Showing papers by "Charles H. Hennekens published in 1999"

Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein-3

Abstract: Background: Insulin-like growth factor-I (IGF-I) is a potent mitogen for normal and neoplastic cells, whereas IGF-binding protein-3 (IGFBP-3) inhibits cell growth in many experimental systems. Acromegalics, who have abnormally high levels of growth hormone and IGF-I, have higher rates of colorectal cancer. We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospective case-control study nested in the Physicians' Health Study. Methods: Plasma samples were collected at baseline from 14916 men without diagnosed cancer. IGF-I, IGF-II, and IGFBP-3 were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 age- and smoking-matched control subjects. All P values are two-sided. Results: IGFBP-3 levels correlated with IGF-I levels (r = .64) and with IGF-II levels (r = .90). After controlling for IGFBP-3, age, smoking, body mass index (weight in kg/[height in m] 2 ), and alcohol intake, men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile (relative risk [RR] = 2.51; 95% confidence interval [CI] = 1.15-5.46; P for trend = .02). After controlling for IGF-I and other covariates, men with higher IGFBP-3 had a lower risk (RR = 0.28; 95% CI = 0.12-0.66 ; P for trend = .005, comparing extreme quintiles). The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men. IGF-II was not associated with risk. Conclusions: Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer.

Fruit and Vegetable Intake in Relation to Risk of Ischemic Stroke

Abstract: ContextFew studies have evaluated the relationship between fruit and vegetable intake and cardiovascular disease.ObjectiveTo examine the associations between fruit and vegetable intake and ischemic stroke.Design, Setting, and SubjectsProspective cohort studies, including 75,596 women aged 34 to 59 years in the Nurses' Health Study with 14 years of follow-up (1980-1994), and 38,683 men aged 40 to 75 years in the Health Professionals' Follow-up Study with 8 years of follow-up (1986-1994). All individuals were free of cardiovascular disease, cancer, and diabetes at baseline.Main Outcome MeasureIncidence of ischemic stroke by quintile of fruit and vegetable intake.ResultsA total of 366 women and 204 men had an ischemic stroke. After controlling for standard cardiovascular risk factors, persons in the highest quintile of fruit and vegetable intake (median of 5.1 servings per day among men and 5.8 servings per day among women) had a relative risk (RR) of 0.69 (95% confidence interval [CI], 0.52-0.92) compared with those in the lowest quintile. An increment of 1 serving per day of fruits or vegetables was associated with a 6% lower risk of ischemic stroke (RR, 0.94; 95% CI, 0.90-0.99; P=.01, test for trend). Cruciferous vegetables (RR, 0.68 for an increment of 1 serving per day; 95% CI, 0.49-0.94), green leafy vegetables (RR, 0.79; 95% CI, 0.62-0.99), citrus fruit including juice (RR, 0.81; 95% CI, 0.68-0.96), and citrus fruit juice (RR, 0.75; 95% CI, 0.61-0.93) contributed most to the apparent protective effect of total fruits and vegetables. Legumes or potatoes were not associated with lower ischemic stroke risk. The multivariate pooled RR for total stroke was 0.96 (95% CI, 0.93-1.00) for each increment of 2 servings per day.ConclusionsThese data support a protective relationship between consumption of fruit and vegetables—particularly cruciferous and green leafy vegetables and citrus fruit and juice—and ischemic stroke risk.

A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women.

Abstract: Background The role of walking, as compared with vigorous exercise, in the prevention of coronary heart disease remains controversial, and data for women on this topic are sparse. Methods We prospectively examined the associations between the score for total physical activity, walking, and vigorous exercise and the incidence of coronary events among 72,488 female nurses who were 40 to 65 years old in 1986. Participants were free of diagnosed cardiovascular disease or cancer at the time of entry and completed serial detailed questionnaires about physical activity. During eight years of follow-up, we documented 645 incident coronary events (nonfatal myocardial infarction or death from coronary disease). Results There was a strong, graded inverse association between physical activity and the risk of coronary events. As compared with women in the lowest quintile group for energy expenditure (expressed as the metabolic-equivalent [MET] score), women in increasing quintile groups had age-adjusted relative risks of 0.77, 0.65, 0.54, and 0.46 for coronary events (P for trend or =6 MET) was associated with similar risk reductions (30 to 40 percent). Sedentary women who became active in middle adulthood or later had a lower risk of coronary events than their counterparts who remained sedentary. Conclusions These prospective data indicate that brisk walking and vigorous exercise are associated with substantial and similar reductions in the incidence of coronary events among women.

Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis.

Abstract: Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and β-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (α- and β-carotene, β-cryptoxanthin, lutein, and lycopene) plus α- and γ-tocopherol and retinol using high-performance liquid chromatography. Results for plasma β-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (CIs), and P s for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active β-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls ( P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54–1.06; P , trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34–0.91; P , trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P , trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to β-carotene supplements. However, in the β-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher α-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming β-carotene supplements. For men with low lycopene, β-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer.

Increased pulse pressure and risk of heart failure in the elderly.

Abstract: ContextArterial stiffness increases with age. Thus, pulse pressure, an index of arterial stiffening, may predict congestive heart failure (CHF) in the elderly.ObjectiveTo study prospectively the association between pulse pressure and risk of CHF.DesignProspective cohort study.SettingThe community-based East Boston Senior Health Project, East Boston, Mass.PatientsA total of 1621 men and women (mean [SD] age, 77.9 [5.0] years) free of CHF who had blood pressure measurements taken in 1988-1989 and were followed up for 3.8 years.Main Outcome MeasureIncidence of CHF as ascertained by hospital discharge diagnosis (n=208) and death certificates (n=13).ResultsAfter controlling for age, sex, mean arterial pressure, history of coronary heart disease, diabetes mellitus, atrial fibrillation, valvular heart disease, and antihypertensive medication use, pulse pressure was an independent predictor of CHF. For each 10-mm Hg elevation in pulse pressure, there was a 14% increase in risk of CHF (95% confidence interval, 1.05-1.24; P=.003). Those in the highest tertile of pulse pressure (>67 mm Hg) had a 55% increased risk of CHF (P=.02) compared with those in the lowest (<54 mm Hg). Pulse pressure was more predictive than systolic blood pressure alone and was independent of diastolic blood pressure.ConclusionPulse pressure, an easily measurable correlate of pulsatile hemodynamic load, is an independent predictor of risk of CHF in this elderly cohort.

Birthweight and the risk for type 2 diabetes mellitus in adult women.

Abstract: Even after adjustment for adult body mass index and maternal history of diabetes, birthweight was found to be inversely associated with risk for type 2 diabetes during adulthood.

Hormone replacement therapy and increased plasma concentration of C-reactive protein.

Abstract: Background—It has been hypothesized that postmenopausal hormone replacement therapy (HRT) may increase levels of C-reactive protein (CRP), a marker of inflammation associated with increased risk of future cardiovascular events. However, data evaluating this hypothesis are sparse and limited to older women. Methods and Results—CRP levels were evaluated in a cross-sectional survey of 493 healthy postmenopausal women; mean age was 51 years. Overall, median CRP levels were 2 times higher among women taking HRT than among women not taking HRT (0.27 versus 0.14 mg/dL; P=0.001). This difference was present in all subgroups evaluated, including those with no history of hypertension, hyperlipidemia, obesity, diabetes, or cigarette consumption or a family history of premature coronary artery disease (all P< 0.01). Compared with nonusers of HRT, median CRP levels were higher among women using estrogen alone (P=0.003) and women using estrogen plus progesterone (P=0.03); however, there was no significant difference in...

A prospective study of egg consumption and risk of cardiovascular disease in men and women.

