women who had had a biopsy for benign breast disease and subjected histologic sections from the biopsies to standardized review. After an average follow-up period of 6.8 years, 915 incident cases of benign proliferative breast disease had been ascertained, with 450 in the intervention group and 465 in the placebo group. Calcium plus vitamin D supplementation was not associated with altered risk of benign proliferative breast disease overall (hazard ratio = 0.99, 95% confidence interval = 0.86–1.13), or by histologic subtype. Risk varied significantly by levels of age at baseline, but not by levels of other variables. Daily use of 1,000 mg of elemental calcium as calcium carbonate plus 400 IU of vitamin D3 for almost 7 years by postmenopausal women did not alter the overall risk of benign proliferative breast disease.
doi:10.1007/s10549-008-0213-0
PMCID: PMC3893102  PMID: 18853250
Calcium; Vitamin D; Benign proliferative breast disease
14.  MULTIVITAMIN USE AND RISK OF CANCER AND CARDIOVASCULAR DISEASE IN THE WOMEN’S HEALTH INITIATIVE COHORTS 
Archives of internal medicine  2009;169(3):10.1001/archinternmed.2008.540.
Context
Millions of postmenopausal women use multivitamins, often believing that supplements prevent chronic diseases such as cancer and cardiovascular disease.
Objective
To examine associations between multivitamin use and risk of cancer, cardiovascular disease and mortality in postmenopausal women.
Design, Setting and Participants
161,808 participants from the Women’s Health Initiative Clinical Trials (n=68,132 in three overlapping trials of hormone therapy, dietary modification and calcium-vitamin D) or Observational Study (n=93,676). Detailed data were collected on multivitamin use at baseline and follow-up time points. Study enrollment occurred between 1993–1998; women were followed for a median of 8.0 years in the clinical trials and 7.9 years in the observational study. Disease endpoints were collected through 2005.
Outcome Measures
Cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary and lung; cardiovascular disease (myocardial infarction, stroke, venous thrombosis); and total mortality.
Results
41.5% of participants used multivitamins. After a median of 8.0 years of follow-up in the CT and 7.9 years in the OS, 9,619 cases of breast, colorectal, endometrium, kidney, bladder, stomach lung or ovary cancer; 8,751 CVD events and 9,865 deaths were reported. Multivariate-adjusted analyses revealed no association of multivitamins with risk of cancer (breast HR=0.98, 95%CI 0.91–1.05; colorectal HR = 0.99, 95% CI 0.88–1.11; endometrial HR = 1.05, 95%CI= 0.90–1.21; lung HR = 1.0, 95% CI=0.88–1.13; ovary HR = 1.07, 95%CI =0.88–1.29); CVD (MI HR= 0.96, 95%CI= 0.89–1.03; stroke HR = 0.99, 95%CI =0.91–1.07; VT HR = 1.05, 95%CI =0.85–1.29); or mortality (HR = 1.02, 95% CI=0.97–1.07).
Conclusion
After a median follow-up of 8.0 and 7.9 years in the CT and OS, respectively, the WHI cohorts provide convincing evidence that multivitamin use has little or no influence on the risk of common cancers, cardiovascular disease or total mortality in postmenopausal women.
