Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study.

Insulin-like growth factor-I (IGF-I) is a mitogen for prostate epithelial cells. To investigate associations between plasma IGF levels and prostate cancer risk, a nested case-control study within the Physicians' Health Study was conducted on prospectively collected plasma from 152 cases and 152 controls. A strong positive association was observed between IGF-I levels and prostate cancer risk. Men in the highest quartile of IGF-I levels had a relative risk of 4.3 (95 percent confidence interval 1.8 to 10.6) compared with men in the lowest quartile. This association was independent of baseline prostate-specific antigen levels. Identification of plasma IGF-I as a predictor of prostate cancer risk may have implications for risk reduction and treatment.

Issues in the design and conduct of clinical trials.

Careful consideration of issues in the design and conduct of clinical trials is essential for valid results to be achieved. Specifically, if the trial is randomized and well designed with respect to timing, pilot studies, choice of study population, sample size, duration of follow-up, and subject compliance, it can offer reliable evidence about a positive, inverse, or null effect of an intervention. With these considerations in mind, the Physicians' Health Study is being conducted among over 21,996 male physicians, 40-84 years of age, in the United States and involved a 2 X 2 factorial design used to test the roles of beta-carotene in the prevention of cancer and aspirin in the reduction of cardiovascular mortality. The choice of physicians as the study population and the implementation of a prerandomization run-in period resulted in 100% mortality and 99.5% morbidity follow-up, as well as 98.5% compliance with the treatment regimen 6 months after randomization. The ultimate goal of these methodologic considerations is to design studies that clearly can prove or refute the hypotheses that was tested.

A prospective study of permanent hair dye use and hematopoietic cancer.

BACKGROUND: Use of permanent hair dye has been suggested as a risk factor for several types of cancer, although epidemiologic data have not generally supported this hypothesis. Retrospective studies have reported a possible association between hair dyes and hematopoietic cancers. PURPOSE: Our purpose was to investigate if permanent hair dye was associated with risks of incident lymphoma, leukemia, and multiple myeloma in the Nurses' Health Study, a prospective cohort study of 99,067 women aged 30-55 years in 1976. METHODS: Questionnaires regarding medical history and other health-related variables were sent to Nurses' Health Study participants every 2 years from 1976 to 1990. The follow-up for mortality in this cohort exceeds 98%. We identified 244 newly diagnosed cases of hematopoietic cancers, confirmed by pathology reports. Permanent hair dye use was ascertained over four cycles of questionnaires from 1976-1982; status of hair dye use established in 1982 was then used for the remainder of the follow-up time (through 1990). Age-specific incidence rates were calculated and used to compute relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We found no evidence of a positive association between ever use of permanent hair dye and all hematopoietic cancers (age-adjusted RR = 0.9; 95% CI = 0.7-1.2) or specific types (Hodgkin's lymphoma [RR = 0.9; 95% CI = 0.4-2.1], non-Hodgkin's lymphoma [RR = 1.1; 95% CI = 0.8-1.6], multiple myeloma [RR = 0.4; 95% CI = 0.2-0.9], chronic lymphocytic leukemia [RR = 0.6; 95% CI = 0.3-1.5], and other leukemias [RR = 0.8; 95% CI = 0.3-1.9]). Further examination of age at first use, duration, frequency, and time since first use and risk of all hematopoietic cancers or non-Hodgkin's lymphoma (the largest diagnostic group), indicated no material associations. CONCLUSION: In this prospective cohort study, permanent hair dye use is not adversely related to risks of hematopoietic cancers.

Low-dose aspirin and incidence of colorectal tumors in a randomized trial.

