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1.  Association between Sex Hormones and Colorectal Cancer Risk in Men and Women 
Background & Aims
There is observational and clinical evidence that indicate that sex hormones affect development of colorectal cancer (CRC) in men and women. However, the relationship between endogenous sex hormone levels and CRC is unclear.
We collected data on lifestyle, medical history, and diet etc. (through 2008), along with blood samples, from the Nurses’ Health Study, the Women’s Health Study, the Health Professional Follow-Up Study, and the Physicians’ Health Study II. We measured plasma levels of estrone, estradiol, testosterone, sex hormone binding globulin (SHBG), and c-peptide among 730 women (293 cases of CRC and 437 healthy individuals, as controls) and 1158 men (439 CRC cases and 719 controls), and used unconditional logistic regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were 2-sided.
Total testosterone, SHBG, and the ratio of estradiol to testosterone were associated with CRC in men after adjustments for matching and risk factors for CRC, including BMI and plasma levels of C-peptide. The RRs in the highest relative to the lowest quartile were 0.62 for testosterone (95% CI, 0.40–0.96), 0.65 for SHBG (95% CI, 0.42−0.99), and 2.63 for the ratio (95% CI, 1.58–4.36) (P-values for trend ≤0.02). However, in women, only the ratio of estradiol to testosterone was (inversely) associated with CRC after adjustments for all factors (RR, 0.43; 95% CI, 0.22−0.84; P-value for trend, .03).
Based on combined data from 4 population studies, there appears to be an association between levels of sex hormones and CRC risk in men. There also appears to be an inverse association between the ratio of estradiol to testosterone and CRC in postmenopausal women.
PMCID: PMC3594467  PMID: 23200979
estrogen; incidence; colorectal cancer; testosterone
2.  Vascular risk factors, cardiovascular disease and restless legs syndrome in men 
The American journal of medicine  2013;126(3):228-235.e2.
Prevalences of vascular risk factors, cardiovascular disease and restless legs syndrome increase with age. Prior studies analyzing the associations between vascular risk factors, cardiovascular disease, and restless legs syndrome found controversial results. We therefore aim to evaluate the association between prevalent vascular risk factors, prevalent cardiovascular disease and restless legs syndrome.
We conducted a cross-sectional study among 22,786 participants of the US Physicians’ Health Studies I and II. Restless legs syndrome was classified according to the four minimal diagnostic criteria. Vascular risk factors and restless legs syndrome symptoms were self-reported. Prevalent cardiovascular disease events including major cardiovascular disease, stroke and myocardial infarction were confirmed by medical record review. Age- and multivariable-adjusted logistic regression models were used to evaluate the association between vascular risk factors, prevalent cardiovascular disease events and restless legs syndrome.
The mean age of the cohort 67.8 years. Restless legs syndrome prevalence was 7.5% and increased significantly with age. Diabetes significantly increased the odds (OR: 1.41, 95%CI: 1.21–1.65), while frequent exercise (OR: 0.78, 95%CI: 0.67–0.91) and alcohol consumption of one or more drinks per day (OR: 0.80, 95%CI: 0.69–0.92) significantly reduced the odds of restless legs syndrome in multivariable-adjusted models. Prevalent stroke showed an increased multivariable-adjusted OR of 1.40 (1.05–1.86) while men with prevalent myocardial infarction had a decreased OR of 0.73 (0.55–0.97) for restless legs syndrome.
The restless legs syndrome prevalence among US male physicians is similar to men of the same age group in other western countries. A history of diabetes is the most consistent risk factor associated with restless legs syndrome. Prevalent stroke and myocardial infarction are related to restless legs syndrome prevalence.
PMCID: PMC3574273  PMID: 23410563
Vascular risk factors; cardiovascular disease; Restless legs syndrome; cohort study
3.  Vascular risk factors, cardiovascular disease and restless legs syndrome in women 
The American journal of medicine  2013;126(3):220-227.e2.
Previous studies evaluating the association between cardiovascular disease and vascular risk factors with restless legs syndrome showed inconsistent results, especially for the potential relation between various vascular risk factors and restless legs syndrome. We therefore aimed to analyze the relationship between vascular risk factors, prevalent cardiovascular disease and restless legs syndrome.
This is a cross-sectional study of 30,262 female health professionals participating in the Women's Health Study (WHS). Restless legs syndrome was defined according to diagnostic criteria of the International Restless Legs Study Group. Information on vascular risk factors (diabetes, hypertension, hypercholesterolemia, body mass index, alcohol, smoking, exercise, family history of myocardial infarction) was self-reported. Cardiovascular disease events (coronary revascularization, myocardial infarction, stroke) were confirmed by medical record review. Prevalent major cardiovascular disease was defined as non-fatal stroke or non-fatal myocardial infarction. Logistic regression models were used to evaluate the association between vascular risk factors, prevalent cardiovascular disease and restless legs syndrome.