Clinical Trial Registration
clinicaltrials.gov identifier: NCT00000611
doi:10.1001/archinternmed.2008.540
PMCID: PMC3868488  PMID: 19204221
dietary supplements; vitamins; minerals; breast cancer; lung cancer; colon cancer; myocardial infarction; stroke
15.  A Meta-Analysis Identifies New Loci Associated with Body Mass index in Individuals of African Ancestry 
Monda, Keri L. | Chen, Gary K. | Taylor, Kira C. | Palmer, Cameron | Edwards, Todd L. | Lange, Leslie A. | Ng, Maggie C.Y. | Adeyemo, Adebowale A. | Allison, Matthew A. | Bielak, Lawrence F. | Chen, Guanji | Graff, Mariaelisa | Irvin, Marguerite R. | Rhie, Suhn K. | Li, Guo | Liu, Yongmei | Liu, Youfang | Lu, Yingchang | Nalls, Michael A. | Sun, Yan V. | Wojczynski, Mary K. | Yanek, Lisa R. | Aldrich, Melinda C. | Ademola, Adeyinka | Amos, Christopher I. | Bandera, Elisa V. | Bock, Cathryn H. | Britton, Angela | Broeckel, Ulrich | Cai, Quiyin | Caporaso, Neil E. | Carlson, Chris | Carpten, John | Casey, Graham | Chen, Wei-Min | Chen, Fang | Chen, Yii-Der I. | Chiang, Charleston W.K. | Coetzee, Gerhard A. | Demerath, Ellen | Deming-Halverson, Sandra L. | Driver, Ryan W. | Dubbert, Patricia | Feitosa, Mary F. | Freedman, Barry I. | Gillanders, Elizabeth M. | Gottesman, Omri | Guo, Xiuqing | Haritunians, Talin | Harris, Tamara | Harris, Curtis C. | Hennis, Anselm JM | Hernandez, Dena G. | McNeill, Lorna H. | Howard, Timothy D. | Howard, Barbara V. | Howard, Virginia J. | Johnson, Karen C. | Kang, Sun J. | Keating, Brendan J. | Kolb, Suzanne | Kuller, Lewis H. | Kutlar, Abdullah | Langefeld, Carl D. | Lettre, Guillaume | Lohman, Kurt | Lotay, Vaneet | Lyon, Helen | Manson, JoAnn E. | Maixner, William | Meng, Yan A. | Monroe, Kristine R. | Morhason-Bello, Imran | Murphy, Adam B. | Mychaleckyj, Josyf C. | Nadukuru, Rajiv | Nathanson, Katherine L. | Nayak, Uma | N’Diaye, Amidou | Nemesure, Barbara | Wu, Suh-Yuh | Leske, M. Cristina | Neslund-Dudas, Christine | Neuhouser, Marian | Nyante, Sarah | Ochs-Balcom, Heather | Ogunniyi, Adesola | Ogundiran, Temidayo O. | Ojengbede, Oladosu | Olopade, Olufunmilayo I. | Palmer, Julie R. | Ruiz-Narvaez, Edward A. | Palmer, Nicholette D. | Press, Michael F. | Rampersaud, Evandine | Rasmussen-Torvik, Laura J. | Rodriguez-Gil, Jorge L. | Salako, Babatunde | Schadt, Eric E. | Schwartz, Ann G. | Shriner, Daniel A. | Siscovick, David | Smith, Shad B. | Wassertheil-Smoller, Sylvia | Speliotes, Elizabeth K. | Spitz, Margaret R. | Sucheston, Lara | Taylor, Herman | Tayo, Bamidele O. | Tucker, Margaret A. | Van Den Berg, David J. | Velez Edwards, Digna R. | Wang, Zhaoming | Wiencke, John K. | Winkler, Thomas W. | Witte, John S. | Wrensch, Margaret | Wu, Xifeng | Yang, James J. | Levin, Albert M. | Young, Taylor R. | Zakai, Neil A. | Cushman, Mary | Zanetti, Krista A. | Zhao, Jing Hua | Zhao, Wei | Zheng, Yonglan | Zhou, Jie | Ziegler, Regina G. | Zmuda, Joseph M. | Fernandes, Jyotika K. | Gilkeson, Gary S. | Kamen, Diane L. | Hunt, Kelly J. | Spruill, Ida J. | Ambrosone, Christine B. | Ambs, Stefan | Arnett, Donna K. | Atwood, Larry | Becker, Diane M. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Borecki, Ingrid B. | Bottinger, Erwin P. | Bowden, Donald W. | Burke, Gregory | Chanock, Stephen J. | Cooper, Richard S. | Ding, Jingzhong | Duggan, David | Evans, Michele K. | Fox, Caroline | Garvey, W. Timothy | Bradfield, Jonathan P. | Hakonarson, Hakon | Grant, Struan F.A. | Hsing, Ann | Chu, Lisa | Hu, Jennifer J. | Huo, Dezheng | Ingles, Sue A. | John, Esther M. | Jordan, Joanne M. | Kabagambe, Edmond K. | Kardia, Sharon L.R. | Kittles, Rick A. | Goodman, Phyllis J. | Klein, Eric A. | Kolonel, Laurence N. | Le Marchand, Loic | Liu, Simin | McKnight, Barbara | Millikan, Robert C. | Mosley, Thomas H. | Padhukasahasram, Badri | Williams, L. Keoki | Patel, Sanjay R. | Peters, Ulrike | Pettaway, Curtis A. | Peyser, Patricia A. | Psaty, Bruce M. | Redline, Susan | Rotimi, Charles N. | Rybicki, Benjamin A. | Sale, Michèle M. | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Strom, Sara S. | Thun, Michael J. | Vitolins, Mara | Zheng, Wei | Moore, Jason H. | Williams, Scott M. | Zhu, Xiaofeng | Zonderman, Alan B. | Kooperberg, Charles | Papanicolaou, George | Henderson, Brian E. | Reiner, Alex P. | Hirschhorn, Joel N. | Loos, Ruth JF | North, Kari E. | Haiman, Christopher A.