Abstract: ContextReduction in egg consumption has been widely recommended to lower blood cholesterol levels and prevent coronary heart disease (CHD). Epidemiologic studies on egg consumption and risk of CHD are sparse.ObjectiveTo examine the association between egg consumption and risk of CHD and stroke in men and women.Design and SettingTwo prospective cohort studies, the Health Professionals Follow-up Study (1986-1994) and the Nurses' Health Study (1980-1994).ParticipantsA total of 37,851 men aged 40 to 75 years at study outset and 80,082 women aged 34 to 59 years at study outset, free of cardiovascular disease, diabetes, hypercholesterolemia, or cancer.Main Outcome MeasuresIncident nonfatal myocardial infarction, fatal CHD, and stroke corresponding to daily egg consumption as determined by a food-frequency questionnaire.ResultsWe documented 866 incident cases of CHD and 258 incident cases of stroke in men during 8 years of follow-up and 939 incident cases of CHD and 563 incident cases of stroke in women during 14 years of follow-up. After adjustment for age, smoking, and other potential CHD risk factors, we found no evidence of an overall significant association between egg consumption and risk of CHD or stroke in either men or women. The relative risks (RRs) of CHD across categories of intake were less than 1 per week (1.0), 1 per week (1.06), 2 to 4 per week (1.12), 5 to 6 per week (0.90), and ≥1 per day (1.08) (P for trend=.75) for men; and less than 1 per week (1.0), 1 per week (0.82), 2 to 4 per week (0.99), 5 to 6 per week (0.95), and ≥1 per day (0.82) (P for trend=.95) for women. In subgroup analyses, higher egg consumption appeared to be associated with increased risk of CHD only among diabetic subjects (RR of CHD comparing more than 1 egg per day with less than 1 egg per week among diabetic men, 2.02 [95% confidence interval, 1.05-3.87; P for trend=.04], and among diabetic women, 1.49 [0.88-2.52; P for trend=.008]).ConclusionsThese findings suggest that consumption of up to 1 egg per day is unlikely to have substantial overall impact on the risk of CHD or stroke among healthy men and women. The apparent increased risk of CHD associated with higher egg consumption among diabetic participants warrants further research.

β-Carotene Supplementation and Incidence of Cancer and Cardiovascular Disease: the Women's Health Study

Abstract: Background In observational studies, individuals with high intakes of fruits and vegetables containing beta-carotene experience lower risks of developing cancer. However, the few randomized trials of beta-carotene supplementation show no overall benefits; some even suggest harm. This trial was designed to test the effects of beta-carotene supplementation in women. Methods The Women's Health Study is a randomized, double-blind, placebo-controlled trial originally testing aspirin, vitamin E, and beta-carotene in the prevention of cancer and cardiovascular disease among 39 876 women aged 45 years or older. The beta-carotene component was terminated early after a median treatment duration of 2.1 years (range = 0.00-2. 72 years). Statistical tests were two-sided. Results Among women randomly assigned to receive beta-carotene (50 mg on alternate days; n = 19 939) or placebo (n =19 937), there were no statistically significant differences in incidence of cancer, cardiovascular disease, or total mortality after a median of 4.1 years (2.1 years' treatment plus another 2.0 years' follow-up). There were 378 cancers in the beta-carotene group and 369 cancers in the placebo group (relative risk [RR] = 1.03; 95% confidence interval [CI] = 0.89-1. 18). There were no statistically significant differences for any site-specific cancer or during years 1 and 2 combined and years 3 and up combined. For cardiovascular disease, there were no statistically significant differences for myocardial infarction (42 in the beta-carotene group versus 50 in the placebo group), stroke (61 versus 43), deaths from cardiovascular causes (14 versus 12), or the combined end point of these three events (116 versus 102; among women with more than one event, only the first was counted). Deaths from any cause were similar in the two groups (59 versus 55). Among smokers at baseline (13% of all women), there were no statistically significant differences in overall incidence of cancer (RR = 1.11; 95% CI = 0.78-1.58) or cardiovascular disease (RR = 1.01; 95% CI = 0. 62-1.63). Conclusion Among apparently healthy women, there was no benefit or harm from beta-carotene supplementation for a limited period on the incidence of cancer and of cardiovascular disease.

Long-term intake of dietary fiber and decreased risk of coronary heart disease among women.

Abstract: ContextEpidemiological studies of men suggest that dietary fiber intake protects against coronary heart disease (CHD), but data on this association in women are sparse.ObjectiveTo examine the association between long-term intake of total dietary fiber as well as fiber from different sources and risk of CHD in women.Design and SettingThe Nurses' Health Study, a large, prospective cohort study of US women followed up for 10 years from 1984. Dietary data were collected in 1984, 1986, and 1990, using a validated semiquantitative food frequency questionnaire.ParticipantsA total of 68,782 women aged 37 to 64 years without previously diagnosed angina, myocardial infarction (MI), stroke, cancer, hypercholesterolemia, or diabetes at baseline.Main Outcome MeasureIncidence of acute MI or death due to CHD by amount of fiber intake.ResultsResponse rate averaged 80% to 90% during the 10-year follow-up. We documented 591 major CHD events (429 nonfatal MIs and 162 CHD deaths). The age-adjusted relative risk (RR) for major CHD events was 0.53 (95% confidence interval [CI], 0.40-0.69) for women in the highest quintile of total dietary fiber intake (median, 22.9 g/d) compared with women in the lowest quintile (median, 11.5 g/d). After controlling for age, cardiovascular risk factors, dietary factors, and multivitamin supplement use, the RR was 0.77 (95% CI, 0.57-1.04). For a 10-g/d increase in total fiber intake (the difference between the lowest and highest quintiles), the multivariate RR of total CHD events was 0.81 (95% CI, 0.66-0.99). Among different sources of dietary fiber (eg, cereal, vegetables, fruit), only cereal fiber was strongly associated with a reduced risk of CHD (multivariate RR, 0.63; 95% CI, 0.49-0.81 for each 5-g/d increase in cereal fiber).ConclusionsOur findings in women support the hypothesis that higher fiber intake, particularly from cereal sources, reduces the risk of CHD.