Of the 30,262 participants (mean age: 63.6 years), 3,624 (12.0%) reported restless legs syndrome. In multivariable-adjusted models, body mass index (OR for BMI ≥35kg/m2: 1.35, 95% CI: 1.17–1.56), diabetes (OR: 1.19, 95%CI: 1.04–1.35), hypercholesterolemia (OR: 1.17, 95% CI: 1.09–1.26), smoking status (OR for ≥15 cigarettes/day: 1.41, 95%CI: 1.19–1.66) and exercise (OR for exercise ≥ 4 times/week: 0.84, 95%CI: 0.74–0.95) were associated with restless legs syndrome prevalence. We found no association between prevalent cardiovascular disease (major cardiovascular disease, myocardial infarction, stroke) and restless legs syndrome prevalence. Women who underwent coronary revascularization had a multivariable-adjusted OR of 1.39 (1.10–1.77) for restless legs syndrome.
In this large cohort of female health professionals, various vascular risk factors are associated with restless legs syndrome prevalence. We could not confirm results of previous reports indicating an association between prevalent cardiovascular disease and restless legs syndrome.
PMCID: PMC3574635  PMID: 23410562
Vascular risk factors; cardiovascular disease; Restless legs syndrome; cohort study
4.  Migraine and Restless Legs Syndrome in Men 
Previous studies suggest an association between migraine and restless legs syndrome (RLS). Population-based data, however, have been limited to women. The aim of this study is to evaluate the association between migraine and RLS in a male cohort.
Cross-sectional study among 22,926 participants in the Physicians’ Health Study. Migraine and RLS information was self-reported. RLS was classified according to four minimal diagnostic criteria. Age-and multivariable-adjusted logistic regression models were calculated.
Of the 22,926 participants (mean age 67.8), 2,816 (12.3%) reported migraine and 1,717 (7.5%) RLS. Migraine was associated with an increased multivariable-adjusted OR (95% CI) of 1.20 (1.04–1.38) for having RLS. The association remained stable after excluding men with potential mimics of RLS and was not modified by age.
Results of our study indicate an association between migraine and RLS in men. The magnitude of effect is similar to what has been reported in women.
PMCID: PMC3528814  PMID: 23155191
migraine; restless legs syndrome; cross-sectional study; epidemiology
5.  Association of Type 2 Diabetes Susceptibility Variants With Advanced Prostate Cancer Risk in the Breast and Prostate Cancer Cohort Consortium 
American Journal of Epidemiology  2012;176(12):1121-1129.
Observational studies have found an inverse association between type 2 diabetes (T2D) and prostate cancer (PCa), and genome-wide association studies have found common variants near 3 loci associated with both diseases. The authors examined whether a genetic background that favors T2D is associated with risk of advanced PCa. Data from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium, a genome-wide association study of 2,782 advanced PCa cases and 4,458 controls, were used to evaluate whether individual single nucleotide polymorphisms or aggregations of these 36 T2D susceptibility loci are associated with PCa. Ten T2D markers near 9 loci (NOTCH2, ADCY5, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, MTNR1B, FTO, and HNF1B) were nominally associated with PCa (P < 0.05); the association for single nucleotide polymorphism rs757210 at the HNF1B locus was significant when multiple comparisons were accounted for (adjusted P = 0.001). Genetic risk scores weighted by the T2D log odds ratio and multilocus kernel tests also indicated a significant relation between T2D variants and PCa risk. A mediation analysis of 9,065 PCa cases and 9,526 controls failed to produce evidence that diabetes mediates the association of the HNF1B locus with PCa risk. These data suggest a shared genetic component between T2D and PCa and add to the evidence for an interrelation between these diseases.
PMCID: PMC3571230  PMID: 23193118
carcinoma; diabetes mellitus, type 2; genetic predisposition to disease; genetics; genome-wide association study; humans; polymorphism, single nucleotide; prostatic neoplasms
6.  A Randomized Trial of Long-term Multivitamin Supplementation and Cognitive Function in Men: The Physicians’ Health Study II 
Archives of internal medicine  2007;167(20):10.1001/archinte.167.20.2184.
Despite widespread use of multivitamin supplements, their effect on cognitive health – a critical issue with aging – remains inconclusive. To date, there have been no long-term clinical trials to study multivitamin use and cognitive decline in older persons.
To evaluate whether long-term multivitamin supplementation affects cognitive health in later-life.
Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to June 1, 2011. The cognitive function sub-study began in 1998; we completed up to four repeated cognitive assessments by telephone interview over 12 years.
The Physicians’ Health Study II.
5,947 male physicians aged ≥ 65 years.
Daily multivitamin, or placebo.
A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary endpoint was a verbal memory score combining 4 tests of verbal memory, a strong predictor of Alzheimer disease.
There was no difference in the mean cognitive change over time between the multivitamin and placebo groups, or in the mean level of cognition at any of the four assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was −0.01 (95% confidence interval [CI] −0.04, 0.02) standard units, comparing treatment versus placebo. Similarly, there was no difference in cognitive performance between the treated and placebo groups on the secondary outcome, verbal memory (e.g., mean difference in cognitive change over follow-up=−0.005, 95% CI −0.04, 0.03).
Doses of vitamins may be too low, or population may be too well-nourished to benefit from multivitamin.