Nature genetics  2013;45(6):690-696.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
doi:10.1038/ng.2608
PMCID: PMC3694490  PMID: 23583978
16.  Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study 
Background
Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning.
Methods and Results
Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity.
Conclusions
CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.
doi:10.1161/JAHA.113.000369
PMCID: PMC3886762  PMID: 24351701
cardiovascular diseases; cognitive decline; postmenopausal women
17.  Trans Fat, Aspirin, and Ischemic Stroke in Postmenopausal Women 
Annals of neurology  2012;72(5):704-715.
Objective
To examine the associations between dietary fat intake and ischemic stroke among postmenopausal women.
Methods
We conducted a prospective cohort study of 87,025 generally healthy postmenopausal women (age 50–79 years) enrolled in the Women’s Health Initiative Observational Study. Repeated and validated dietary assessments were done using a self-administered food frequency questionnaire. We used Cox proportional hazards models to estimate hazard ratios (HR) of ischemic stroke based on quintiles of the cumulative average of fat intake.
Results
We documented 1,049 incident cases of ischemic stroke over 663,041 person-years of follow-up. Women in the highest quintile of trans fat intake had a significantly higher incidence of ischemic stroke (HR 1.39, 95% confidence interval [CI] 1.08–1.79, P-trend = 0.048) compared with women in the lowest quintile, while controlling for multiple covariates. The observed association was modified by aspirin use (P-interaction=0.02). The HR was 1.66 (95% CI 1.21–2.36, P-trend<0.01) among baseline non-aspirin users (n=67,288) and 0.95 (95% CI 0.60–1.48, P-trend=0.43) among aspirin users (n=19,736). No significant associations were found between intakes of saturated, monounsaturated, or polyunsaturated fat and ischemic stroke or any ischemic stroke subtypes.
Interpretation
In this large cohort of postmenopausal women, higher intake of trans fat was associated with incident ischemic stroke independent of major lifestyle/dietary factors. Aspirin use may attenuate the potential adverse effect of trans fat intake on ischemic stroke.
doi:10.1002/ana.23555
PMCID: PMC3371162  PMID: 22383309
18.  Adipokines Linking Obesity with Colorectal Cancer Risk in Postmenopausal Women 
Cancer research  2012;72(12):3029-3037.
Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case–cohort study nested within the Women’s Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines—adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of antiinflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HRQ4–Q1), 1.84; 95% CI, 1.17–2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women.
doi:10.1158/0008-5472.CAN-11-2771
PMCID: PMC3790260  PMID: 22511581
19.  Prevalence of Major Cardiovascular Risk Factors and Cardiovascular Diseases Among Hispanic/Latino Individuals of Diverse Backgrounds in the United States 
Context
Major cardiovascular diseases (CVDs) are leading causes of mortality among US Hispanic and Latino individuals. Comprehensive data are limited regarding the prevalence of CVD risk factors in this population and relations of these traits to socioeconomic status (SES) and acculturation.
Objectives
To describe prevalence of major CVD risk factors and CVD (coronary heart disease [CHD] and stroke) among US Hispanic/Latino individuals of different backgrounds, examine relationships of SES and acculturation with CVD risk profiles and CVD, and assess cross-sectional associations of CVD risk factors with CVD.
Design, Setting, and Participants
Multicenter, prospective, population-based Hispanic Community Health Study/Study of Latinos including individuals of Cuban (n =2201), Dominican (n = 1400), Mexican (n=6232), Puerto Rican (n=2590), Central American (n=1634), and South American backgrounds (n = 1022) aged 18 to 74 years. Analyses involved 15 079 participants with complete data enrolled between March 2008 and June 2011.