Age at natural menopause and risk of cardiovascular disease.

Abstract: Background: Early natural menopause has been postulated to increase the risk of cardiovascular disease. Objective: To examine the relation of age at natural menopause with risk of coronary heart disease (CHD) and stroke in the Nurses’ Health Study. Methods: Analysis was restricted to 35 616 naturally postmenopausal women who never used estrogen replacement therapy and with no diagnosed cardiovascular disease at baseline, followed up from 1976 to 1994. Information on menopausal status, age at menopause, and other risk factors was obtained in 1976 and updated every 2 years by mailed questionnaires. Results: During 354 326 person-years of follow-up, we documented 757 incident cases of CHD and 350 incident cases of stroke. After adjusting for age, smoking status, and other cardiovascular risk factors, the relative risks (RRs) across categories of age at natural menopause (,40, 40-44, 45-49, 50-54, and $55 years) were 1.53, 1.42, 1.10, 1.00 (reference), and 0.95, respectively; the RR for each 1-year decrease in age at natural menopause was 1.03 (95% confidence interval, 1.01-1.05). Elevated risk with younger age at menopause was observed among current smokers (RR, 1.04 [95% CI, 1.01-1.07] for each 1-year decrease in age at natural menopause) but not among never smokers (RR, 1.00; 95% CI, 0.96-1.04). Age at natural menopause was not significantly associated with ischemic stroke (RR, 1.01; 95% CI, 0.97-1.04) or hemorrhagic stroke (RR, 1.03; 95% CI, 0.97-1.10). Conclusions: We observed an overall significant association between younger age at menopause and higher risk of CHD among women who experienced natural menopause and never used hormone therapy. This increased risk was observed among current smokers but not among never smokers. The apparent elevated risk of CHD with decreased age at natural menopause among smokers might reflect residual confounding by smoking.

Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men.

Abstract: Several prospective studies have demonstrated a direct association between C-reactive protein (CRP) levels and the risks of developing cardiovascular disease. Few studies, however, have explored the interrelations between CRP levels and other risk factors for cardiovascular disease. We evaluated the relation of CRP with several cardiovascular risk factors in a cross-sectional survey of 1,172 apparently healthy men. There were significant positive associations between CRP levels and age, number of cigarettes smoked per day, body mass index, systolic and diastolic blood pressure, total cholesterol, triglycerides, lipoprotein(a), apolipoprotein B, tissue-type plasminogen activator antigen, D-dimers, total homocysteine, and fibrinogen (all p values <0.05). Significant inverse associations were observed for exercise frequency, high-density lipoprotein cholesterol, and apolipoprotein A-I and A-II (all p values <0.02). In multivariate analysis, age, smoking status, and serum levels of tissue-type plasminogen activator antigen, fibrinogen, lipoprotein(a), and total homocysteine were independent correlates of CRP levels. Finally, in an analysis controlled either for all the independent correlates or for several usual risk factors, we observed progressive increases in levels of CRP with increasing prevalence of risk factors (p for trend <0.001 for independent correlates and <0.01 for usual risk factors). In conclusion, in a large cohort of apparently healthy men, CRP levels were associated with several cardiovascular risk factors. These data are compatible with the hypothesis that CRP levels may be a marker for preclinical cardiovascular disease.