BACKGROUND: Laboratory, clinical, and epidemiologic studies have recently suggested that regular use of aspirin can reduce colorectal cancer incidence or mortality. However, observational epidemiologic analyses have had limited opportunity to control for confounding bias or to specify aspirin doses used. PURPOSE: Our purpose was to examine the relationship between regular use of low-dose aspirin and incidence of invasive and noninvasive colorectal tumors by utilizing data from the Physicians' Health Study, a randomized, double-blinded, placebo-controlled trial of aspirin and beta carotene. We also attempted to determine whether invasive cancers among aspirin users were associated with rectal bleeding and early stage at diagnosis. METHODS: The Physicians' Health Study includes 22071 U.S. male physicians. The aspirin arm was terminated in 1988 after a mean follow-up of 5 years. Stage at diagnosis and signs and/or symptoms during presentation were abstracted from medical records. Cox proportional hazards models were used to estimate relative risk (RR), 95% confidence intervals (CIs), and the association between aspirin and bleeding. Differences between aspirin and placebo groups in tumor risk over time were visualized with Kaplan-Meier curves. We assessed the association between aspirin and stage at diagnosis with a Mann-Whitney rank sum statistic for non-parametric comparison of two ordinal distributions. RESULTS: The RR of developing colorectal cancer for aspirin compared with placebo was 1.15 (95% CI = 0.80-1.65). For in situ cancers and polyps, the RR was 0.86 (95% CI = 0.68-1.10). There was no significant trend for decreasing RR by year of follow-up for invasive cancers (P = .09) or noninvasive tumors (P = .96). Aspirin and placebo groups did not differ in stage or prevalence of rectal bleeding at diagnosis. CONCLUSIONS: Regular aspirin use, at a dose adequate for preventing myocardial infarction, was not associated with a substantial reduction in the incidence of colorectal cancer during 5 years of randomized treatment and follow-up. A small decrease in polyps in the aspirin group could not be reliably distinguished from a chance association. Our results suggest that among low-dose aspirin users, (a) colorectal cancer mortality is not likely to be reduced by earlier detection and (b) incidence is not likely to be increased due to aspirin-induced gastrointestinal bleeding. IMPLICATIONS: The potential for a benefit from higher doses of aspirin or longer duration of use should be addressed by more detailed observational epidemiologic studies and prevention trials with longer follow-up of randomized participants.

Prospective study of sex hormone levels and risk of prostate cancer.

BACKGROUND: Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted. PURPOSE: We conducted a prospective, nested case-control study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer. METHODS: Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3 alpha-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 degrees C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided. RESULTS: No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all P < .001). When hormone and SHBG levels were adjusted simultaneously, a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and 2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse trend in risk was seen with increasing levels of SHBG (ORs by quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P for trend = .01), and a non-linear inverse association was found with increasing levels of estradiol (ORs by quartile = 1.00, 0.53, 0.40, and 0.56 [95% CI = 0.32-0.98]; P for trend = .03). No associations were detected between the levels of DHT or prolactin and prostate cancer risk; for AAG, a marker of 5 alpha-reductase activity, only suggestive evidence of a positive association was found. The results were essentially unchanged when case patients diagnosed within 4 years of plasma collection, case patients diagnosed with localized (i.e., nonaggressive) disease, or control subjects with elevated prostate serum antigen levels (> 2.5 ng/mL) were excluded from the analyses. CONCLUSIONS: High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor. Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk.

Oral contraceptive use and malignant melanoma.

There was no overall relationship between a prior history of oral contraceptive (OC) use and the development of melanoma among 141 cases of nonfatal malignant melanoma and 2,820 age-matched controls drawn from respondents to a large postal survey of registered U.S. nurses; crude relative risk (RR) was 0.93 and 95% confidence limits (CL) were between 0.64 and 1.36. Adjustment for a number of additional variables did not alter this estimate materially. Duration of OC use and interval since first use were similarly unrelated to the occurrence of melanoma. For women diagnosed before age 40, there was a crude positive association of "ever" use of OC and melanoma (RR = 1.78; 95% CL, 1.11-2.86). However, adjustment for geography and other variables diminished this association and rendered it statistically not significant (RR = 1.43, 95% CL, 0.83-2.46). These data do not support the hypothesis that OC use is an independent risk factor for melanoma.

Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study.

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.

Prospective study of plasma fatty acids and risk of prostate cancer.

