No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3).

Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.

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

BACKGROUND: Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic. To examine the effects of reproductive factors and exogenous hormones on risk, we conducted a prospective analysis among a large group of US women. METHODS: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, data from 799,500 women in 11 cohorts were pooled and harmonised. Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of reproductive factors and exogenous hormones with HCC (n=248). RESULTS: Bilateral oophorectomy was associated with a significantly increased risk of HCC (HR=2.67, 95% CI=1.22-5.85), which did not appear to be related to a shorter duration of exposure to endogenous hormones or to menopausal hormone therapy use. There was no association between OC use and HCC (HR=1.12, 95% CI=0.82-1.55). Nor were there associations with parity, age at first birth, age at natural menopause, or duration of fertility. CONCLUSIONS: The current study suggests that bilateral oophorectomy increases the risk of HCC but the explanation for the association is unclear. There was no association between OC use and HCC risk. Examination of endogenous hormone levels in relation to HCC may help to clarify the findings of the current study.

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

BACKGROUND: Body mass index (BMI), a measure of obesity typically assessed in middle age or later, is known to be positively associated with pancreatic cancer. However, little evidence exists regarding the influence of central adiposity, a high BMI during early adulthood, and weight gain after early adulthood on pancreatic cancer risk. DESIGN: We conducted a pooled analysis of individual-level data from 20 prospective cohort studies in the National Cancer Institute BMI and Mortality Cohort Consortium to examine the association of pancreatic cancer mortality with measures of central adiposity (e.g. waist circumference; n = 647 478; 1947 pancreatic cancer deaths), BMI during early adulthood (ages 18-21 years) and BMI change between early adulthood and cohort enrollment, mostly in middle age or later (n = 1 096 492; 3223 pancreatic cancer deaths). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. RESULTS: Higher waist-to-hip ratio (HR = 1.09, 95% CI 1.02-1.17 per 0.1 increment) and waist circumference (HR = 1.07, 95% CI 1.00-1.14 per 10 cm) were associated with increased risk of pancreatic cancer mortality, even when adjusted for BMI at baseline. BMI during early adulthood was associated with increased pancreatic cancer mortality (HR = 1.18, 95% CI 1.11-1.25 per 5 kg/m(2)), with increased risk observed in both overweight and obese individuals (compared with BMI of 21.0 to <23 kg/m(2), HR = 1.36, 95% CI 1.20-1.55 for BMI 25.0 < 27.5 kg/m(2), HR = 1.48, 95% CI 1.20-1.84 for BMI 27.5 to <30 kg/m(2), HR = 1.43, 95% CI 1.11-1.85 for BMI ≥30 kg/m(2)). BMI gain after early adulthood, adjusted for early adult BMI, was less strongly associated with pancreatic cancer mortality (HR = 1.05, 95% CI 1.01-1.10 per 5 kg/m(2)). CONCLUSIONS: Our results support an association between pancreatic cancer mortality and central obesity, independent of BMI, and also suggest that being overweight or obese during early adulthood may be important in influencing pancreatic cancer mortality risk later in life.

Association of body mass index in early adulthood and middle age with future site-specific cancer mortality: the Harvard Alumni Health Study.

BACKGROUND: The association between adiposity in early adulthood and subsequent development of specific malignancies is unclear. Further, the potential for mediation by adiposity in middle age has not been well examined. In a rare study, we investigated the association of body mass index (BMI) in early adulthood with mortality from several site-specific cancers. DESIGN: In the Harvard Alumni Health Study cohort, 19 593 males had a physical examination at the university between 1914 and 1952 (mean age: 18.4 years) and returned a questionnaire in 1962 or 1966 (mean age = 45.1 years). BMI was computed using weight (kg)/height(2) (m(2)) at both time points. Vital status follow up continued for a maximum of 82 years. RESULTS: Positive early adulthood cancer mortality gradients by BMI were found for all malignancies combined (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI]: 1.05-1.17 for a one standard deviation increase in early adulthood BMI), and for lung (HR = 1.24; 95% CI = 1.10-1.40) and skin (HR = 1.29; 95% CI = 0.96-1.75) cancers. There were also apparent associations for cancers of the oesophagus and urogenital sites. Mediation by BMI in middle age was found to be minimal. CONCLUSION: Higher BMI in early adulthood appears to be a direct risk factor for selected malignancies several decades later.