Prospective Study of Calcium, Potassium, and Magnesium Intake and Risk of Stroke in Women

Abstract: Background and purpose High intakes of calcium, potassium, and magnesium have been hypothesized to reduce risks of cardiovascular disease, but only a few prospective studies have examined intakes of these cations in relation to risk of stroke. Methods In 1980, 85 764 women in the Nurses' Health Study cohort, aged 34 to 59 years and free of diagnosed cardiovascular disease and cancer, completed dietary questionnaires from which we calculated intakes of calcium, potassium, and magnesium. By 1994, after 1.16 million person-years of follow-up, 690 incident strokes (129 subarachnoid hemorrhages, 74 intraparenchymal hemorrhages, 386 ischemic strokes, and 101 strokes of undetermined type) had been documented. Results Intakes of calcium, potassium, and magnesium were each inversely associated with age- and smoking-adjusted relative risks of ischemic stroke, excluding embolic infarction of nonatherogenic origin (n=347). Adjustment for other cardiovascular risk factors, including history of hypertension, attenuated these associations, particularly for magnesium intake. In a multivariate analysis, women in the highest quintile of calcium intake had an adjusted relative risk of ischemic stroke of 0.69 (95% CI, 0.50 to 0.95; P for trend=0.03) compared with those in the lowest quintile; for potassium intake the corresponding relative risk was 0.72 (95% CI, 0.51 to 1.01; P for trend=0.10). Further simultaneous adjustment for calcium and potassium intake suggested an independent association for calcium intake. The association of risk with calcium intake did not appear to be log linear; the increase in risk was limited to the lowest quintile of intake, and intakes > approximately 600 mg/d did not appear to reduce risk of stroke further. The inverse association with calcium intake was stronger for dairy than for nondairy calcium intake. Intakes of calcium, potassium, and magnesium were not related to risk of other stroke subtypes. Conclusions Low calcium intake, and perhaps low potassium intake, may contribute to increased risk of ischemic stroke in middle-aged American women. It remains possible that women in the lowest quintile of calcium intake had unknown characteristics that made them susceptible to ischemic stroke.

G20210A Mutation in Prothrombin Gene and Risk of Myocardial Infarction, Stroke, and Venous Thrombosis in a Large Cohort of US Men

Abstract: Background—A single base pair mutation in the prothrombin gene has recently been identified that is associated with increased prothrombin levels. Whether this mutation increases the risks of arterial and venous thrombosis among healthy individuals is controversial. Methods and Results—In a prospective cohort of 14 916 men, we determined the prevalence of the G20210A prothrombin gene variant in 833 men who subsequently developed myocardial infarction, stroke, or venous thrombosis (cases) and in 1774 age- and smoking status–matched men who remained free of thrombosis during a 10-year follow-up (control subjects). Gene sequencing was used to confirm mutation status in a subgroup of participants. Overall, carrier rates for the G20210A mutation were similar among case and control subjects; the relative risk of developing any thrombotic event in association with the 20210A allele was 1.05 (95% CI, 0.7 to 1.6; P=0.8). We observed no evidence of association between mutation and myocardial infarction (RR=0.8, P=0....

A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk.

Abstract: We previously reported (J. Chen et al., Cancer Res., 56: 4862-4864, 1996; J. Ma et al., Cancer Res., 57: 1098-1102, 1997) that a 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism (677C-->T, ala-->val) was associated with lower risk of colorectal cancer. In this study, we examined the relationship of a polymorphism (2756A-->G, asp-->gly) in the gene (MTR) for methionine synthase, another important enzyme in the same folate/methionine/homocyst(e)ine metabolic pathway, with risk of colorectal cancer among 356 cases and 476 cancer-free controls. The frequency of the homozygous variant genotype (gly/gly) was slightly lower among cases (3%) than controls (5%). The odds ratio for the gly/gly genotype was 0.59 [95% confidence interval (CI), 0.27-1.27] compared with those with the homozygous wild type (asp/asp). There were no significant differences in plasma levels of folate, vitamin B12, and homocyst(e)ine (tHcy) among the MTR genotypes, in contrast to the MTHFR polymorphism. However, similar to the interaction observed for the MTHFR polymorphism among men who consumed less than 1 alcoholic drink/day, those with the gly/gly genotype had a lower risk of colorectal cancer with an odds ratio of 0.27 (95% CI, 0.09-0.81) compared with those with the asp/asp genotype. The possible association of the MTR polymorphism with lower risk of colorectal cancer especially among those with low alcohol consumption, in the same direction as for the MTHFR polymorphism, is intriguing. However, our study had limited statistical power because of the low frequency of the MTR variant genotype, which is reflected in the wide CIs. Hence, these findings need to be confirmed in larger populations.

