Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3).

BACKGROUND: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. MATERIALS AND METHODS: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. RESULTS: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). CONCLUSION: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.

Aspirin has potential benefits for primary prevention of cardiovascular outcomes in diabetes: updated literature-based and individual participant data meta-analyses of randomized controlled trials.

BACKGROUND: The clinical benefit of aspirin for the primary prevention of cardiovascular disease (CVD) in diabetes remains uncertain. To evaluate the efficacy and safety of aspirin for the primary prevention of cardiovascular outcomes and all-cause mortality events in people with diabetes, we conducted an updated meta-analysis of published randomised controlled trials (RCTs) and a pooled analysis of individual participant data (IPD) from three trials. METHODS: Randomised controlled trials of aspirin compared with placebo (or no treatment) in participants with diabetes with no known CVD were identified from MEDLINE, Embase, Cochrane Library, and manual search of bibliographies to January 2019. Relative risks with 95% confidence intervals were used as the summary measures of associations. RESULTS: We included 12 RCTs based on 34,227 participants with a median treatment duration of 5.0 years. Comparing aspirin use with no aspirin, there was a significant reduction in risk of major adverse cardiovascular events (MACE)0.89 (0.83-0.95), with a number needed to treat (NNT)of 95 (95% CI 61 to 208) to prevent one MACE over 5 years average follow-up. Evidence was lacking of heterogeneity and publication bias among contributing trials for MACE. Aspirin use had no effect on other endpoints including all-cause mortality; however, there was a significant reduction in stroke for aspirin dosage ≤ 100 mg/day 0.75 (0.59-0.95). There were no significant effects of aspirin use on major bleeding and other bleeding events, though some of the estimates were imprecise. Pooled IPD from the three trials (2306 participants) showed no significant evidence of an effect of aspirin on any of the outcomes evaluated; however, aspirin reduced the risk of MACE in non-smokers 0.70 (0.51-0.96) with a NNT of 33 (95% CI 20 to 246) to prevent one MACE. CONCLUSIONS: Aspirin has potential benefits in cardiovascular primary prevention in diabetes. The use of low dose aspirin may need to be individualised and based on each individual's baseline CVD and bleeding risk. Systematic review registration PROSPERO: CRD42019122326.

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.

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.

Telomere length and Parkinson's disease in men: a nested case-control study.

BACKGROUND AND PURPOSE: Telomere shortening has been implicated in neurodegenerative disorders. However, available data on the association between telomere length and Parkinson's disease (PD) are inconclusive. METHODS: A nested case-control design was used amongst men participating in the prospective Physicians' Health Study. A large proportion of participants provided blood samples in 1997 and they were followed through 2010. Men with self-reported PD were age-matched to controls in a 1:2 ratio. Quantitative PCR was used to determine the telomere repeat copy number to single gene copy number ratio (TSR) in genomic DNA extracted from peripheral blood leukocytes. TSR was used as a measure for relative telomere length (RTL) in our analyses. Conditional logistic regression was used to determine the risk of PD associated with RTL. RESULTS: Data on RTL were available from 408 cases and 809 controls. Median TSR was shorter in controls than in cases (47.7 vs. 50.2; P = 0.02). The age-adjusted odds ratio (OR) for PD was 0.66 [95% confidence interval (CI) 0.46-0.95; Ptrend over quartiles 0.02] comparing the lowest to the highest quartile. The pattern of association was unchanged when comparing RTL below versus above the median (age-adjusted OR 0.75; 95% CI 0.59-0.96). Associations were similar after additional adjustment for many covariates. CONCLUSION: Contrary to what was expected, in this large nested case-control study amongst men shorter telomeres were associated with reduced PD risk. Future research on the nature of this counterintuitive association is warranted.

A candidate gene approach to searching for low-penetrance breast and prostate cancer genes.

Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.

Association between modifiable lifestyle factors and residual lifetime risk of diabetes.