In male physicians aged ≥ 65 years, long-term use of a daily multivitamin did not provide cognitive benefits.
Trial Registration identifier: NCT00270647
PMCID: PMC3858850  PMID: 17998490
multivitamin; cognitive function; randomized clinical trial; men
7.  Fish consumption, omega-3 fatty acids and risk of heart failure: a meta-analysis 
Background and Aims
While marine omega-3 fatty acids have been associated with a lower mortality in heart failure patients, data on omega-3 and incident heart failure are inconsistent. We systematically reviewed the evidence on the association of omega-3 fatty acids and fish intake with the incidence of heart failure in this meta-analysis.
We identified relevant studies by searching MEDLINE and EMBASE databases up to August 31, 2011 without restrictions and by reviewing reference lists from retrieved articles.
A total of 176,441 subjects and 5,480 incident cases of heart failure from 7 prospective studies were included in this analysis. Using random effect model, the pooled relative risk for heart failure comparing the highest to lowest category of fish intake was 0.85 (95% CI; 0.73–0.99), p=0.04; corresponding value for marine omega-3 fatty acids was 0.86 (0.74–1.00), p=0.05. There was no evidence for heterogeneity across studies of fish consumption (I2=8%). In contrast, there was modest heterogeneity for omega-3 fatty acid analysis (I2= 44%). Lastly, there was no evidence for publication bias.
This meta-analysis is consistent with a lower risk of heart failure with intake of marine omega-3 fatty acids. These observational findings should be confirmed in a large randomized trial.
PMCID: PMC3509256  PMID: 22682084
Heart failure; epidemiology; diet; nutrition; omega-3 fatty acids; risk factors
8.  Multivitamins in the Prevention of Cancer in Men: The Physicians’ Health Study II Randomized Controlled Trial 
Multivitamin preparations are the most common dietary supplement, taken by at least one-third of all US adults. Limited observational studies have not provided evidence regarding associations of multivitamin use with total and site-specific cancer incidence or mortality.
To determine whether long-term multivitamin supplementation decreases the risk of total and site-specific cancer events among men.
The Physicians’ Health Study II is a randomized, double-blind, placebo-controlled trial of a common multivitamin that began in 1997 with treatment and follow-up through June 1, 2011.
Setting and Participants
A total of 14,641 male U.S. physicians initially aged ≥50 years (mean [± SD] age; 64.3 [± 9.2] years), including 1,312 men with a history of cancer at randomization, were enrolled.
Daily multivitamin, as Centrum Silver.
Main Outcome Measures
A primary outcome was total cancer (excluding non-melanoma skin cancer), with prostate, colorectal, and other site-specific cancers among secondary endpoints included in this report.
During a median (interquartile range) follow-up of 11.2 (10.7 to 13.3) years, there were 2,669 men with confirmed cancer, including 1,373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer (active and placebo multivitamin groups, 17.0 and 18.3 events, respectively, per 1,000 person-years; hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.86–0.998; P=0.044). There was no significant effect of a daily multivitamin on prostate cancer (HR, 0.98; 95% CI, 0.88–1.09; P=0.76), colorectal cancer (HR, 0.89; 95% CI, 0.68–1.17; P=0.39), or other site-specific cancers There was a lower risk of cancer mortality that did not reach statistical significance (HR, 0.88; 95% CI, 0.77–1.01; P=0.07). Daily multivitamin use was associated with a reduction in total cancer among 1,312 men with a baseline history of cancer (HR, 0.73; 95% CI, 0.56–0.96; P=0.022), but this did not differ significantly from that among 13,329 men initially free of cancer (HR, 0.94; 95% CI, 0.87–1.02; P=0.15) (P, interaction = 0.07).
In this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer.
PMCID: PMC3517179  PMID: 23162860
multivitamin; total cancer; prostate cancer; randomized clinical trial; men
9.  Multivitamins in the Prevention of Cardiovascular Disease in Men: The Physicians' Health Study II Randomized Controlled Trial 
Though multivitamins aim to prevent vitamin and mineral deficiency, there is a perception that multivitamins may prevent cardiovascular disease (CVD). Observational studies examining regular multivitamin use have been inconsistently associated with CVD, with no long-term clinical trials of multivitamin use.
To determine whether long-term multivitamin supplementation decreases the risk of major cardiovascular events among men.
The Physicians' Health Study II is a randomized, double-blind, placebo-controlled trial of a common daily multivitamin, that began in 1997 with continued treatment and follow-up through June 1, 2011.
Setting and Participants
A total of 14,641 male U.S. physicians initially aged ≥50 years (mean [± SD] age; 64.3 [± 9.2] years), including 754 men with a history of CVD at randomization, were enrolled.
Daily multivitamin, as Centrum Silver.
Main Outcome Measures
The primary cardiovascular outcome was a composite endpoint of major cardiovascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, and fatal CVD. Secondary outcomes included MI and stroke individually.