Main Outcome Measures
Adverse CVD risk factors defined using national guidelines for hypercholesterolemia, hypertension, obesity, diabetes, and smoking. Prevalence of CHD and stroke were ascertained from self-reported data.
Results
Age-standardized prevalence of CVD risk factors varied by Hispanic/Latino background; obesity and current smoking rates were highest among Puerto Rican participants (for men, 40.9% and 34.7%; for women, 51.4% and 31.7%, respectively); hypercholesterolemia prevalence was highest among Central American men (54.9%) and Puerto Rican women (41.0%). Large proportions of participants (80% of men, 71% of women) had at least 1 risk factor. Age- and sex-adjusted prevalence of 3 or more risk factors was highest in Puerto Rican participants (25.0%) and significantly higher (P<.001) among participants with less education (16.1%), those who were US-born (18.5%), those who had lived in the United States 10 years or longer (15.7%), and those who preferred English (17.9%). Overall, self-reported CHD and stroke prevalence were low (4.2% and 2.0% in men; 2.4% and 1.2% in women, respectively). In multivariate-adjusted models, hypertension and smoking were directly associated with CHD in both sexes as were hypercholesterolemia and obesity in women and diabetes in men (odds ratios [ORs], 1.5–2.2). For stroke, associations were positive with hypertension in both sexes, diabetes in men, and smoking in women (ORs, 1.7–2.6).
Conclusion
Among US Hispanic/Latino adults of diverse backgrounds, a sizeable proportion of men and women had adverse major risk factors; prevalence of adverse CVD risk profiles was higher among participants with Puerto Rican background, lower SES, and higher levels of acculturation.
doi:10.1001/jama.2012.14517
PMCID: PMC3777250  PMID: 23117778
20.  Association between Annual Visit-to-Visit Blood Pressure Variability and Stroke in Postmenopausal Women: Data from the Women's Health Initiative 
Hypertension  2012;60(3):625-630.
Accumulating evidence suggests that increased visit-to-visit variability (VVV) of blood pressure is associated with stroke. No study has examined the association between VVV of blood pressure and stroke in postmenopausal women, and scarce data exists as to whether this relation is independent of the temporal trend of blood pressure. We examined the association of VVV of blood pressure with stroke in 58,228 postmenopausal women enrolled in the Women's Health Initiative. Duplicate blood pressure readings, which were averaged, were taken at baseline and at each annual visit. VVV was defined as the standard deviation about the participant's mean systolic blood pressure (SBP) across visits (SD), and about the participant's regression line with SBP regressed across visits (SDreg). Over a median follow-up of 5.4 years, 997 strokes occurred. In an adjusted model including mean SBP over time, the hazard ratios (95% CI) of stroke for higher quartiles of SD of SBP compared to the lowest quartile (referent) were 1.39 (1.03-1.89) for quartile 2, 1.52 (1.13-2.03) for quartile 3, and 1.72 (1.28-2.32) for quartile 4 (P trend<0.001). The relation was similar for SDreg of SBP quartiles in a model that additionally adjusted for the temporal trend in SBP (P trend<0.001). The associations did not differ by stroke type (ischemic vs. hemorrhagic). There was a significant interaction between mean SBP and SDreg on stroke with the strongest association seen below 120 mmHg. In postmenopausal women, greater VVV of SBP was associated with increased risk of stroke, particularly in the lowest range of mean SBP.
doi:10.1161/HYPERTENSIONAHA.112.193094
PMCID: PMC3427141  PMID: 22753206
hypertension; blood pressure; stroke; postmenopause; women
21.  Clinical Utility of Lp-PLA2 for Cardiovascular Disease Prediction in a Multiethnic Cohort of Women 
Clinical chemistry  2012;58(9):1352-1363.
Background
Findings regarding the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass with incident cardiovascular disease (CVD) have been inconsistent, and their role in risk prediction is uncertain.
Methods
A case-cohort sample from the Women’s Health Initiative Observational Study (WHI-OS) comprised 1,821 CVD cases and a subcohort of 1,992. Cox regression models with inverse sampling weights assessed the association of Lp-PLA2 mass and activity with CVD (myocardial infarction [MI], stroke, and CVD mortality).