BACKGROUND AND AIMS: While clinical trials have reported beneficial effects of diet, exercise, and weight loss on incident diabetes in subjects with obesity or impaired glucose tolerance, little is known about the incremental benefit of not smoking and moderate drinking on diabetes risk. We sought to examine the association between modifiable lifestyle factors and residual lifetime risk of diabetes. METHODS AND RESULTS: Prospective cohorts involving 20,915 men (1982-2008) and 36,594 women (1992-2008). Modifiable lifestyle factors and adiposity were ascertained at baseline in each cohort and incident diabetes was ascertained during follow up. The mean age at baseline was 53.5 y in men and 54.6 y in women. During an average follow up of 22.6 y in men and 13.0 y in women, 2096 men and 2390 women developed diabetes. At age 45 y, the residual lifetime risk of diabetes (95% CI) for men with 0, 1, 2, 3, and 4 + healthy lifestyle factors was 30.5 (27.3-33.7); 21.5 (19.9-23.0); 15.1 (13.9-16.3); 10.3 (9.1-11.5); and 7.3 (5.7-8.9) percent; respectively. Corresponding values for women were 31.4 (28.3-34.5); 24.1 (21.8-26.5); 14.2 (12.7-15.7); 11.6 (9.7-13.5); and 6.4 (4.2-8.6) percent, respectively. CONCLUSIONS: These data show an inverse and graded relation between desirable lifestyle factors and residual lifetime risk of diabetes in men and women. Not smoking and moderate drinking may have additional benefits when added to exercise, weight control, and diet.

Nut consumption and risk of atrial fibrillation in the Physicians' Health Study.

BACKGROUND: Atrial Fibrillation is highly prevalent in clinical practice affecting approximately 2.3 million people in USA and 4.5 million people in European Union. The aim of the study was to examine the association between nut consumption and incident atrial fibrillation. METHODS: Prospective cohort of 21,054 male participants of Physicians' Health Study I. Nut consumption was estimated using food frequency questionnaire and incident atrial fibrillation was ascertained through yearly follow-up questionnaires. Cox regression was used to estimate relative risks of atrial fibrillation. RESULTS: The average age was 54.6 ± 9.5 years (40.7-87.1). During a mean follow up of 20 years (median 24 years), 3,317 cases of atrial fibrillation occurred. The crude incidence rate was 7.6, 7.4, 8.2, 7.9, and 6.8 cases/1000 person-years for people reporting nut consumption of rarely/never, 1-3/month, 1/per week, 2-6/week, and ≥ 7/week, respectively. Multivariable adjusted hazard ratios (95% CI) for incident atrial fibrillation were 1.00 (ref), 1.00 (0.90-1.11), 1.09 (0.97-1.21), 1.07 (0.95-1.21), and 0.91 (0.70-1.17) for nut consumption from the lowest to the highest category of nut consumption (p for trend 0.26). No statistically significant association between nut consumption and atrial fibrillation was found when stratified by body mass index (BMI < 25 vs ≥ 25 kg/m2) or age (< 65 vs. ≥ 65 years). CONCLUSIONS: Our data did not show an association between nut consumption and incident atrial fibrillation among US male physicians.

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.

Effects of G/A polymorphism, rs266882, in the androgen response element 1 of the PSA gene on prostate cancer risk, survival and circulating PSA levels.

Prostate-specific antigen (PSA) is a protease produced in the prostate that cleaves insulin-like growth factor binding protein-3 and other proteins. Production is mediated by the androgen receptor (AR) binding to the androgen response elements (ARE) in the promoter region of the PSA gene. Studies of a single nucleotide polymorphism (PSA -158 G/A, rs266882) in ARE1 of the PSA gene have been conflicting for risk of prostate cancer and effect on plasma PSA levels. In this nested case-control analysis of 500 white cases and 676 age- and smoking-matched white controls in the Physicians' Health Study we evaluated the association of rs266882 with risk and survival of prostate cancer and prediagnostic total and free PSA plasma levels, alone or in combination with AR CAG repeats. We used conditional logistic regression, linear regression and Cox regression, and found no significant associations between rs266882 (GG allele vs AA allele) and overall prostate cancer risk (RR=1.21, 95% confidence intervals (CI): 0.88-1.67) or prostate cancer-specific survival (RR=0.94, 95%CI: 0.56-1.58). Similarly, no associations were found among high grade or advanced stage tumours, or by calendar year of diagnosis. There was no significant association between rs266882 and baseline total or free PSA levels or the AR CAG repeats, nor any interaction associated with prostate cancer risk. Meta-analysis of 12 studies of rs266882 and overall prostate cancer risk was null.