A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals.

Abstract: Objective To study the association of cigarette smoking with risk of rheumatoid arthritis (RA), among 377,481 female health professionals in the Women's Health Cohort Study. Methods Subjects completed mailed questionnaires regarding demographics, health habits, including cigarette smoking history, and medical history, including RA diagnosis made by a physician and date of diagnosis. Of 7,697 women who self-reported RA, 3,416 reported seropositive RA. Cox proportional hazards regression models were used to retrospectively assess the associations of smoking intensity and duration with the risk of developing RA or seropositive RA. Cigarette smoking status was treated as a time-varying exposure in these regression models. Results In multivariate analyses controlling for age, race, education, age at menarche, pregnancy history, menopausal status, and postmenopausal hormone use, duration of smoking was associated with a significantly increased risk of both RA and seropositive RA (both P < 0.01 for trend), after adjusting for smoking intensity. Women who smoked ≥25 cigarettes/day for more than 20 years experienced a 39% increased risk of RA and 49% increased risk of seropositive RA. However, smoking intensity (number of cigarettes/day) was unrelated to risk of RA or seropositive RA (both P = 0.3 for trend), after adjusting for duration of smoking. Conclusion Duration, but not intensity, of cigarette smoking is associated with a modest increased risk of RA in women.

Homocysteine and risk of cardiovascular disease among postmenopausal women.

Abstract: ContextIndividuals with elevated levels of homocysteine tend to have higher prevalence of cardiovascular disease. However, prospective studies of homocysteine are inconsistent and data among women are limited.ObjectiveTo determine whether elevated homocysteine levels in healthy postmenopausal women predict risk of developing cardiovascular disease.DesignProspective, nested case-control study with a mean 3-year follow-up.SettingThe Women's Health Study, an ongoing US primary prevention trial initiated in 1993.ParticipantsFrom a total cohort of 28,263 postmenopausal women with no history of cardiovascular disease or cancer at baseline, 122 women who subsequently experienced cardiovascular events were defined as cases, and 244 age- and smoking status–matched women who remained free of disease during follow-up were defined as controls.Main Outcome MeasuresIncidence of death due to cardiovascular disease, nonfatal myocardial infarction (MI), stroke, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft by baseline homocysteine level.ResultsOf the 122 cases, there were 85 events of MI or stroke and 37 coronary revascularizations. Case subjects had significantly higher baseline homocysteine levels than controls (14.1 vs 12.4 µmol/L; P=.02). Subjects with homocysteine levels in the highest quartile had a 2-fold increase in risk of any cardiovascular event (relative risk [RR], 2.0; 95% confidence interval [CI], 1.1-3.8). This effect was largely due to an excess of cases with high levels of homocysteine; the RR for those with homocysteine levels at or higher than the 95th percentile (20.7 µmol/L) was 2.6 (95% CI, 1.1-5.7). Risk estimates were independent of traditional risk factors and were greatest for the end points of MI and stroke (RR for those with baseline homocysteine levels in the top quartile, 2.2; 95% CI, 1.1-4.6). Self-reported multivitamin supplement use at study entry was associated with significantly reduced levels of homocysteine (P<.001). However, the association between increasing quartile of homocysteine level and risk of MI or stroke remained significant in analyses controlling for baseline multivitamin supplement use (P=.003 for trend), and subgroup analyses limited to women who were (P=.02 for trend) or were not (P=.04 for trend) taking multivitamin supplements.ConclusionsAmong healthy postmenopausal US women, elevated levels of homocysteine moderately increased the risk of future cardiovascular disease. Whether lowering the homocysteine level reduces risk of cardiovascular events requires testing in randomized controlled trials.