Physical activity and weight gain prevention in older men.

BACKGROUND: Physical activity and adiposity are important predictors of mortality, even in older individuals. However, it is unclear how much physical activity is needed to prevent weight gain in older persons. PURPOSE: To examine the associations of different amounts of physical activity with weight gain prevention in older men. METHODS: A total of 5973 healthy men (mean age, 65.0 years) from the Harvard Alumni Health Study were followed from 1988 to 1998. At baseline (1988), in 1993 and 1998, men reported their recreational physical activity and body weight. Physical activity was categorized as: <7.5 metabolic equivalent (MET)-h per week (7.5 MET-h per week corresponds to the minimum required by the 2008 US federal guidelines), 7.5 to <21 MET-h per week (21 MET-h per week corresponds to the 2002 Institute of Medicine (IOM) guideline) and 21 MET-h per week. Meaningful weight gain was defined as an increase of ≥3% of body weight. RESULTS: Overall, weight tended to be stable over any 5-year period; mean change, -0.08 (s.d.=4.44) kg. However, ∼21% of men experienced meaningful weight gain over any 5-year period. In multivariate analyses, compared with men expending ≥ 21 MET-h per week, those expending 7.5 to <21 MET-h per week had an odds ratio (OR) of 1.35 (95% confidence interval: 1.03, 1.77) for meaningful weight gain, and men expending <7.5 MET-h per week, an OR of 1.16 (1.01, 1.33; P trend=0.09). CONCLUSIONS: Among older men, those with lesser levels of physical activity were more likely to gain weight than men satisfying the 2002 IOM guidelines of ≥21 MET-h per week (∼60 min day(-1) of moderate-intensity physical activity).

Long-Term Aspirin Use and Self-Reported Walking Speed in Older Men: The Physicians' Health Study.

BACKGROUND: Mobility limitation is a component of frailty that shares a bidirectional relationship with cardiovascular disease (CVD). Data are limited on the role of established CVD prevention therapies, such as aspirin, for prevention of frailty and mobility limitation. OBJECTIVES: Examine the association between long-term aspirin use and walking speed. DESIGN, SETTING, PARTICIPANTS: Prospective cohort of 14,315 men who participated in the Physicians' Health Study I, a completed randomized controlled trial of aspirin (1982-1988), with extended post-trial follow-up. MEASUREMENTS: Annual questionnaires collected data on aspirin use, lifestyle and other factors. Average annual aspirin use was categorized for each participant: ≤60 days/year and >60 days/year. Mobility was defined according to self-reported walking pace, categorized as: don't walk regularly (reference), easy/casual <2mph, normal ≥2-2.9mph, or brisk/very brisk ≥3mph. Propensity scoring balanced covariates between aspirin categories. Multinomial logistic regression models estimated odds of being in each self-reported walking category. RESULTS: Mean age was 70±8 years; mean aspirin use 11 years. There were 2,056 (14.3%) participants who reported aspirin use ≤60 days/year. Aspirin use >60 days/year was associated with drinking alcohol, smoking, hypertension, heart disease and stroke, while ≤60 days/year was associated with anticoagulation use and bleeding history. In all, 13% reported not walking regularly, 12% walked <2 mph, 44% walked ≥2-2.9 mph, and 31% walked ≥3 mph. After propensity score adjustment, regular aspirin use was associated with a faster walking speed. Odds ratios (95% confidence intervals) were 1.16 (0.97 to 1.39), 1.24 (1.08 to 1.43), and 1.40 (1.21 to 1.63) for <2 mph, ≥2-2.9 mph and ≥3 mph, respectively, compared to not walking regularly (p-trend<0.001). CONCLUSIONS: In this cohort of older men, long-term aspirin use is associated with a greater probability of faster walking speed later in life.

Systematic review with meta-analysis: the comparative effectiveness of aspirin vs. screening for colorectal cancer prevention.