Randomised aspirin assignment and risk of adult-onset asthma in the Women's Health Study.

BACKGROUND: Randomised data in men show a small but significant reduction in the risk of adult-onset asthma among those given aspirin. The results from an observational study in women suggest that frequent use of aspirin decreases the risk of adult-onset asthma, but randomised data in women are lacking. A study was undertaken to test the effect of 100 mg aspirin or placebo on alternate days on the risk of adult-onset asthma in the Women's Health Study. METHODS: A randomised, double-blind, placebo-controlled clinical trial of aspirin and vitamin E was performed in apparently healthy women with no indication or contraindication to aspirin therapy and no history of asthma at study entry. Female health professionals self-reported an asthma diagnosis on yearly questionnaires. RESULTS: Among 37 270 women with no reported history of asthma prior to randomisation and during 10 years of follow-up, there were 872 new cases diagnosed with asthma in the aspirin group and 963 in the placebo group (hazard ratio 0.90; 95% CI 0.82 to 0.99; p = 0.027). This apparent 10% lower relative risk of incident adult-onset asthma among those assigned to aspirin was significantly modified by body mass index, with no effect in women with a body mass index of >/=30 kg/m2. The effect of aspirin on adult-onset asthma was not significantly modified by age, smoking status, exercise levels, postmenopausal hormone use or randomised vitamin E assignment. CONCLUSIONS: In this large randomised clinical trial of apparently healthy adult women, administration of 100 mg aspirin on alternate days reduced the relative risk of a newly reported diagnosis of asthma.

Parental history of myocardial infarction and risk of heart failure in male physicians.

BACKGROUND: Although heart failure (HF) remains a major public health issue, limited data are available on the utility of parental information on the risk of HF in offspring. MATERIALS AND METHODS: We prospectively examined the association between parental history of myocardial infarction (MI) and incident HF among 20,187 offspring in the Physicians' Health Study I. Parental history and age at MI was assessed by a questionnaire and a Cox regression was used to estimate relative risks of HF. RESULTS: After an average follow-up of 19.6 years, 1036 new HF cases were documented. Overall, while a history of early parental MI (before age 55) was associated with a 32% increased risk of HF in offspring compared with subjects whose parent did not have MI, parental MI at older ages was not associated with HF risk. However, the relation between parental history of MI and HF was stronger and mainly observed for HF with antecedent MI. Compared with subjects without parental history of MI, multivariable adjusted hazard ratios (95% CI) for HF with antecedent MI were 3.44 (2.15-5.51), 2.24 (1.20-4.21), 1.26 (0.63-2.51), and 1.37 (0.92-2.03) for parental MI occurred at the age of < 55, 55-59, 60-64, and 65 + y, respectively. CONCLUSIONS: Our data suggest that parental MI at an early age is a strong and independent predictor of HF with antecedent MI among US male physicians. This information, along with existing tools, may help clinicians identify patients at risk of HF with antecedent MI.

Low-dose alpha-tocopherol improves and high-dose alpha-tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits.