BACKGROUND: Although some evidence suggests that dietary fat intake is related to prostate cancer, epidemiologic studies have been inconsistent. PURPOSE: Our purpose was to assess the association between plasma lipid levels, particularly linoleic and alpha-linolenic acids, and the development of prostate cancer. METHODS: In 1982, at the start of the Physicians' Health Study, 14916 U.S. male physicians provided plasma samples, which were frozen at -82 degrees C. Data accumulated from a series of questionnaires were used to assess the intake of various foods. We used a nested case-control design to compare the fatty acid compositions in plasma from 120 men who later developed prostate cancer with 120 matched controls who did not. Individual fatty acids were measured in plasma as a percentage of total fatty acids, using capillary gas chromatography. Conditional logistic regression models were used to obtain odds ratio estimates while adjusting simultaneously for the effects of one or more potential confounders. RESULTS: The relative risks (RRs) of prostate cancer for men in successively higher quartiles of plasma alpha-linolenic acid level were 3.0 (95% confidence interval [CI] = 1.2-7.3), 3.4 (95% CI = 1.6-7.5), and 2.1 (95% CI = 0.9-4.9), compared with those with levels below the detection threshold (P trend = .03). For linoleic acid, RRs in successively higher quartiles were 0.7 (95% CI = 0.4-1.5), 0.8 (95% CI = 0.4-1.6), and 0.6 (95% CI = 0.3-1.3), with the lowest quartile as referent (P trend = .24). The effect estimates were not notably altered by adjustment for exercise, body mass, meat and dairy consumption, or other fatty acid levels in the plasma. The RR for eating red meat at least five times per week compared with less than once a week was 2.5 (95% CI = 0.9-6.7) and was little changed by adjustment for alpha-linolenic acid, although alpha-linolenic acid levels were correlated with intake of red meat and butter. The association of alpha-linolenic acid levels with prostate cancer was greater among men with low linoleic acid and reduced meat intake. CONCLUSIONS: These results suggest that low plasma levels of alpha-linolenic acid might be associated with reduced risk of prostate cancer, independently of high meat intake. High linoleic acid and low marine fatty oils were not associated with increased risk, as previously hypothesized. IMPLICATIONS: The effects of dietary alpha-linolenic acid, particularly from vegetable sources, warrant further study. The effects of dietary linoleic acid and marine fatty acids seen in animal bioassays might not apply to human prostate cancer.

Use of permanent hair dyes and risk of breast cancer.

Aromatic amines contained in permanent hair dyes can be absorbed percutaneously and are mutagenic and carcinogenic in some laboratory studies. Concern has been raised that use of these dyes may increase the risk of human cancers. Therefore, the present study examined the relationship between permanent hair dye use and incidence of breast cancer among 118,404 U.S. women aged 30-55 years who were followed prospectively for 6 years. Among women who had ever used permanent hair dyes, 353 developed breast cancer during 246,848 person-years of follow-up, while 505 cases occurred during 397,460 person-years among never users (age-adjusted rate ratio = 1.1; 95% confidence interval = 0.9-1.2). Identical rate ratios were observed when women who had ever used hair dyes were subdivided into current and past users. Adjustment for known determinants of breast cancer in multivariate models did not alter these relationships. The risk of breast cancer did not increase with more frequent use, longer duration of use, or interval since first use. On the basis of these data and previous findings, it appears unlikely that the use of permanent hair dyes causes any important increase in risk of breast cancer.

Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3.

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.

Vitamin A supplementation and plasma retinol levels: a randomized trial among women.

Although dietary intake of vitamin A has little, if any, overall effect on blood retinol in generally well-nourished populations, subgroups may exist that would be responsive to supplementation. The hypothesis that vitamin A supplementation increases blood retinol in apparently well-fed individuals with lower than usual blood levels was tested in female health workers, with relatively low blood retinol values, who were randomly assigned to receive vitamin A (10,000 IU daily) or placebo. After 4 weeks the mean change in plasma retinol was -0.4 micrograms/dl for the group receiving placebo and +4.1 micrograms/dl (an increase of 9% over base-line values) for the group receiving vitamin A (P = .02). The results were similar when the base-line retinol level and several other covariates were considered. Thirteen women who had initially received placebo were then switched to vitamin A for 4 weeks. These women experienced a mean increase of 5.3 micrograms/dl in plasma retinol (P = .04). Responses to vitamin A supplementation tend to be greater among women with lower previous total vitamin A intake, as assessed by questionnaire [Spearman rank correlation coefficient (r) = 0.50; P = .01].