Results
Subcohort means were 184.3 mmol/min/mL for Lp-PLA2 activity and 499.2 ng/mL for Lp-PLA2 mass, with 99% having mass above 200 ng/mL, the clinically recommended cut-point. Both activity and mass were positively associated with incident CVD in age- and race/ethnicity-adjusted analyses. Following adjustment by CVD risk factors, the association with activity became null (hazard ratio [HR] = 1.02 for top vs. bottom quartile, 95% confidence interval [CI] = 0.79-1.33, p-trend=0.65), but the association with mass remained (HR = 1.84, 95% CI = 1.45-2.34, p-trend <0.0001). In contrast to blood pressure, HDL, and hsCRP, reclassification statistics for Lp-PLA2 mass did not suggest improvement for overall CVD after full adjustment.
Conclusion
In the WHI-OS Lp-PLA2 mass, but not activity, was independently associated with CVD. However, model fit did not significantly improve with Lp-PLA2, and assay calibration remains a clinical concern.
doi:10.1373/clinchem.2012.188870
PMCID: PMC3621122  PMID: 22859728
22.  Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci 
Liu, Ching-Ti | Monda, Keri L. | Taylor, Kira C. | Lange, Leslie | Demerath, Ellen W. | Palmas, Walter | Wojczynski, Mary K. | Ellis, Jaclyn C. | Vitolins, Mara Z. | Liu, Simin | Papanicolaou, George J. | Irvin, Marguerite R. | Xue, Luting | Griffin, Paula J. | Nalls, Michael A. | Adeyemo, Adebowale | Liu, Jiankang | Li, Guo | Ruiz-Narvaez, Edward A. | Chen, Wei-Min | Chen, Fang | Henderson, Brian E. | Millikan, Robert C. | Ambrosone, Christine B. | Strom, Sara S. | Guo, Xiuqing | Andrews, Jeanette S. | Sun, Yan V. | Mosley, Thomas H. | Yanek, Lisa R. | Shriner, Daniel | Haritunians, Talin | Rotter, Jerome I. | Speliotes, Elizabeth K. | Smith, Megan | Rosenberg, Lynn | Mychaleckyj, Josyf | Nayak, Uma | Spruill, Ida | Garvey, W. Timothy | Pettaway, Curtis | Nyante, Sarah | Bandera, Elisa V. | Britton, Angela F. | Zonderman, Alan B. | Rasmussen-Torvik, Laura J. | Chen, Yii-Der Ida | Ding, Jingzhong | Lohman, Kurt | Kritchevsky, Stephen B. | Zhao, Wei | Peyser, Patricia A. | Kardia, Sharon L. R. | Kabagambe, Edmond | Broeckel, Ulrich | Chen, Guanjie | Zhou, Jie | Wassertheil-Smoller, Sylvia | Neuhouser, Marian L. | Rampersaud, Evadnie | Psaty, Bruce | Kooperberg, Charles | Manson, JoAnn E. | Kuller, Lewis H. | Ochs-Balcom, Heather M. | Johnson, Karen C. | Sucheston, Lara | Ordovas, Jose M. | Palmer, Julie R. | Haiman, Christopher A. | McKnight, Barbara | Howard, Barbara V. | Becker, Diane M. | Bielak, Lawrence F. | Liu, Yongmei | Allison, Matthew A. | Grant, Struan F. A. | Burke, Gregory L. | Patel, Sanjay R. | Schreiner, Pamela J. | Borecki, Ingrid B. | Evans, Michele K. | Taylor, Herman | Sale, Michele M. | Howard, Virginia | Carlson, Christopher S. | Rotimi, Charles N. | Cushman, Mary | Harris, Tamara B. | Reiner, Alexander P. | Cupples, L. Adrienne | North, Kari E. | Fox, Caroline S.
PLoS Genetics  2013;9(8):e1003681.
Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10−6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10−8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10−8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10−8; RREB1: p = 5.7×10−8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
Author Summary
Central obesity is a marker of body fat distribution and is known to have a genetic underpinning. Few studies have reported genome-wide association study (GWAS) results among individuals of predominantly African ancestry (AA). We performed a collaborative meta-analysis in order to identify genetic loci associated with body fat distribution in AA individuals using waist circumference (WC) and waist to hip ratio (WHR) as measures of fat distribution, with and without adjustment for body mass index (BMI). We uncovered 2 genetic loci potentially associated with fat distribution: LHX2 in association with WC-adjusted-for-BMI and at RREB1 for WHR-adjusted-for-BMI. Six of fourteen previously reported loci for waist in EA populations were significant in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). These findings reinforce the concept that there are loci for body fat distribution that are independent of generalized adiposity.
doi:10.1371/journal.pgen.1003681
PMCID: PMC3744443  PMID: 23966867
23.  Testing the proportional hazards assumption in case-cohort analysis 
Background
Case-cohort studies have become common in epidemiological studies of rare disease, with Cox regression models the principal method used in their analysis. However, no appropriate procedures to assess the assumption of proportional hazards of case-cohort Cox models have been proposed.
Methods
We extended the correlation test based on Schoenfeld residuals, an approach used to evaluate the proportionality of hazards in standard Cox models. Specifically, pseudolikelihood functions were used to define “case-cohort Schoenfeld residuals”, and then the correlation of these residuals with each of three functions of event time (i.e., the event time itself, rank order, Kaplan-Meier estimates) was determined. The performances of the proposed tests were examined using simulation studies. We then applied these methods to data from a previously published case-cohort investigation of the insulin/IGF-axis and colorectal cancer.
Results
Simulation studies showed that each of the three correlation tests accurately detected non-proportionality. Application of the proposed tests to the example case-cohort investigation dataset showed that the Cox proportional hazards assumption was not satisfied for certain exposure variables in that study, an issue we addressed through use of available, alternative analytical approaches.
Conclusions
The proposed correlation tests provide a simple and accurate approach for testing the proportional hazards assumption of Cox models in case-cohort analysis. Evaluation of the proportional hazards assumption is essential since its violation raises questions regarding the validity of Cox model results which, if unrecognized, could result in the publication of erroneous scientific findings.
doi:10.1186/1471-2288-13-88
PMCID: PMC3710085  PMID: 23834739
Proportional hazards; Schoenfeld residuals; Case-cohort studies; Cox models
24.  Vitamin D Supplementation and Depression in the Women’s Health Initiative Calcium and Vitamin D Trial 
While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D3 combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995–2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D3 along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.
doi:10.1093/aje/kwr482
PMCID: PMC3385159  PMID: 22573431
antidepressive agents; calcium; clinical trial; depression; dietary supplements; postmenopause; vitamin D; women
25.  Laxative use and incident falls, fractures and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative 
BMC Geriatrics  2013;13:38.
Background
Laxatives are among the most widely used over-the-counter medications in the United States but studies examining their potential hazardous side effects are sparse. Associations between laxative use and risk for fractures and change in bone mineral density [BMD] have not previously been investigated.
Methods
This prospective analysis included 161,808 postmenopausal women (8907 users and 151,497 nonusers of laxatives) enrolled in the WHI Observational Study and Clinical Trials. Women were recruited from October 1, 1993, to December 31, 1998, at 40 clinical centers in the United States and were eligible if they were 50 to 79 years old and were postmenopausal at the time of enrollment. Medication inventories were obtained during in-person interviews at baseline and at the 3-year follow-up visit on everyone. Data on self-reported falls (≥2), fractures (hip and total fractures) were used. BMD was determined at baseline and year 3 at 3 of the 40 clinical centers of the WHI.
Results
Age-adjusted rates of hip fractures and total fractures, but not for falls were similar between laxative users and non-users regardless of duration of laxative use. The multivariate-adjusted hazard ratios for any laxative use were 1.06 (95% confidence interval [CI], 1.03-1.10) for falls, 1.02 (95% CI, 0.85-1.22) for hip fractures and 1.01 (95% CI, 0.96-1.07) for total fractures. The BMD levels did not statistically differ between laxative users and nonusers at any skeletal site after 3-years intake.
Conclusion
These findings support a modest association between laxative use and increase in the risk of falls but not for fractures. Its use did not decrease bone mineral density levels in postmenopausal women. Maintaining physical functioning, and providing adequate treatment of comorbidities that predispose individuals for falls should be considered as first measures to avoid potential negative consequences associated with laxative use.
doi:10.1186/1471-2318-13-38
PMCID: PMC3645973  PMID: 23635086
Laxative use; Falls; Fractures; Bone mineral density; Aging

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