Abnormalities in endothelium-dependent arterial relaxation develop early in atherosclerosis and may, in part, result from the effects of modified low-density lipoprotein (LDL) on agonist-mediated endothelium-derived relaxing factor (EDRF) release and EDRF degradation. alpha-Tocopherol (AT) is the main lipid-soluble antioxidant in human plasma and lipoproteins, therefore, we investigated the effects of AT on endothelium-dependent arterial relaxation in male New Zealand White rabbits fed diets containing (a) no additive (controls), (b) 1% cholesterol (cholesterol group), or 1% cholesterol with either (c) 1,000 IU/kg chow AT (low-dose AT group) or (d) 10,000 IU/kg chow AT (high-dose AT group). After 28 d, we assayed endothelial function and LDL susceptibility to ex vivo copper-mediated oxidation. Acetylcholine-and A23187-mediated endothelium-dependent relaxations were significantly impaired in the cholesterol group (P < 0.001 vs. control), but preserved in the low-dose AT group (P = NS vs. control). Compared to the control and cholesterol groups, vessels from the high-dose AT group demonstrated profound impairment of arterial relaxation (P < 0.05) and significantly more intimal proliferation than other groups (P < 0.05). In normal vessels, alpha-tocopherol had no effect on endothelial function. LDL derived from both the high- and low-dose AT groups was more resistant to oxidation than LDL from control animals (P < 0.05). These data indicate that modest dietary treatment with AT preserves endothelial vasodilator function in cholesterol-fed rabbits while a higher dose of AT is associated with endothelial dysfunction and enhanced intimal proliferation despite continued LDL resistance to ex vivo copper-mediated oxidation.

Polymorphisms of prostaglandin-endoperoxide synthase 2 gene, and prostaglandin-E receptor 2 gene, C-reactive protein concentrations and risk of atherothrombosis: a nested case-control approach.

OBJECTIVE: Recent data have shown an association between polymorphisms of prostaglandin-endoperoxide synthase-2 gene (PTGS2; alias COX-2), and prostaglandin-E receptor-2 gene (PTGER2) and risk of atherothrombotic disorders. METHODS: We evaluated two PTGS2 (rs20417, rs689470), and three PTGER2 (rs708494/uS5, rs708495/uS7, and chr14: 50 764 013/uS10) gene polymorphisms among 600 Caucasian male participants of the Physicians' Health Study with incident myocardial infarction (MI) or ischemic stroke and 600 age- and smoking-matched controls who remained free of all reported cardiovascular disease. RESULTS: Genotype distributions were in Hardy-Weinberg equilibrium in the control groups. Genotype and allele distribution were similar between cases and controls. The polymorphisms tested were in linkage disequilibrium. Results from the adjusted haplotype-based conditional logistic regression analysis showed a modest association of the PTGER2 2-1-1 haplotype with reduced risk of MI (odds ratio = 0.50, 95% CI; CI = 0.26-0.97, P = 0.04), and the 2-2-1 haplotype with reduced risk of ischemic stroke (odds ratio = 0.68, 95% CI = 0.47-0.99, P = 0.048). In contrast to prior data, we found no evidence for an association of the PTGS2 polymorphisms/haplotypes tested with risk of incident MI nor with ischemic stroke. However, we found suggestive evidence for an association of specific PTGER2 haplotypes with reduced risk of these outcomes. CONCLUSION: Although these prospective data implicate the potential involvement of prostaglandin-E receptor-2 gene variation in atherothrombosis, external validation of our findings is needed.

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.

Milk intake, circulating levels of insulin-like growth factor-I, and risk of colorectal cancer in men.