During a median (interquartile range) follow-up of 11.2 (10.7 to 13.3) years, there were 1,732 confirmed major cardiovascular events. Compared with placebo, there was no significant effect of a daily multivitamin on major cardiovascular events (active and placebo multivitamin groups, 11.0 and 10.8 events per 1,000 person-years; hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.91–1.10; P=0.91). Further, a daily multivitamin had no effect on total MI (active and placebo multivitamin groups, 3.9 and 4.2 events per 1,000 person-years; HR, 0.93; 95% CI, 0.80–1.09; P=0.39), total stroke (active and placebo multivitamin groups, 4.1 and 3.9 events per 1,000 person-years; HR, 1.06; 95% CI, 0.91–1.23; P=0.48), or cardiovascular mortality (active and placebo multivitamin groups, 5.0 and 5.1 events per 1,000 person-years; HR, 0.95; 95% CI, 0.83–1.09; P=0.47). A daily multivitamin was also not significantly associated with total mortality (HR, 0.94; 95% CI, 0.88–1.02; P=0.13). The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD (P, interaction = 0.62).
A daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up.
PMCID: PMC3501249  PMID: 23117775
multivitamin; cardiovascular disease; myocardial infarction; stroke; randomized clinical trial; men
10.  Plasma Phospholipid Concentration of Cis Palmitoleic Acid and Risk of Heart Failure 
Circulation. Heart failure  2012;5(6):703-709.
While plasma palmitoleic acid has been positively associated with blood pressure, inflammation, and insulin resistance, its association with heart failure has not been investigated. We assessed whether plasma phospholipid cis palmitoleic acid was associated with heart failure risk.
Methods and Results
This ancillary study of the Physicians’ Health Study used a risk set sampling method to select 788 matched pairs. For each case of incident heart failure, we randomly selected a control among subjects that were free of heart failure and alive at the time of index case diagnosis and matched on age, year of birth, race, and time of blood collection. Plasma phospholipid fatty acids were measured using gas chromatography. Heart failure was ascertained using annual follow-up questionnaire and validated in a subsample. In a multivariable conditional logistic regression, odds ratios (95% CI) for heart failure were 1.0 (ref), 1.06 (0.75-1.48), 1.20 (0.85-1.68), and 1.58 (1.11-2.25) across consecutive quartiles of cis palmitoleic acid (p for trend 0.009). Each standard deviation increase in plasma cis palmitoleic acid was associated with 17% higher odds of heart failure (95% CI: 2% to 33%) in a multivariable model. In a secondary analysis, each standard deviation increase of log-stearoyl-coA desaturase activity (16:1n-7/16:0 ratio) was positively associated with the risk of heart failure [OR: 1.14 (95% CI: 1.00-1.29)] whereas oleic acid and cis-vaccenic acid concentrations were not related to heart failure risk.
Our data showed a positive association between plasma phospholipid cis-palmitoleic acid and heart failure risk in male physicians.
PMCID: PMC3618485  PMID: 23065037
heart failure; epidemiology; fatty acids; cis-palmitoleic acids; risk factors
11.  Association between adiponectin and heart failure risk in the Physicians' Health Study 
Obesity (Silver Spring, Md.)  2013;21(4):831-834.
Limited data are available on the association between adiponectin and incident heart failure. In the current ancillary study to the Physicians' Health Study, we used a prospective nested-case control design to examine whether plasma adiponectin concentration was related to the risk of heart failure. We selected 787 incident heart failure cases and 787 matched controls for the current analysis. Each control was selected using a risk set sampling technique at the time of the occurrence of the index case and matched on year of birth, age at blood collection, and race. Adiponectin was measured using ELISA. Heart failure occurrence was self-reported in annual follow-up questionnaire. Validation of self-reported heart failure in this cohort has been published. The mean age was 58.7 years. In a conditional logistic regression adjusting for age, race, time of blood collection, year of birth, hypertension, atrial fibrillation, smoking, alcohol intake, and exercise, estimates of the relative risk (95% confidence interval) were 1.0 (ref), 0.74 (0.53–1.04), 0.67 (0.48–0.94), 0.70 (0.50–0.99), and 0.92 (0.65–1.30) from the lowest to the highest quintile of adiponectin, respectively, p for quadratic trend 0.004. Additional adjustment for potential mediating factors including diabetes, C-reactive protein, and body mass index led to the attenuation of the estimate of effect [1.0 (ref), 0.81 (0.57–1.15), 0.75 (0.53–1.06), 0.83 (0.58–1.18), and 1.26 (0.87–1.81) across consecutive quintiles of adiponectin]. Our data are consistent with a J-shaped association between total adiponectin and the risk of heart failure among US male physicians.
PMCID: PMC3479315  PMID: 23712986
Adiponectin; epidemiology; heart failure; risk factors
12.  Plasma Adiponectin and the Risk of Hypertension in White and Black Postmenopausal Women 
Clinical chemistry  2012;58(10):1438-1445.
Adiponectin may have a protective role in the development of obesity-related metabolic and vascular disorders including hypertension. We conducted a prospective, nested case-control study to investigate the relationship between baseline plasma adiponectin, measures of adiposity, and subsequent risk of hypertension.
We selected 400 White and 400 Black postmenopausal women, aged <70 years, who have developed incident hypertension during 5.9-year follow-up and an equal number of age and race matched controls in the Women's Health Initiative Observational Study. We measured plasma concentrations of total adiponectin in their baseline bloods.
