John Michael Gaziano

Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.

BACKGROUND Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation. METHODS In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene. RESULTS Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points. CONCLUSIONS In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.

Moderate Alcohol Intake, Increased Levels of High-Density Lipoprotein and Its Subfractions, and Decreased Risk of Myocardial Infarction

BACKGROUND Previous studies have suggested that moderate alcohol intake exerts a protective effect against coronary heart disease. Alterations in plasma lipoprotein levels represent one plausible mechanism of this apparent protective effect. METHODS We therefore examined the interrelation among alcohol consumption, plasma lipoprotein levels, and the risk of myocardial infarction in 340 patients who had had myocardial infarctions and an equal number of age- and sex-matched controls. The case patients were men or women less than 76 years of age with no history of coronary disease who were discharged from one of six hospitals in the Boston area with a diagnosis of a confirmed myocardial infarction. Alcohol consumption was estimated by means of a food-frequency questionnaire. RESULTS We observed a significant inverse association between alcohol consumption and the risk of myocardial infarction (P for trend, < 0.001 after control for known coronary risk factors). In multivariate analyses, the relative risk for the highest intake category (subjects who consumed three or more drinks per day) as compared with the lowest (those who had less than one drink a month) was 0.45 (95 percent confidence interval, 0.26 to 0.80). The levels of total high-density lipoprotein cholesterol (HDL) and its HDL2 and HDL3 subfractions were strongly associated with alcohol consumption (P for trend, < 0.001 for each). The addition of HDL or either of its subfractions to the multivariate model substantially reduced the inverse association between alcohol intake and myocardial infarction, whereas the addition of the other plasma lipid measurements did not materially alter the relation. CONCLUSIONS These data confirm the inverse association of moderate alcohol intake with the risk of myocardial infarction and support the view that the effect is mediated, in large part, by increases in both HDL2 and HDL3.

Migraine, headache, and the risk of stroke in women A prospective study

Background: Migraine and headache in general have been associated with subsequent risk of stroke, primarily in retrospective case-control studies. Prospective data evaluating the association between specific headache forms and stroke are sparse. Methods: A prospective cohort study was conducted among 39,754 US health professionals age 45 and older participating in the Women’s Health Study with an average follow-up of 9 years. Incident stroke was self-reported and confirmed by medical record review. Results: A total of 385 strokes (309 ischemic, 72 hemorrhagic, and 4 undefined) occurred. Compared with nonmigraineurs, participants who reported migraine overall or migraine without aura had no increased risk of any stroke type. Participants who reported migraine with aura had increased adjusted hazards ratios (HRs) of 1.53 (95% CI 1.02 to 2.31) for total stroke and 1.71 (95% CI 1.11 to 2.66) for ischemic stroke but no increased risk for hemorrhagic stroke. Participants with migraine with aura who were <55 years old had a greater increase in risk of total (HR 1.75; 95% CI 1.02 to 3.00) and ischemic (HR 2.25; 95% CI 1.30 to 3.91) stroke. Compared with participants without headache, headache in general and nonmigraine headache were not associated with total, ischemic, or hemorrhagic stroke. Conclusions: In these prospective data, migraine was not associated with total, ischemic, or hemorrhagic stroke. In subgroup analyses, we found increased risks of total and ischemic stroke for migraineurs with aura. The absolute risk increase was, however, low, with 3.8 additional cases per year per 10,000 women.

Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development.

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.

A common 8q24 variant in prostate and breast cancer from a large nested case-control study.

Two recent studies independently identified polymorphisms in the 8q24 region, including a single nucleotide polymorphism (rs1447295), strongly associated with prostate cancer risk. Here, we replicate the overall association in a large nested case-control study from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium using 6,637 prostate cancer cases and 7,361 matched controls. We also examine whether this polymorphism is associated with breast cancer among 2,604 Caucasian breast cancer cases and 3,118 matched controls. The rs1447295 marker was strongly associated with prostate cancer among Caucasians (P = 1.23 x 10(-13)). When we exclude the Multiethnic Cohort samples, previously reported by Freedman et al., the association remains highly significant (P = 8.64 x 10(-13)). Compared with wild-type homozygotes, carriers with one copy of the minor allele had an OR(AC) = 1.34 (99% confidence intervals, 1.19-1.50) and carriers with two copies of the minor allele had an OR(AA) = 1.86 (99% confidence intervals, 1.30-2.67). Among African Americans, the genotype association was statistically significant in men diagnosed with prostate cancer at an early age (P = 0.011) and nonsignificant for those diagnosed at a later age (P = 0.924). This difference in risk by age at diagnosis was not present among Caucasians. We found no statistically significant difference in risk when tumors were classified by Gleason score, stage, or mortality. We found no association between rs1447295 and breast cancer risk (P = 0.590). Although the gene responsible has yet to be identified, the validation of this marker in this large sample of prostate cancer cases leaves little room for the possibility of a false-positive result.