BACKGROUND: Milk and dietary calcium may have antiproliferative effects against colorectal cancer, but milk intake also raises serum levels of insulin-like growth factor-I (IGF-I). A high ratio of IGF-I to IGF-binding protein-3 (IGFBP-3) has been linked to an increased risk of colorectal cancer. METHODS: In a case-control study nested in the Physicians' Health Study, plasma samples were collected from the period 1982 through 1983 from 14 916 men, aged 40-84 years, who also answered dietary questionnaires. Circulating levels of IGF-I and IGFBP-3 were assayed among 193 men who developed colorectal cancer during 13 years of follow-up and 318 age- and smoking-matched cancer-free control men. Conditional logistic regression was used to assess relative risks (RRs) of colorectal cancer for tertiles of IGF-I/IGFBP-3 and dietary factors. Statistical tests were two-sided. RESULTS: Overall, there was a moderate but statistically nonsignificant inverse association between intake of low-fat milk or calcium from dairy food and colorectal cancer risk. Intake of dairy food (especially low-fat milk) was also positively and moderately associated with plasma levels of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 among control men. We observed a statistically significant interaction between low-fat milk intake and IGF-I/IGFBP-3 in association with risk of colorectal cancer (P(interaction) =.03). Nondrinkers with IGF-I/IGFBP-3 in the highest tertile had a threefold higher risk than nondrinkers with IGF-I/IGFBP-3 in the lowest tertile (RR = 3.05; 95% confidence interval [CI] = 1.29 to 7.24), but no such increase was seen among frequent low-fat milk drinkers (RR = 1.05; 95% CI = 0.41 to 2.69). Conversely, among men with high IGF-I/IGFBP-3, frequent low-fat milk drinkers had a 60% lower risk (95% CI = 0.17 to 0.87; P(trend) =.02) than nondrinkers. CONCLUSION: Intake of dairy products was associated with a modest increase in circulating IGF-I levels, but intake of low-fat milk was associated with lower risk of colorectal cancer, particularly among individuals with high IGF-I/IGFBP-3. This subpopulation, which is at increased risk of colorectal cancer, might benefit the most from specific dietary intervention.

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.

Alcohol consumption and risk of coronary heart disease by diabetes status.

BACKGROUND: An inverse association between moderate alcohol consumption and coronary heart disease (CHD) has been observed in several epidemiological studies. To assess whether a similar association exists among diabetics, we examined the relation between light to moderate alcohol consumption and CHD in men with and without diabetes mellitus in a prospective cohort study. METHODS AND RESULTS: A total of 87 938 US physicians (2790 with diagnosed diabetes mellitus) who were invited to participate in the Physicians' Health Study and were free of myocardial infarction, stroke, cancer, or liver disease at baseline were followed for an average of 5.5 years for death with CHD as the underlying cause. During 480 876 person-years of follow-up, 850 deaths caused by CHD were documented: 717 deaths among nondiabetic men and 133 deaths among diabetic men. Among men without diabetes at baseline, the relative risk estimates for those reporting rarely/never, monthly, weekly, and daily alcohol consumption were 1.00 (referent), 1.02, 0. 82, and 0.61 (95% CI 0.49 to 0.78; P for trend <0.0001) after adjustment for age, aspirin use, smoking, physical activity, body mass index, and history of angina, hypertension, and high cholesterol. Among men with diabetes at baseline, the relative risk estimates were 1.00 (referent), 1.11, 0.67, and 0.42 (95% CI 0.23 to 0.77; P for trend=0.0019). CONCLUSIONS: These results suggest that light to moderate alcohol consumption is associated with similar risk reductions in CHD among diabetic and nondiabetic men.

Moderate alcohol consumption and the risk of sudden cardiac death among US male physicians.

BACKGROUND: Individuals who consume high amounts of alcohol (>5 drinks/d) have increased risks of ventricular arrhythmia and sudden cardiac death (SCD). However, the relationship is less clear for drinkers of light-to-moderate amounts. METHODS AND RESULTS: We prospectively assessed whether light-to-moderate alcohol drinkers have a decreased risk of SCD among 21 537 male participants in the Physicians Health Study who were free of self-reported cardiovascular disease and provided complete information on alcohol intake at study entry. Over 12 years of follow-up, 141 SCDs were confirmed. After control for multiple confounders, men who consumed 2 to 4 drinks/wk (RR=0.40; 95% CI, 0.22 to 0.75; P=0.004) or 5 to 6 drinks/wk (RR=0.21; 95% CI, 0.08 to 0.56; P=0.002) at baseline had significantly reduced risks of SCD compared with those who rarely or never consumed alcohol. The relationship for SCD was U-shaped (P=0. 002), with the risk approaching unity at >/=2 drinks/d. In contrast, the relationship of alcohol intake and nonsudden CHD death was L-shaped or linear (P for trend=0.02). CONCLUSIONS: In these prospective data, men who consumed light-to-moderate amounts of alcohol (2 to 6 drinks/wk) had a significantly reduced risk of SCD compared with those who rarely or never consumed alcohol.

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.