BACKGROUND: Both aspirin use and screening with flexible sigmoidoscopy or guaiac faecal occult blood testing (FOBT) may reduce mortality from colorectal cancer, but comparative effectiveness of these interventions is unknown. AIM: To compare aspirin to guaiac FOBT screening with regard to incidence and mortality of colorectal cancer in a network meta-analysis. METHODS: We searched Medline, EMBASE and the COCHRANE central register (CENTRAL) for relevant randomised trials identified until 31 October 2015. Randomised trials in average-risk populations that reported colorectal cancer mortality, colorectal cancer incidence, or both, with a minimum follow-up of 2 years, and more than 100 randomised individuals were included. Three investigators independently extracted data. We calculated relative risks [RR with 95% predictive intervals (PrIs)] for the comparison of the interventions by frequentist network meta-analyses. RESULTS: The effect of aspirin on colorectal cancer mortality was similar to FOBT (RR 1.03; 95% PrI 0.76-1.39) and flexible sigmoidoscopy (RR 1.16; 95% PrI 0.84-1.60). Aspirin was more effective than FOBT (RR 0.36; 95% PrI 0.22-0.59) and flexible sigmoidoscopy (RR 0.37; 95% PrI 0.22-0.62) in preventing death from or cancer in the proximal colon. Aspirin was equally effective as screening in reducing colorectal cancer incidence, while flexible sigmoidoscopy was superior to FOBT (RR 0.84; 95% PrI 0.72-0.97). CONCLUSIONS: Low-dose aspirin seems to be equally effective as flexible sigmoidoscopy or guaiac FOBT screening to reduce colorectal cancer incidence and mortality, and more effective for cancers in the proximal colon. A randomised comparative effectiveness trial of aspirin vs. screening is warranted.

Physical activity and risk of Parkinson's disease: a prospective cohort study.

BACKGROUND: Despite the fact that Parkinson's disease is the second most common neurodegenerative disease, little is known about risk factors for the disease. Laboratory experiments indicate that physical activity may have a neuroprotective effect; however, there are few data on whether physical activity is associated with decreased risk of Parkinson's disease. AIM: To investigate the relationship between physical activity and Parkinson's disease in 10,714 men (mean age, 67.6 years) from the Harvard Alumni Health Study, who were diagnosed as free of self-reported Parkinson's disease in 1988. METHODS: Physical activity was assessed in 1988 by asking about the daily number of blocks walked and stairs climbed, and participation in sports and recreational activities in the past week. Energy expenditure was then estimated and men were categorised into four groups: < 1000, 1000-1999, 2000-2999 or > or = 3000 kcal/week. In addition, physical activity data were available for three past time points: during college, 1962 or 1966, and 1977. Incident cases of Parkinson's disease occurring after 1988 (n = 101) were identified through a follow-up health questionnaire in 1993 and death certificates obtained until 1997. RESULTS: In multivariate analyses, the relative risks (RR) for Parkinson's disease associated with < 1000, 1000-1999, 2000-2999 and > or = 3000 kcal/week of physical activity were 1 (referent), 1.15 (95% confidence interval (95% CI) 0.71 to 1.88), 0.92 (0.50 to 1.71) and 0.63 (0.36 to 1.12), respectively; p for trend was 0.12. When walking was examined separately, somewhat lower, but not significant, risks were observed for Parkinson's disease. The multivariate RRs (95% CI) for walking < 5, 5-10, 10-20 and > 20 km/week were 1 (referent), 0.67 (0.37 to 1.23), 0.81 (0.50 to 1.31) and 0.72 (0.39 to 1.34), respectively; p for trend was 0.26. Analyses that considered physical activity at other time points before 1988 did not show any significant associations. CONCLUSIONS: These data do not strongly support the hypothesis that physical activity lowers the risk of Parkinson's disease. However, as the number of patients with Parkinson's disease in this study was not large, statistical power may have been limited and further large studies are needed to provide additional data.

Homocysteine and risk of developing hypertension in men.

In cross-sectional studies, elevated homocysteine levels are associated with higher blood pressure, but it remains unclear whether plasma homocysteine is a risk factor for hypertension. In a prospective nested case-control study, participants who developed hypertension (n=396) had significantly higher levels of baseline plasma homocysteine (12.6 mol/l) than matched controls (11.8 mol/l, P=0.03); compared to those in the lowest quintile, those in the highest quintile had a crude relative risk (RR) of 1.56 (95% confidence interval (CI), 0.98-2.48; P for trend=0.10) and a multivariable RR of 1.63 (95% CI, 0.97-2.74; P for trend=0.13). Higher plasma homocysteine levels at baseline were associated with an increased but non-significant risk of incident hypertension that was minimally affected by multivariable adjustment.