Lipid levels and the risk of ischemic stroke in women

Objective: To evaluate the association between total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol to HDL-C ratio, and non-HDL-C with the risk of ischemic stroke in a large cohort of apparently healthy women. Methods: Prospective cohort study among 27,937 US women aged ≥45 years participating in the Women’s Health Study who provided baseline blood samples. Stroke occurrence was self-reported and confirmed by medical record review. We categorized plasma lipid measurements into quintiles. We used Cox proportional hazards models to evaluate the association between lipids and risk of ischemic stroke. Results: During 11 years of follow-up, 282 ischemic strokes occurred. All lipid levels were strongly associated with increased risk of ischemic stroke in age-adjusted models. The association attenuated particularly for HDL-C after adjustment for potential confounders. For the comparison of the highest to the lowest quintile, the multivariable-adjusted hazard ratios (95% CI; p for trend across mean quintile values) of ischemic stroke were 2.27 (1.43, 3.60; ptrend < 0.001) for total cholesterol; 1.74 (1.14, 2.66; ptrend = 0.003) for LDL-C; 0.78 (0.52, 1.17; ptrend = 0.27) for HDL-C; 1.65 (1.06, 2.58; ptrend = 0.02) for the total cholesterol to HDL-C ratio; and 2.45 (1.54, 3.91; ptrend < 0.001) for non-HDL-C. Conclusions: In this large cohort of apparently healthy women, total cholesterol, low-density lipoprotein cholesterol, the total cholesterol to high-density lipoprotein cholesterol ratio, and non-high-density lipoprotein cholesterol were significantly associated with increased risk of ischemic stroke.

Genetic Polymorphism of Methylenetetrahydrofolate Reductase and Myocardial Infarction A Case-Control Study

BACKGROUND Elevated total plasma homocyst(e)ine (tHcy; the composite of homocysteine-derived moieties in their oxidized and reduced forms) levels are a risk factor for coronary heart disease, stroke, and venous thrombosis. tHcy plasma levels are influenced by folate, vitamins B6 and B12, as well as by hereditary factors. A point mutation (C677T) in the gene encoding methylenetetrahydrofolate reductase, an enzyme involved in homocysteine remethylation, has been reported to render the enzyme thermolabile and less active and has been associated with elevated tHcy in homozygous carriers (+/+ genotype) as well as with increased risk of premature cardiovascular disease. METHODS AND RESULTS We investigated whether this mutation influences risk for myocardial infarction (MI) and plasma levels of tHcy and whether this effect may be modified by dietary folate intake in 190 MI cases and 188 control subjects from the Boston Area Health Study. Genotype frequencies were 37.8% for -/-, 47.8% for +/-, and 14.4% for +/+ in the control group and 50.0% for -/-, 34.7% for +/-, and 15.3% for +/+ in the case group. The relative risk for MI associated with the +/+ genotype (compared with +/- and -/-) was 1.1 (95% CI, 0.6 to 1.9; P = .8). Stratification by folate intake values above and below the median did not significantly alter these results. Plasma tHcy levels were 9.9 +/- 2.7 mumol/L in -/- individuals, 10.6 +/- 3.8 mumol/L in +/- individuals, and 9.1 +/- 2.3 mumol/L in +/+ individuals (Ptrend = NS; determined in 68 cases and 59 control subjects). CONCLUSIONS Our data show that homozygosity for the C677T mutation in this largely white, middle-class US population is not associated with increased risk for MI, irrespective of folate intake. This suggests that this mutation does not represent a useful marker for increased cardiovascular risk in this and in similar populations.