In crude matched models, plasma adiponectin was inversely associated with risk of hypertension among both White and Black women. The association appeared to be non-linear in White women but dose-related in Black women. Adjustment for lifestyle factors, measures of obesity, and obesity-related clinical factors attenuated these associations. The multivariable relative risks (95% confidence interval) of hypertension across increasing quartiles of plasma adiponectin were 1.00, 0.98 (0.66-1.46), 0.63 (0.41-0.97), and 0.92 (0.60-1.42) in White women (p, trend: 0.38) and 1.00, 0.96 (0.64-1.46), 0.83 (0.53-1.29), and 0.58 (0.36-0.94) in Black women (p, trend: 0.02). Further adjustment for inflammatory markers and endothelial markers eliminated the association in White, but not Black, women.
In this prospective, nested case-control study, we found an inverse association between plasma adiponectin and risk of hypertension in White and Black postmenopausal women. The reduced risk of hypertension was limited to intermediate levels of adiponectin in White women while was graded across quartiles of adiponectin in Black women.
PMCID: PMC3462274  PMID: 22859729
adiponectin; hypertension; epidemiology; prospective study; postmenopausal women
13.  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.
PMCID: PMC3465767  PMID: 22825588
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
14.  Genetic Variation in the Vitamin D Pathway in Relation to Risk of Prostate Cancer – Results from Breast and Prostate Cancer Cohort Consortium (BPC3) 
Studies suggest that vitamin D status may be associated with prostate cancer risk, although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D (25(OH)D) status. We examined prostate cancer risk in relation to SNPs in four genes shown to predict circulating levels of 25(OH)D.
SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the NCI Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer.
We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D (per A allele, OR=0.86, 95%CI=0.80–0.93, p-trend=0.0002), but an increased risk for non-aggressive disease (per a allele: OR=1.10, 95%CI=1.04–1.17, p-trend=0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6–8 vs. 0–1 alleles = 0.66, 95% CI = 0.44 – 0.98; p-trend=0.003).
In this large, pooled analysis, genetic variants related to lower 25(OH)D were associated with a decreased risk of aggressive prostate cancer.
Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk.
PMCID: PMC3617077  PMID: 23377224
Vitamin D; prostatic neoplasms; data pooling; genes; SNPs
15.  Association between adult height, genetic susceptibility and risk of glioma 
Background Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease.
Methods We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case–control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants.
Results Among men, we found a positive association between height and glioma risk (≥190 vs 170–174 cm, pooled OR = 1.70, 95% CI: 1.11–2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17–3.38; P-trend = 0.02). Among women, these associations were less clear (≥175 vs 160–164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70–1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77–2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk.
Conclusion An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease.
PMCID: PMC3429876  PMID: 22933650
Height; brain cancer; glioma; cancer; epidemiology
16.  Plasma levels of FABP4, but not FABP3, are associated with increased risk of diabetes 
Lipids  2012;47(8):757-762.
Little is known about the association between plasma concentrations of fatty acid binding protein 3 and 4 and the risk of diabetes in population-based cohorts. In a prospective nested case-control design, we studied 149 cases of diabetes and 149 matched controls from the Physicians’ Health Study. Plasma fatty acid binding proteins were measured on frozen specimens collected between 1995–2001 by ELISA. Cases of diabetes were self-reported and validated in a subsample via review of medical records. We used conditional logistic regression to estimate multivariable relative risks. The mean age at baseline was 64.9 years and median plasma fatty acid binding protein 3 and 4 were 2.12 ng/ml (IQR 1.62–2.66) and 15.32 ng/ml (IQR: 12.14–18.73), respectively. In separate models, each fatty acid binding protein was positively associated with the risk of diabetes in a conditional logistic regression adjusting for matching variables, smoking, and hypertension. However, upon adjustment for each other, only fatty acid binding protein 4 (but not 3) was positively associated with the risk of diabetes [relative risk (95% CI): 1.0 (reference), 2.73 (1.08–6.89), 2.66 (1.11–6.42), and 6.89 (2.83–16.80) across consecutive quartiles of fatty acid binding protein 4), p for trend <0.0001. The FABP4-diabetes association was modified by body mass index (p interaction 0.03). Our data showed a positive association between plasma fatty acid binding protein 4 but not 3 and the risk of diabetes in US male physicians. The interaction with body mass index warrants further investigations.
PMCID: PMC3523883  PMID: 22706792
Diabetes; epidemiology; fatty acid binding proteins; adipokines; risk factors
17.  Vitamins E and C and Medical Record-Confirmed Age-related Macular Degeneration in a Randomized Trial of Male Physicians 
Ophthalmology  2012;119(8):1642-1649.
To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of the diagnosis of age-related macular degeneration (AMD) in a large-scale randomized trial of male physicians.
Randomized, double-masked, placebo-controlled trial.
We included 14 236 apparently healthy United States male physicians aged ≥50 years who did not report a diagnosis of AMD at baseline.