Common variation in BRCA1 may have a role in progression to lethal prostate cancer after radiation treatment.

BACKGROUND: To evaluate whether single-nucleotide polymorphisms (SNPs) reflecting common variation in the tumor suppressor BRCA1 affect prostate cancer outcomes. Because radiation therapy (RT) induces DNA damage, we hypothesized that common variation in BRCA1 has a role in progression to lethal prostate cancer, particularly in patients receiving RT. METHODS: We followed 802 men diagnosed with localized prostate cancer (cT1-T3/N0/M0) who were treated with RT in the US Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS), for progression to lethal prostate cancer. Six SNPs (rs3737559, rs1799950, rs799923, rs915945, rs4474733 and rs8176305) were genotyped in HPFS to capture common variation across BRCA1. rs4474733 and rs8176305 were also evaluated in the PHS cohort. Cox proportional hazards models were used to estimate per-allele hazard ratios (HR) and 95% confidence intervals (CI) stratified by primary treatment. RESULTS: In the RT group (n=802), 71 men progressed to lethal disease during a mean follow-up of 12 years. We found that two SNPs, rs4473733 (HR: 0.65; 95% CI 0.42-0.99) and rs8176305 (HR: 2.03; 95% CI 1.33-3.10), were associated with lethal prostate cancer in men receiving RT. CONCLUSIONS: Common variation in BRCA1 may influence clinical outcomes in patients receiving RT for localized prostate cancer by modifying the response to RT. Our findings merit further follow-up studies to validate these SNPs and better understand their functional and biological significance.

Physical activity and coronary heart disease in men: The Harvard Alumni Health Study.

BACKGROUND: The quantity and intensity of physical activity required for the primary prevention of coronary heart disease (CHD) remain unclear. Therefore, we examined the association of the quantity and intensity of physical activity with CHD risk and the impact of other coronary risk factors. METHODS AND RESULTS: We followed 12 516 middle-aged and older men (mean age 57.7 years, range 39 to 88 years) from 1977 through 1993. Physical activity was assessed at baseline in kilojoules per week (4.2 kJ=1 kcal) from blocks walked, flights climbed, and participation in sports or recreational activities. During follow-up, 2,135 cases of incident CHD, including myocardial infarction, angina pectoris, revascularization, and coronary death, occurred. Compared with men expending <2,100 kJ/wk, men expending 2,100 to 4,199, 4,200 to 8,399, 8,400 to 12,599, and >/=12,600 kJ/wk had multivariate relative risks of 0.90, 0.81, 0.80, and 0.81, respectively (P: for trend=0.003). When we considered the independent effects of specific physical activity components, only total sports or recreational activities (P: for trend=0.042) and vigorous activities (P: for trend=0.02) were inversely associated with the risk of CHD. These associations did not differ within subgroups of men defined by coronary risk factors. Finally, among men with multiple coronary risk factors, those expending >/=4,200 kJ/wk had reduced CHD risk compared with men expending <4,200 kJ/wk. CONCLUSIONS: Total physical activity and vigorous activities showed the strongest reductions in CHD risk. Moderate and light activities, which may be less precisely measured, showed nonsignificant inverse associations. The association between physical activity and a reduced risk of CHD also extends to men with multiple coronary risk factors.

Physical activity and coronary heart disease risk in men: does the duration of exercise episodes predict risk?

BACKGROUND: Physical activity is associated with a decreased risk of coronary heart disease (CHD). However, it is unclear whether the duration of exercise episodes is important: Are accumulated shorter sessions as predictive of decreased risk as longer sessions if the same amount of energy is expended? METHODS AND RESULTS: In the Harvard Alumni Health Study, we prospectively followed 7307 Harvard University alumni (mean age 66.1 years) from 1988 through 1993. At baseline, men reported their walking, stair climbing, and participation in sports or recreational activities. For each of the latter activities, they also reported the frequency and average duration per episode. During follow-up, 482 men developed CHD. In age-adjusted analysis, a longer duration of exercise episodes predicted lower CHD risk (P: trend=0.04). However, after total energy expended on physical activity and potential confounders was accounted for, duration no longer had an independent effect on CHD risk (P: trend=0.25); that is, longer sessions of exercise did not have a different effect on risk compared with shorter sessions, as long as the total energy expended was similar. In contrast, higher levels of total energy expenditure significantly predicted decreased CHD risk in both age-adjusted (P: trend=0.009) and multivariate (P: trend=0.046) analyses. CONCLUSIONS: These data clearly indicate that physical activity is associated with decreased CHD risk. Furthermore, they lend some support to recent recommendations that allow for the accumulation of shorter sessions of physical activity, as opposed to requiring 1 longer, continuous session of exercise. This may provide some impetus for those sedentary to become more active.