A case-control study of oral contraceptive use and breast cancer.

Among 989 cases of breast cancer and 9,890 controls selected from a cohort of married, female registered nurses aged 30-55 years, the relative risk (RR) of breast cancer for women who had ever used oral contraceptives (OC) compared with those who had never used them was 1.0, with 95% confidence limits 0.9-1.2. Among OC users, there was no consistent pattern of excess risk with increasing duration; in fact, the few women who had used OC longest (greater than 10 yr) had a slightly lower risk than never-users. Moreover, there was no association between OC use and breast cancer among women with a positive history of breast cancer in the mother or sister or with OC use before their first pregnancy. The only subgroup of women among whom any adverse effect was apparent was current OC users aged 50-55 years (two onsets expected vs. seven observed). This finding is consistent with earlier reports of an increased risk of breast cancer among older OC users; however, it is also likely to reflect, at least to some extent, the play of chance, since at ages 45-49 and in each younger age group fewer cases than expected were observed among current OC users.

Prospective study of oral contraceptive use and risk of breast cancer in women.

In 1976, 118,273 female nurses 30-55 years of age with no history of cancer completed a questionnaire regarding possible risk factors. By 1986, after 1,137,415 person-years of follow-up, we had documented 1,799 newly diagnosed cases of breast cancer. Compared with the risk of breast cancer for nonusers of oral contraceptives, the multivariate relative risks were 1.07 (95% confidence interval, 0.97-1.19) for all users, 1.06 (95% confidence interval, 0.96-1.18) for past users, and 1.53 (95% confidence interval, 1.06-2.19) for current users--women who used oral contraceptives up to 2 years before diagnosis of breast cancer. We conclude that overall past use of oral contraceptives is not associated with a substantial increase in the risk of breast cancer. Although we did not find women who used oral contraceptives before the first pregnancy to have an increased risk of breast cancer, the number of women who used oral contraceptives for a long duration in early reproductive life was too small to permit firm conclusions regarding the risk in this subgroup.

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

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 beta-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 (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps 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 beta-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 beta-carotene supplements. However, in the beta-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 alpha-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 beta-carotene supplements. For men with low lycopene, beta-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.

A prospective study of N-acetyltransferase genotype, red meat intake, and risk of colorectal cancer.

Carcinogenic heterocyclic amines are activated by N-acetyltransferase (NAT) enzymes, encoded by NAT1 and NAT2, to genotoxic compounds that can form DNA adducts in the colon epithelium. We have examined the relation of polymorphisms in the genes coding for both enzymes to risk of colorectal cancer and the gene-environment interaction with red meat intake among participants in the prospective Physicians' Health Study. Baseline blood samples from 212 men subsequently diagnosed with colorectal cancer during 13 years of follow-up were genotyped, along with 221 controls. NAT genotypes were analyzed by a PCR-restriction fragment length polymorphism method. Effect modification of the relation of red meat intake and risk of colorectal cancer by NAT genotype was assessed using conditional logistic regression. There was no overall independent association of NAT acetylation genotypes and colorectal cancer risk. The relative risks for the rapid acetylation genotype were 0.93 [95% confidence interval (CI), 0.61-1.42] for NAT1, 0.80 (95% CI, 0.53-1.19) for NAT2, and 0.81 (95% CI, 0.52-1.27) for NAT1/NAT2 combined. We observed a stronger association of red meat intake with cancer risk among NAT rapid acetylators, especially among men 60 years old or older. Among those men who were rapid acetylators for both NAT1 and NAT2, consumption of >1 serving of red meat per day was associated with a relative risk of 5.82 (95% CI, 1.11-30.6) compared with consumption of < or = 0.5 serving per day (P, trend = 0.02). These prospective data, which need to be confirmed in other studies, suggest that polymorphisms in the NAT genes confer differential susceptibility to the effect of red meat consumption on colorectal cancer risk.

The V89L polymorphism in the 5alpha-reductase type 2 gene and risk of prostate cancer.

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.

Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer.