Participants were randomly assigned to receive 400 international units (IU) of vitamin E or placebo on alternate days, and 500 mg of vitamin C or placebo daily. Participants reported new diagnoses of AMD on annual questionnaires and medical record data were collected to confirm the reports.
Main Outcome Measures
Incident diagnosis of AMD responsible for a reduction in best-corrected visual acuity to ≤20/30.
After 8 years of treatment and follow-up, a total of 193 incident cases of visually significant AMD were documented. There were 96 cases in the vitamin E group and 97 in the placebo group (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.78–1.37). For vitamin C, there were 97 cases in the active group and 96 in the placebo group (HR, 0.99; 95% CI, 0.75–1.31).
In a large-scale, randomized trial of United States male physicians, alternate-day use of 400 IU of vitamin E and/or daily use of 500 mg of vitamin C for 8 years had no appreciable beneficial or harmful effect on risk of incident diagnosis of AMD.
PMCID: PMC3535014  PMID: 22503302
18.  Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) 
Secondary analyses of two randomized controlled trials (RCTs) and supportive epidemiologic and preclinical indicated the potential of selenium and vitamin E for preventing prostate cancer.
To determine whether selenium or vitamin E or both could prevent prostate cancer with little or no toxicity in relatively healthy men.
Design, Setting, and Participants
Randomization of a planned 32,400 men to selenium, vitamin E, selenium plus vitamin E, and placebo in a double-blinded fashion. Participants were recruited and followed in community practices, local hospitals and HMOs, and tertiary cancer centers in the United States, Canada and Puerto Rico. Baseline eligibility included 50 years or older (African American) or 55 years or older (all others), a serum prostate-specific antigen (PSA) ≤ 4 ng/mL, and a digital rectal examination (DRE) not suspicious for prostate cancer. Between 2001 and 2004, 35,533 men (10% more than planned because of a faster-than-expected accrual rate) were randomly assigned to the four study arms, which were well balanced with respect to all potentially important risk factors.
Oral selenium (200 µg/day from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/day of all rac-α-tocopheryl acetate) and matched selenium placebo, or the two combined or placebo plus placebo for a planned minimum of 7 and maximum of 12 years.
Main Outcome Measures
Prostate cancer (as determined by routine community diagnostic standards) and prespecified secondary outcomes including lung, colorectal and overall cancer.
Study supplements were discontinued at the recommendation of the Data and Safety Monitoring Committee at a planned 7-year interim analysis because the evidence convincingly demonstrated no benefit from either study agent (p < 0.0001) and no possibility of a benefit to the planned degree with additional follow-up. As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17 and 7.33). Hazard ratios (number of prostate cancers, 99% confidence intervals [CIs]) for prostate cancer were 1.13 for vitamin E (n=473; CI, 0.91–1.41), 1.04 for selenium (n=432; CI, 0.83–1.30), and 1.05 for the combination (n=437; CI, 0.83–1.31) compared with placebo (n=416). There were no significant differences (all p-values > 0.15) in any prespecified cancer endpoints. There were nonsignificant increased risks of prostate cancer in the vitamin E arm (p=0.06; relative risk [RR]=1.13; 99% CI, 0l95–1.35) and of Type 2 diabetes mellitus in the selenium arm (p=0.16; RR=1.07; 99% CI, 0.94–1.22), but they were not observed in the combination arm.
Selenium or vitamin E, alone or in combination, did not prevent prostate cancer in this population at the doses and formulations used.
PMCID: PMC3682779  PMID: 19066370
19.  High-density lipoprotein and mortality before age 90 years in male physicians 
In cross-sectional and some cohort studies with shorter follow-up, high-density lipoprotein cholesterol (HDL-C) has been associated with longer life. We sought to examine the relationship between HDL-C and death prior to age 90 years in the Physicians’ Health Study (PHS).
Of PHS enrollees who had blood collected at PHS II baseline (approximately 1997) we selected 1351 men old enough to reach age 90 years by March 4, 2009 and with complete data on HDL-C and total cholesterol, lifestyle factors, and comorbidities. We used Cox proportional hazards to determine the HRs and 95% CIs for all-cause, CVD-, and non-CVD mortality prior to age 90, adjusting for potential confounders. After a mean (SD) follow-up of 6.8(3.2) years, 44.1% of men in the lowest baseline HDL-C quartile (<32.8 mg/dL) compared to 32.9% (11.2 % absolute risk reduction) in the highest HDL-C quartile (≥54.1 mg/dL) died prior to age 90. In multivariable adjusted analyses, men in the highest HDL-C quartile had a 28% lower risk (HR 0.72, 95% CI 0.55–0.94) of death prior to age 90 compared to men in the lowest HDL-C quartile. In age-adjusted analyses, increasing baseline HDL-C was associated with a lower risk of CVD death (p for trend 0.004), though this association was attenuated slightly after adjusting for all confounders. No association was found between HDL-C and non-CVD mortality.
In male physicians, higher baseline HDL-C levels were associated with a lower risk of all-cause and CVD mortality prior to age 90.
PMCID: PMC3357896  PMID: 22474245
aging; lipoproteins; epidemiology; prevention
20.  Physical activity and the risk of becoming overweight or obese in middle aged and older women 
Obesity (Silver Spring, Md.)  2011;20(5):1096-1103.