Two-year changes in blood pressure and subsequent risk of cardiovascular disease in men.

BACKGROUND-It is unclear whether, given a current blood pressure level, the previous 2-year change in blood pressure adds important predictive information for cardiovascular disease (CVD). METHODS AND RESULTS-We conducted a prospective cohort study of 11 150 middle-aged and older men reporting blood pressure in the Physicians' Health Study. These men had no history of CVD or antihypertensive medication use through the time of the 2-year follow-up questionnaire; after this time, follow-up for the current study began. A total of 905 incident cases of CVD (705 cases of coronary heart disease and 200 cases of stroke) occurred during a median follow-up of 10.8 years. After controlling for current blood pressure and other coronary risk factors, we found that previous 2-year changes in systolic blood pressure were not associated with the risk of CVD. A similar lack of association was found for individual end points of coronary heart disease and stroke. However, previous 2-year changes in diastolic blood pressure (DBP) may be inversely associated with the risk of CVD (linear trend, P=0.049) independent of coronary risk factors and current DBP. In subgroup analyses, previous 2-year blood pressure changes only added information in leaner men (body mass index <24.39 kg/m(2)). CONCLUSIONS-In this normotensive population of men, the prior 2-year change in DBP, but not systolic blood pressure, may add information to current levels in relation to the risk of CVD. Clinicians may need to consider the previous pattern of DBP change when considering the risk associated with the current DBP level. These data require confirmation in other studies in which blood pressure is measured.

Maternal and paternal history of myocardial infarction and risk of cardiovascular disease in men and women.

BACKGROUND: Few studies have examined the effects of paternal and maternal history of myocardial infarction (MI), including age at MI, on cardiovascular disease (CVD) risk, particularly among women. METHODS AND RESULTS: We prospectively studied 22 071 men from the Physicians' Health Study and 39 876 women from the Women's Health Study with data on parental history and age at MI. Among men, 2654 CVD cases developed over 13.0 years; among women, 563 CVD cases occurred over 6.2 years. Compared with men with no parental history, only maternal, only paternal, and both maternal and paternal history of MI conferred relative risks (RRs) of CVD of 1.71, 1.40, and 1.85; among women, the respective RRs were 1.46, 1.15, and 2.05. For men, maternal age at MI of <50, 50 to 59, 60 to 69, 70 to 79, and >/=80 years had RRs of 1.00, 1.88, 1.88, 1.67, and 1.17; for women, the RRs for maternal age at MI of <50, 50 to 59, and >/=60 years were 2.57, 1.33, and 1.52. Paternal age at MI of <50, 50 to 59, 60 to 69, 70 to 79, and >/=80 years in men had RRs of 2.19, 1.64, 1.42, 1.16, and 0.92; in women, for paternal age at MI of <50, 50 to 59, and >/=60 years, the RRs were 1.63, 1.33, and 1.13. CONCLUSIONS: An early history of parental MI (<60 years) conferred a greater risk of CVD than did MI at older ages. However, an increased risk of CVD remained for maternal age at MI of 70 to 79 years in men and >/=60 years in women, which suggests that any maternal history of MI may be important.

Light-to-moderate alcohol consumption and mortality in the Physicians' Health Study enrollment cohort.