Folate derivatives are important in experimental colorectal carcinogenesis; low folate intake, particularly with substantial alcohol intake, is associated with increased risk. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate, required for purine and thymidine syntheses, to 5-methyltetrahydrofolate, the primary circulatory form of folate necessary for methionine synthesis. A common mutation (677C-->T) in MTHFR reduces enzyme activity, leading to lower levels of 5-methyltetrahydrofolate. To evaluate the role of folate metabolism in human carcinogenesis, we examined the associations of MTHFR mutation, plasma folate levels, and their interaction with risk of colon cancer. We also examined the interaction between genotype and alcohol intake. We used a nested case-control design within the Physicians' Health Study. Participants were ages 40-84 at baseline when alcohol intake was ascertained and blood samples were drawn. During 12 years of follow-up, we identified 202 colorectal cancer cases and matched them to 326 cancer-free controls by age and smoking status. We genotyped for the MTHFR polymorphism and measured plasma folate levels. Men with the homozygous mutation (15% in controls) had half the risk of colorectal cancer [odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27-0.87] compared with the homozygous normal or heterozygous genotypes. Overall, we observed a marginal significant increased risk of colorectal cancer (OR, 1.78; 95% CI, 0.93-3.42) among those whose plasma folate levels indicated deficiency (<3 ng/ml) compared with men with adequate folate levels. Among men with adequate folate levels, we observed a 3-fold decrease in risk (OR, 0.32; 95% CI, 0.15-0.68) among men with the homozygous mutation compared with those with the homozygous normal or heterozygous genotypes. However, the protection due to the mutation was absent in men with folate deficiency. In men with the homozygous normal genotype who drank little or no alcohol as reference, those with the homozygous mutation who drank little or no alcohol had an 8-fold decrease in risk (OR, 0.12; 95% CI, 0.03-0.57), and for moderate drinkers, a 2-fold decrease in risk (OR, 0.42; 95% CI, 0.15-1.20); no decrease in risk was seen in those drinking 1 or more drinks/day. Our findings provide support for an important role of folate metabolism in colon carcinogenesis. In particular, these results suggest that the 677C-->IT mutation in MTHFR reduces colon cancer risk, perhaps by increasing 5,10-methylenetetrahydrofolate levels for DNA synthesis, but that low folate intake or high alcohol consumption may negate some of the protective effect.

Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.

BACKGROUND: Interleukin-6 (IL-6) plays a central role in inflammation and tissue injury. However, epidemiological data evaluating the role of IL-6 in atherogenesis are sparse. METHODS AND RESULTS: In a prospective study involving 14 916 apparently healthy men, we measured baseline plasma concentration of IL-6 in 202 participants who subsequently developed myocardial infarction (MI) and in 202 study participants matched for age and smoking status who did not report vascular disease during a 6-year follow-up. Median concentrations of IL-6 at baseline were higher among men who subsequently had an MI than among those who did not (1.81 versus 1. 46 pg/mL; P=0.002). The risk of future MI increased with increasing quartiles of baseline IL-6 concentration (P for trend <0.001) such that men in the highest quartile at entry had a relative risk 2.3 times higher than those in the lowest quartile (95% CI 1.3 to 4.3, P=0.005); for each quartile increase in IL-6, there was a 38% increase in risk (P=0.001).This relationship remained significant after adjustment for other cardiovascular risk factors, was stable over long periods of follow-up, and was present in all low-risk subgroups, including nonsmokers. Although the strongest correlate of IL-6 in these data was C-reactive protein (r=0.43, P<0.001), the relationship of IL-6 with subsequent risk remained after control for this factor (P<0.001). CONCLUSIONS: In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future MI. These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis.

G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men.

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=0.4) or stroke (RR=1.1, P=0.8). For venous thrombosis, a modest nonsignificant increase in risk was observed (RR=1.7, P=0.08) that was smaller in magnitude than that associated with factor V Leiden (RR=3.0, P<0. 001). Nine individuals carried both the prothrombin mutation and factor V Leiden (5 controls and 4 cases). One individual, a control subject, was homozygous for the prothrombin mutation. CONCLUSIONS: In a large cohort of US men, the G20210A prothrombin gene variant was not associated with increased risk of myocardial infarction or stroke. For venous thrombosis, risk estimates associated with the G20210A mutation were smaller in magnitude than risk estimates associated with factor V Leiden.

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.