Although public health campaigns stress leisure time physical activity (LTPA) as essential for obesity prevention, few epidemiological studies have focused on the association of specific types and intensities of LTPA and the clinical endpoints of overweight and obesity. Therefore, we prospectively assessed whether moderate and vigorous intensity as well as total LTPA were associated with the risk of becoming either overweight or obese using a prospective cohort design of 19,003 women enrolled in the Women’s Health Study. Women reported their participation in walking and LTPA at baseline. During a median follow-up of 11.6 years, 7865 women became overweight or obese. In multivariable-adjusted models that included demographic, lifestyle, and dietary factors, both vigorous intensity and total LTPA showed a modest inverse relationship with the development of overweight/obesity. The hazard ratios (HR) and 95% confidence interval (CI) for the highest categories of vigorous intensity LTPA (>2000 kilocalories/week) and total LTPA (>3000 kilocalories/week) compared to no LTPA were 0.79 (0.71–0.89) and 0.87 (0.78–0.96), respectively. In addition, a greater percentage of total LTPA spent performing vigorous intensity activities was associated with a lower risk of overweight/obesity (multivariable HR 0.93, 95% CI 0.87–0.98 for performing > 50% compared to < 50% of activity as vigorous). In conclusion, higher amounts of total LTPA should be encouraged to prevent obesity. Among those willing to participate in vigorous LTPA, and for whom such activities are not contraindicated, vigorous LPTA should be encouraged.
PMCID: PMC3359055  PMID: 22193920
21.  Beta-Carotene Antioxidant Use During Radiation Therapy and Prostate Cancer Outcome in the Physicians' Health Study 
The safety of antioxidant supplements during radiation therapy (RT) for cancer is controversial. Antioxidants could potentially counteract the pro-oxidant effects of RT and compromise therapeutic efficacy. We performed a prospective study nested within the Physicians' Health Study (PHS) randomized trial to determine if supplemental antioxidant use during RT for prostate cancer is associated with an increased risk of prostate cancer death or metastases.
Methods and Materials
383 PHS participants received RT for prostate cancer while randomized to beta-carotene (50 mg on alternate days), or placebo. The primary endpoint was time from RT to lethal prostate cancer, defined as prostate cancer death or bone metastases. The Kaplan-Meier method was used to estimate survival probabilities, and the log-rank test to compare groups. Cox proportional hazards regression was used to estimate the effect of beta-carotene compared with placebo during RT.
With a median follow-up of 10.5 years, there was no significant difference in risk of lethal prostate cancer with use of beta-carotene during RT compared with placebo (HR=0.72; 95% CI, 0.42 to 1.24; P=0.24). After adjusting for age at RT, PSA, Gleason score, and clinical stage, the difference remained non-significant. The 10-year freedom from lethal prostate cancer was 92% (95% CI, 87-95%) in the beta-carotene group and 89% (95% CI, 84-93%) in the placebo group.
Use of the supplemental antioxidant, beta-carotene, during RT was not associated with an increased risk of prostate cancer death or metastases. This study suggests a lack of harm from supplemental beta-carotene during radiation therapy for prostate cancer.
PMCID: PMC3386602  PMID: 22079732
Antioxidants; prostate cancer; vitamins; beta-carotene; outcomes
22.  Height and Risk of Heart Failure in the Physicians’ Health Study I 
The American Journal of Cardiology  2012;109(7):994-997.
While previous studies have reported an association between height and cardiovascular disease, it is unclear whether height is associated with the risk of heart failure (HF). We hypothesized that height will be inversely associated with HF risk. We used prospective data from 22 042 male physicians (mean age 53.8 years) from the Physicians’ Health Study I. Height was self-reported at baseline. Incident HF was ascertained via follow-up questionnaires and validated through review of medical records in a subsample. Cox proportional hazard model was used to compute hazard ratios (HR) with corresponding 95% confidence intervals (CI). Mean height (± standard deviation) was 1.78 (0.07) m. A total of 1444 HF cases occurred during a mean follow-up of 22.3 years. Compared to subjects in the lowest height category (1.40 – 1.73 m), HR (95% CI) for HF were 0.86(0.74-0.99), 0.82 (0.70-0.95) and 0.76 (0.63-0.91) for height categories of 1.74-1.78 m, 1.79-1.83 m, and 1.84-2.08 m, respectively, after adjustment for age, weight, hypertension, and diabetes mellitus (ptrend = 0.0023). HR (95% CI) per SD increment in height was 0.92(0.86-0.98) in a fully adjusted model. Exclusion of individuals with prevalent atrial fibrillation, left ventricular hypertrophy, valvular heart disease, and a history of coronary artery bypass graft, yielded similar results [HR per SD: 0.88(0.83 – 0.94)]. In conclusion, our data demonstrated an inverse association between height and incident HF in US male physicians. Additional studies to elucidate underlying biologic mechanisms are warranted.