OBJECTIVES: This study examined the relationship between light-to-moderate alcohol consumption and cause-specific mortality. BACKGROUND: Previous studies suggest a J-shaped relation between alcohol and total mortality in men. A decrease in cardiovascular disease (CVD) mortality without a significant increase in other causes of mortality may explain the overall risk reduction at light-to-moderate levels. METHODS: We conducted a prospective cohort study of 89,299 U.S. men from the Physicians' Health Study enrollment cohort who were 40 to 84 years old in 1982 and free of known myocardial infarction, stroke, cancer or liver disease at baseline. Usual alcohol consumption was estimated by a limited food frequency questionnaire. RESULTS: There were 3,216 deaths over 5.5 years of follow-up. We observed a U-shaped relationship between alcohol consumption and total mortality. Compared with rarely/never drinkers, consumers of 1, 2 to 4 and 5 to 6 drinks per week and 1 drink per day had significant reductions in risk of death (multivariate relative risks [RRs] of 0.74, 0.77, 0.78 and 0.82, respectively) with no overall benefit or harm detected at the > or =2 drinks per day level (RR = 0.95; 95% confidence interval (CI), 0.79 to 1.14). The relationship with CVD mortality was inverse or L-shaped with apparent risk reductions even in the highest category of > or =2 drinks per day (RR = 0.76; 95% CI, 0.57 to 1.01). We found no clear harm or benefit for total or common site-specific cancers. For remaining other cancers, there was a nonsignificant 28% increased risk for those consuming > or =2 drinks per day. CONCLUSIONS: These data support a U-shaped relation between alcohol and total mortality among light-to-moderate drinking men. The U-shaped curve may reflect an inverse association for CVD mortality, no association for common site-specific cancers and a possible positive association for less common cancers.

Seven-year changes in alcohol consumption and subsequent risk of cardiovascular disease in men.

BACKGROUND: Few studies have examined whether changes in alcohol consumption influence future cardiovascular risk. OBJECTIVE: To examine whether 7-year changes in alcohol consumption are associated with the subsequent risk of cardiovascular disease (CVD). METHODS: We prospectively followed up 18,455 men aged 40 to 84 years from the Physicians' Health Study with no history of CVD or cancer. Alcohol consumption was reported on the baseline and the 7-year questionnaires; follow-up for this analysis began after the 7-year questionnaire (median follow-up, 5.8 years). There were 1091 CVD cases, including myocardial infarction, angina pectoris, revascularization, stroke, and CVD-related death. RESULTS: Among men initially consuming 1 drink per week or less (n=7360), those with moderate increases (>1 to <6 drinks per week) in alcohol consumption had a borderline significant (P=.05) 29% reduced risk of CVD compared with men with no changes (-1 to 1 drink per week). Among men initially consuming greater than 1 to 6 drinks per week (n=6612), those with moderate increases had a nonsignificant (P=.32) 15% decrease in CVD risk compared with men with no changes. Finally, among men initially consuming 1 drink per day or more (n=4483), those who increased intake had a 63% increased risk of CVD compared with men with no changes. CONCLUSIONS: These prospective data suggest that, among men with initially low alcohol consumption (

Replication of a genetic variant for prostate cancer-specific mortality.

BACKGROUND: Few genetic variants have been confirmed as being associated with prostate cancer-specific mortality (PCSM). A recent study identified 22 candidate single-nucleotide polymorphisms (SNPs) associated with PCSM in a Seattle-based patient cohort. Five of these associations were replicated in an independent Swedish cohort. METHODS: We genotyped these 22 SNPs in Physicians' Health Study (PHS) participants diagnosed with prostate cancer (PCa). Using the same model that was found to be most significant in the Seattle cohort, we examined the association of these SNPs with lethal disease with Cox proportional hazards models. RESULTS: One SNP, rs5993891 in the ARVCF gene on chromosome 22q11, which had also replicated in the Swedish cohort, was also significantly associated with PCSM in the PHS cohort (hazard ratio (HR)=0.32; P=0.01). When we tested this SNP in an additional cohort (Health Professionals Follow-up Study, HPFS), the association was null (HR=0.95, P=0.90); however, a meta-analysis across all studies showed a statistically significant association with a HR of 0.52 (0.29-0.93, P=0.03). CONCLUSIONS: The association of rs5993891 with PCSM was further replicated in PHS and remains significant in a meta-analysis, though there was no association in HPFS. This SNP may contribute to a genetic panel of SNPs to determine at diagnosis whether a patient is more likely to exhibit an indolent or aggressive form of PCa. This study also emphasizes the importance of multiple rounds of replication.

Depression and the risk of coronary heart disease in the Normative Aging Study.