Exercise and Risk of Stroke in Male Physicians

Abstract: Background and Purpose—From a physiological perspective, physical activity might be expected to decrease the risk of developing stroke. However, epidemiological studies of physical activity and stroke risk have yielded divergent findings. We therefore sought to examine the association between exercise and stroke risk. Methods—This was a prospective cohort study of 21 823 men, followed up for an average of 11.1 years. Participants were from the Physicians’ Health Study, a randomized trial of low-dose aspirin and beta carotene. Men, aged 40 to 84 years at baseline, were free of self-reported myocardial infarction, stroke, transient ischemic attack, and cancer. At baseline, they reported on the frequency of exercise vigorous enough to work up a sweat. Stroke occurrence was reported by participants and confirmed after medical record review (n=533). We used Cox proportional hazards regression to analyze the data. Results—With adjustment for age, treatment assignment, smoking, alcohol intake, history of angina,...

Cross-Sectional Study of Soluble Intercellular Adhesion Molecule-1 and Cardiovascular Risk Factors in Apparently Healthy Men

Abstract: An elevated plasma concentration of the soluble intercellular adhesion molecule-1 (sICAM-1) is associated with increased risk for future coronary events. However, data exploring the interrelations of sICAM-1 with known cardiovascular risk factors are sparse. We determined sICAM-1 levels in 948 middle-aged men with no prior history of cardiovascular disease. sICAM-1 levels increased with age (P 4 risk factors, respectively (P<0.01 for trend). In multivariate analysis, age, smoking status, diabetes, systolic blood pressure, positive family history of coronary disease, and serum levels of total homocysteine and fibrinogen were all independently associated with sICAM-1 levels (all P

β-Carotene supplementation for patients with low baseline levels and decreased risks of total and prostate carcinoma

Abstract: BACKGROUND The Physicians' Health Study was a randomized, double-blind, placebo-controlled trial using a 2 × 2 factorial design including supplementation with β-carotene (50 mg every other day) in the primary prevention of cancer among 22,071 U.S. male physicians ages 40–84 years at randomization. Before randomization, the authors collected baseline blood specimens to determine whether any benefit was greater among or confined to those with low baseline levels of β-carotene. METHODS Baseline blood samples were collected from 14,916 participants. These samples were assayed, according to a nested case–control design, from 1439 men subsequently diagnosed with cancer over 12 years of follow-up (631 with prostate carcinoma) and 2204 controls matched by age and smoking habits. RESULTS Men in the lowest quartile for plasma β-carotene at baseline had a marginally significant (P = 0.07) increased risk of cancer compared with those in the highest quartile (relative risk [RR] = 1.30, 95% confidence interval [CI], 0.98–1.74). Men in the lowest quartile assigned at random to β-carotene supplementation had a possible but nonsignificant decrease in overall cancer risk (RR = 0.83, 95% CI, 0.63–1.09) compared with those assigned to placebo. This was primarily due to a significant reduction in the risk of prostate carcinoma (RR = 0.68, 95% CI, 0.46–0.99) in this group. After the first 2 years of follow-up were excluded, the results were virtually unchanged. CONCLUSIONS These prespecified subgroup analyses appeared to support the idea that β-carotene supplementation may reduce risk of prostate carcinoma among those with low baseline levels. Further follow-up of this population will help determine whether these findings are valid. [See editorial on pages 1629–31, this issue.] Cancer 1999;86:1783–92. © 1999 American Cancer Society.

Baseline IgG Antibody Titers to Chlamydia pneumoniae, Helicobacter pylori, Herpes Simplex Virus, and Cytomegalovirus and the Risk for Cardiovascular Disease in Women

Abstract: In apparently healthy postmenopausal women, little evidence was found to support the notion that previous infection (as measured by IgG antibody titers to Chlamydia pneumoniae, Helicobacter pylori,...

Long-term β-Carotene Supplementation and Risk of Type 2 Diabetes Mellitus: A Randomized Controlled Trial

Abstract: ContextRecent data suggest a protective role of carotenoids in the development of type 2 diabetes mellitus (DM), possibly via an antioxidant effect, but no randomized trial has directly assessed the efficacy of β-carotene to prevent DM.ObjectiveTo determine whether long-term β-carotene supplementation reduces the risk of developing type 2 DM.Design, Setting, and ParticipantsA total of 22,071 healthy US male physicians aged 40 to 84 years in a randomized, double-blind, placebo-controlled trial, from 1982 to 1995. More than 99% of the participants had complete follow-up (median duration, 12 years).InterventionSubjects were randomly assigned to receive β-carotene (50 mg on alternate days) or placebo.Main Outcome MeasureIncidence of type 2 DM.ResultsA total of 10,756 subjects were assigned to β-carotene and 10,712 to placebo. Incidence of type 2 DM did not differ between groups: 396 men in the β-carotene group and 402 men in the placebo group developed type 2 DM (relative risk, 0.98; 95% confidence interval, 0.85-1.12). The lack of association between β-carotene supplementation and incidence of type 2 DM persisted despite multivariate adjustment. There was no evidence of benefit when the period of risk was subdivided into years of follow-up or increasing duration of treatment.ConclusionIn this trial of apparently healthy men, supplementation with β-carotene for an average of 12 years had no effect on the risk of subsequent type 2 DM.