Pancreatic Cancer Risk and ABO Blood Group Alleles: Results from the Pancreatic Cancer Cohort Consortium

A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18-1.62], 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk.A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with pancreatic cancer risk; however, the mechanisms underlying these associations and the influence of specific ABO genotypes remain unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, BB) in 1534 cases and 1583 controls from 12 prospective cohort studies participating in PanScan. We also grouped participants by genotype-derived serologic blood type (O, A, AB, B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared to blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 (95% confidence interval [CI], 1.18-1.62), 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates (cases per 100,000 subjects per year) for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5. An increase in risk was noted with the addition of each non-O allele. Compared to OO, subjects with AO and AA had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), while subjects with BO and BB had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54), compared with non-smokers with blood type O. Among participants in a large prospective cohort consortium, ABO genotypes were significantly associated with pancreatic cancer risk.

Parkinson disease and risk of mortality: a prospective comorbidity-matched cohort study.

Objective: To evaluate the association between Parkinson disease (PD) and mortality after adjustment for comorbidities. Methods: We conducted a matched cohort analysis among 22,071 participants in the Physicians’ Health Study. Five hundred sixty incident PD cases were identified by self-report. We used a modified Charlson Comorbidity Index to calculate a comorbidity score. Each PD case was matched by age to a comparator who was alive and had an identical comorbidity score at the time of PD diagnosis of the case. Both cohorts were followed for all-cause mortality. We used proportional hazards models to calculate hazard ratios (HRs) for mortality. Results: A total of 330 participants died over a median follow-up of 5.8 years, 200 (35.7%) in the PD group and 130 (23.2%) in the reference group. After adjustment for smoking and age at PD onset, the HR for mortality was 2.32 (95% CI 1.85–2.92). The mortality risk remained significant with increasing age at onset, even in those aged ≥80 years (HR = 2.10; 95% CI 1.44–3.00). The increased risk was apparent for short PD duration (<2 years) and remained stable with increasing duration. We found no different risk of mortality associated with PD according to smoking status. Conclusions: In this large prospective cohort of men and after matching on comorbidities, we found that Parkinson disease patients had an increased risk of all-cause mortality. Mortality was increased regardless of disease duration, did not diminish with increasing age at onset, and was not influenced by smoking status. GLOSSARY: BMI = body mass index; COPD = chronic obstructive pulmonary disease; HR = hazard ratio; ICD-9 = International Classification of Diseases, 9th Revision; PD = Parkinson disease; PHS = Physicians’ Health Study; RR = relative risk; WHO = World Health Organization.

A Prospective Cohort Study of Cancer Incidence Following the Diagnosis of Parkinson's Disease

Background: Prior studies suggest a decreased risk of cancer among patients with Parkinsons disease (PD). Methods: Matched cohort analysis among the 22,071 participants in the Physicians Health Study. A total of 487 incident cases of PD without preceding cancer were identified by self-report. Each PD case was matched by age to a reference participant who was alive and cancer free at the time of PD diagnosis. Both cohorts were followed for incident cancer. We used proportional hazards models to calculate adjusted relative risks (RR) for cancer. Results: A total of 121 cancers were confirmed during a median follow-up of 5.2 years (PD) and 5.9 years (reference). Those with PD developed less cancer (11.0% versus 14.0%), with an adjusted RR of 0.85 [95% confidence interval (95% CI), 0.59-1.22]. Reduced risk was present for smoking-related cancers such as lung (RR, 0.32), colorectal (RR, 0.54), and bladder (RR, 0.68), as well as for most non–smoking-related cancers such as prostate cancer (RR, 0.74). In contrast, PD patients were at significantly increased risk (RR, 6.15; 95% CI, 1.77-21.37) for melanoma. PD patients who smoked were at reduced risk for smoking-related cancer (RR, 0.33; 95% CI, 0.12-0.92), whereas nonsmokers with PD were at increased risk (RR, 1.80; 95% CI, 0.60-5.39). This interaction was statistically significant (Pinteraction = 0.02). Conclusions: Our results suggest a decreased incidence of most cancers in patients with PD. PD patients had a significantly increased risk of malignant melanoma, a finding consistent with prior studies. We confirmed an interaction between smoking and the relationship of PD to smoking-related cancer that may fit the pattern of a gene-environment interaction. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1260–5)