Increasing evidence supports an association between symptomatic depression and the risk of coronary heart disease (CHD), although no single study has compared multiple depression scales. We hypothesized that higher levels of symptomatic depression assessed from different depression scales were associated with the risk of CHD. We examined this relation in the Normative Aging Study, a prospective cohort of older men. A total of 1,305 men free of diagnosed CHD in 1986 completed the revised Minnesota Multiphasic Personality Inventory (MMPI-2). We categorized scores for the MMPI-2 D, MMPI-2 DEP, and Symptom Checklist-90 (SCL-90) depression scales. During an average 7.0 years of follow-up, 110 cases of incident CHD occurred, including 30 cases of nonfatal myocardial infarction, 20 cases of fatal CHD, and 60 cases of angina pectoris. Compared with men reporting the lowest level of depression, men in the highest level of depression had multivariate-adjusted relative risks of incident CHD (total CHD and angina) of 1.46 (95% confidence interval 0.83 to 2.57), 2.07 (95% confidence interval 1.13 to 3.81), and 1.73 (95% confidence interval 0.97 to 3.10) for the MMPI-2 D, MMPI-2 DEP, and SCL-90 scales, respectively. Similar RRs were obtained for each CHD subtype according to each depression scale. We found strong dose-response relations between level of depression measured by the MMPI-2 DEP scale and incidence of both angina pectoris (p value for trend, 0.039) and CHD (p value for trend, 0.016). Among older men, symptomatic depression measured by any of 3 depression scales may be positively associated with the risk of CHD.

Relation between systemic hypertension and blood lipids on the risk of myocardial infarction.

We sought to evaluate the potential interactions between systemic hypertension and blood lipids on the risk of myocardial infarction (MI). Recent evidence suggests that hypertension may interact with other risk factors such as dyslipidemia in the development of coronary heart disease. However, the precise nature of that interrelation remains unclear. We selected 340 cases of first MI and an equal number of age-, sex-, and community-matched controls. Data were collected on a large number of coronary risk factors, and fasting blood samples were obtained. Logistic regression was used to calculate the odds ratio (OR) of nonfatal MI. The age- and sex-adjusted OR of MI was 1.61 (95% confidence interval [CI] 1.15 to 2.25) among treated hypertensives compared with nonhypertensives. Further adjustment for coronary risk factors did not materially alter the results (OR 1.67, 95% CI 1.16 to 2.41). To explore the interrelations among hypertension, lipids, and risk of MI, each lipoprotein parameter was individually added to the risk factor-adjusted multivariate model. The apparent risk associated with hypertension was substantially attenuated by the addition of either high-density lipoprotein cholesterol (OR 1.25, 95% CI 0.82 to 1.90) or triglycerides (OR 1.37, 95% CI 0.91 to 2.05). No significant interactions were found between hypertension and any lipoprotein parameter. These data indicate that the risk of MI associated with treated hypertension may have a lipid mechanism involving high-density lipoprotein cholesterol and/or triglycerides.

Sense of exhaustion and coronary heart disease among college alumni.

Vital exhaustion, defined as a combination of fatigue, lack of energy, feelings of hopelessness, loss of libido, and increased irritability, has been proposed as a risk indicator for the development of coronary heart disease (CHD). It is unclear if the association between vital exhaustion and CHD is independent of sleep behavior, depression, and physical activity. We ascertained sense of exhaustion among 5,053 male college alumni who were free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease by asking, "How often do you experience sense of exhaustion (except after exercise)?" on a health survey in 1980. Eight hundred fifteen men died during 12 years of follow-up, 25% due to CHD. After adjustment for age, body mass index, smoking status, and history of physician-diagnosed diabetes and hypertension, frequent sense of exhaustion was associated with a twofold increase in CHD mortality (rate ratio 2.07; 95% confidence interval 1.08 to 3.96). After additional adjustment for insomnia, sleep duration, use of sleeping pills and tranquilizers, physical activity, history of physician-diagnosed depression, and alcohol intake, the rate ratio was not appreciably altered; however, the association now was of borderline significance (rate ratio 2.06; 95% confidence interval: 0.98 to 4.36) because there were only 10 deaths from CHD among men who were frequently exhausted. In a prospective observational study, frequent sense of exhaustion appeared to be independently associated with increased risk of CHD mortality in men.