The Gene Encoding Atrial Natriuretic Peptide and the Risk of Human Stroke

Abstract: Background —Recent evidence from an animal model of stroke, the stroke-prone spontaneously hypertensive rat, implicated the gene encoding atrial natriuretic peptide ( ANP ) as a possible candidate contributing to the likelihood of experiencing a stroke. The purpose of the present study was to investigate the role of ANP in the pathogenesis of cerebrovascular accidents in humans. Methods and Results —We investigated 2 previously known markers at ANP , G1837A and T2238C , for their possible association with the occurrence of stroke. This was the largest matched case-controlled sample studied thus far; the sample was drawn from a large prospective study (the Physician’s Health Study). When assuming a dominant mode of inheritance, a statistically significant positive association was observed for the 1837A allele, indicating an odds ratio of 1.64 (95% confidence interval, 1.01 to 2.65) for stroke. This observation led to the discovery of a new molecular variant in exon 1, G664A, which was responsible for a valine-to-methionine substitution in the proANP peptide. This mutation, which was in linkage disequilibrium with the G1837A marker, was associated with the occurrence of stroke (odds ratio, 2.0; 95% confidence interval, 1.17 to 3.19; P =0.01). Conclusions —Our findings suggest that molecular variants of the ANP gene may represent an independent risk factor for cerebrovascular accidents in humans. The strong parallelism to the experimental data obtained in the stroke-prone animal model provides assurance for the relevance of our observation.

The V89L Polymorphism in the 5α-Reductase Type 2 Gene and Risk of Prostate Cancer

Abstract: 5alpha-Reductase type 2, the predominant prostatic isozyme of this protein, converts testosterone to dihydrotestosterone. It has been hypothesized that individuals with greater 5alpha-reductase activity are at increased risk for prostate cancer (CaP). A single nucleotide polymorphism of the 5alpha-reductase type 2 gene (SRD5A2) gives rise to a substitution of leucine (leu) for valine (val) at codon 89 (V89L), the presence of which may affect serum androstanediol glucuronide (AAG) levels. We studied the effect of this polymorphism on the risk of prostate cancer in a prospective, nested, case-control design within the Physicians' Health Study. In all controls (n = 799), the leu allele frequency was 0.30. Among the 386 controls with plasma AAG levels available, there was no significant association between AAG levels and V89L genotype. We also detected no significant association between risk for CaP and genotype [odds ratio: val/val = 1.0 (reference), leu/val = 0.96 (95% confidence interval, 0.76-1.20), and leu/ leu = 0.84 (95% confidence interval, 0.57-1.24)]. These data do not support a moderate to large effect of the SRD5A2 V89L polymorphism on plasma AAG levels or CaP risk in this predominantly Caucasian cohort, although a small effect cannot be completely excluded.

Prospective Study of Aspirin Use and Risk of Stroke in Women

Abstract: Background and Purpose—In secondary prevention, aspirin reduces risk of ischemic stroke. In primary prevention of stroke, however, the role of aspirin is uncertain, especially in women. Methods—In 1980, 79 319 women in the Nurses’ Health Study cohort, 34 to 59 years of age and free of diagnosed cardiovascular disease, cancer, and rheumatoid arthritis, completed questionnaires that included information on aspirin use. Data on aspirin use were updated in 1982, 1984, and 1988. By 1994, after 994 231 person-years of follow-up, 503 incident strokes (295 ischemic strokes, 100 subarachnoid hemorrhages, 52 intraparenchymal hemorrhages, and 56 strokes of undetermined type) were documented. Results—There was no clear relationship between aspirin use and risk of total stroke; risk was slightly reduced among women who took 1 to 6 aspirin per week and slightly increased among women who took 7 or more aspirin per week. Women who took 1 to 6 aspirin per week had a lower risk of large-artery occlusive infarction compared...