PMCID: PMC3313006  PMID: 22221952
Heart Failure; Stature; Height; Epidemiology
23.  Insulin Resistance and Incident Peripheral Artery Disease in the Cardiovascular Health Study 
Type 2 diabetes is a risk factor for PAD, and insulin resistance is a key feature of diabetes and pre-diabetes. No longitudinal epidemiological study has examined the relation between insulin resistance and PAD. Our study analyzed the association of quartiles of the homeostatic model of insulin resistance (HOMA-IR) and the development of PAD defined by 2 methods. PAD was first defined as the development of an abnormal ankle brachial index (ABI) (dichotomous outcome) after six years of follow-up. PAD was alternatively defined as the development of clinical PAD (time to event analysis). The study samples included adults over the age of 65 who were enrolled in the Cardiovascular Health Study, had fasting measurements of insulin and glucose, had ABI measurements, and were not receiving treatment for diabetes. Multivariable models were adjusted for potential confounders, including age, sex, field center and cohort, BMI, smoking status, alcohol use, and exercise intensity. Additional models adjusted for potential mediators, including blood pressure, lipids, kidney function, and prevalent vascular disease. In the ABI analysis (n=2108), multivariable adjusted models demonstrated a positive relation between HOMA-IR and incident PAD (Odds Ratio=1.80 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval 1.20-2.71). In the clinical PAD analysis (n=4208), we found a similar relation (Hazard ratio=2.30 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval 1.15-4.58). As expected, further adjustment for potential mediators led to some attenuation of effect estimates. In conclusion, insulin resistance is associated with a higher risk of PAD in older adults.
PMCID: PMC3563259  PMID: 22402937
Peripheral artery disease; Diabetes; Insulin Resistance; Epidemiology
24.  Fruit and vegetable intake and the risk of hypertension in middle-aged and older women 
American Journal of Hypertension  2011;25(2):180-189.
Despite the promising findings from short-term intervention trials, the long-term effect of habitual fruit and vegetable intake on blood pressure (BP) remains uncertain. We therefore assessed the prospective association between baseline intake of fruits and vegetables and the risk of hypertension in a large cohort of middle-aged and older women.
We conducted analyses among 28,082 US female health professionals aged ≥39 years, free of cardiovascular disease, cancer, and hypertension at baseline. Baseline intake of fruits and vegetables was assessed using semi-quantitative food frequency questionnaires. Incident hypertension was identified from annual follow-up questionnaires.
During 12.9 years of follow-up, 13,633 women developed incident hypertension. After basic adjustment including age, race, and total energy intake, the hazard ratio and 95% CI of hypertension was 0.97 (0.89-1.05), 0.93 (0.85-1.01), 0.89 (0.82-0.97), and 0.86 (0.78-0.94) comparing women who consumed 2-<4, 4-<6, 6-<8, and ≥8 servings/day of total fruits and vegetables with those consuming <2 servings/day. These associations did not change after additionally adjusting for lifestyle factors but were attenuated after further adjustment for other dietary factors. When fruits and vegetables were analyzed separately, higher intake of all fruits but not all vegetables remained significantly associated with reduced risk of hypertension after adjustment for lifestyle and dietary factors. Adding body mass index to the models eliminated all associations.
Higher intake of fruits and vegetables, as part of a healthy dietary pattern, may only contribute a modest beneficial effect to hypertension prevention, possibly through improvement in body weight regulation.
PMCID: PMC3258456  PMID: 21993367
fruits; vegetables; diet; hypertension; prospective; women
25.  Breakfast cereals and risk of hypertension in the Physicians’ Health Study I 
Background and aims
Hypertension is a major public health problem. While many dietary factors affect the risk of developing hypertension, limited data are available on the association between consumption of breakfast cereal and incident hypertension. We examined the association between breakfast cereal consumption and the risk of hypertension.
We prospectively analyzed data from 13,368 male participants of the Physicians’ Health Study I. Consumption of breakfast cereals was estimated using an abbreviated food frequency questionnaire and incident hypertension was ascertained through yearly follow-up questionnaires.
The average age of study participants was 52.4 ±8.9 years (range 39.7-85.9) during the initial assessment of cereal intake (1981-1983). During a mean follow up of 16.3 years, 7,267 cases of hypertension occurred. The crude incidence rates of hypertension were 36.7, 34.0, 31.7, and 29.6 cases/1,000 person-years for people reporting breakfast cereal intake of 0, ≤ 1, 2-6, and ≥ 7 servings/week, respectively. In a Cox regression model adjusting for age, smoking, body mass index, alcohol consumption, fruit and vegetable consumption, physical activity, and history of diabetes mellitus, hazard ratios (95% CI) for hypertension were 1.0 (reference), 0.93 (0.88-0.99), 0.88 (0.83-0.94), and 0.81 (0.75-0.86) from the lowest to the highest category of cereal consumption, respectively (p for trend <0.0001). This association was strongest for whole grain cereals and was observed in lean as well as overweight or obese participants.
The results of this longitudinal cohort study suggest that whole grain breakfast cereal consumption confers a lower risk of hypertension in middle-aged adult males
PMCID: PMC3289098  PMID: 21868140
cereals; hypertension; epidemiology

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