Key Findings on Alcohol Consumption and a Variety of Health Outcomes From the Nurses' Health Study.

OBJECTIVES: To review critical contributions from the Nurses' Health Study (NHS) on alcohol consumption and health outcomes. METHODS: We performed a narrative review of NHS (1980-2012) and NHS II (1989-2011) publications. RESULTS: Using detailed information on self-reported alcohol drinking patterns obtained approximately every 4 years combined with extensive information on diet, lifestyle habits, and physician-diagnosed health conditions, NHS investigators have prospectively examined the risks and benefits associated with alcohol consumption. Moderate intake, defined as up to 1 drink a day, is associated with a lower risk of hypertension, myocardial infarction, stroke, sudden cardiac death, gallstones, cognitive decline, and all-cause mortality. However, even moderate intake places women at higher risk for breast cancer and bone fractures, and higher intake increases risk for colon polyps and colon cancer. CONCLUSIONS: Regular alcohol intake has both risks and benefits. In analyses using repeated assessments of alcohol over time and deaths from all causes, women with low to moderate intake and regular frequency (> 3 days/week) had the lowest risk of mortality compared with abstainers and women who consumed substantially more than 1 drink per day.

Y chromosome haplogroups and prostate cancer in populations of European and Ashkenazi Jewish ancestry.

Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I (P = 0.012, OR = 0.51; 95% confidence interval 0.30-0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry (P(meta) = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk (P(meta) = 0.010, OR = 0.77; 95% confidence interval 0.62-0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds.

Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis.

BACKGROUND: Excess body-mass index (BMI) has been associated with adverse outcomes in prostate cancer, and hyperinsulinaemia is a candidate mediator, but prospective data are sparse. We assessed the effect of prediagnostic BMI and plasma C-peptide concentration (reflecting insulin secretion) on prostate cancer-specific mortality after diagnosis. METHODS: This study involved men diagnosed with prostate cancer during the 24 years of follow-up in the Physicians' Health Study. BMI measurements were available at baseline in 1982 and eight years later in 1990 for 2546 men who developed prostate cancer. Baseline C-peptide concentration was available in 827 men. We used Cox proportional hazards regression models controlling for age, smoking, time between BMI measurement and prostate cancer diagnosis, and competing causes of death to assess the risk of prostate cancer-specific mortality according to BMI and C-peptide concentration. FINDINGS: Of the 2546 men diagnosed with prostate cancer during the follow-up period, 989 (38.8%) were overweight (BMI 25.0-29.9 kg/m(2)) and 87 (3.4%) were obese (BMI >/=30 kg/m(2)). 281 men (11%) died from prostate cancer during this follow-up period. Compared with men of a healthy weight (BMI <25 kg/m(2)) at baseline, overweight men and obese men had a significantly higher risk of prostate cancer mortality (proportional hazard ratio [HR] 1.47 [95% CI 1.16-1.88] for overweight men and 2.66 [1.62-4.39] for obese men; p(trend)<0.0001). The trend remained significant after controlling for clinical stage and Gleason grade and was stronger for prostate cancer diagnosed during the PSA screening era (1991-2007) compared with during the pre-PSA screening era (1982-1990) or when using BMI measurements obtained in 1990 compared with those obtained in 1982. Of the 827 men with data available for baseline C-peptide concentration, 117 (14%) died from prostate cancer. Men with C-peptide concentrations in the highest quartile (high) versus the lowest quartile (low) had a higher risk of prostate cancer mortality (HR 2.38 [95% CI 1.31-4.30]; p(trend)=0.008). Compared with men with a BMI less than 25 kg/m(2) and low C-peptide concentrations, those with a BMI of 25 kg/m(2) or more and high C-peptide concentrations had a four-times higher risk of mortality (4.12 [1.97-8.61]; p(interaction)=0.001) independent of clinical predictors. INTERPRETATION: Excess bodyweight and a high plasma concentration of C-peptide both predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of their disease. Patients with both factors have the worst outcome. Further studies are now needed to confirm these findings.

Prediagnostic plasma C-peptide and pancreatic cancer risk in men and women.

BACKGROUND: Hyperinsulinemia and insulin resistance have been proposed as underlying mechanisms for the increase in pancreatic cancer among long-standing diabetics and obese individuals. An association between serum insulin levels and pancreatic cancer risk was reported in a recent study, but the population was composed of heavy smokers and their findings may not be generalizable to nonsmokers. METHODS: Pancreatic cancer cases and matched controls were obtained from four large-scale prospective cohorts to examine the association between prediagnostic plasma levels of C-peptide and insulin and pancreatic cancer. One hundred ninety-seven pancreatic cancer cases were diagnosed during a maximum of 20 years of follow-up, after excluding cases diagnosed within 2 years of blood collection or with baseline diabetes. We estimated OR and confidence intervals (CI) using conditional logistic regression with adjustment for pancreatic cancer risk factors. RESULTS: Prediagnostic plasma C-peptide was positively associated with pancreatic cancer risk (OR, 1.52; 95% CI, 0.87-2.64, highest compared with the lowest quartile, P(trend) = 0.005). The association was not modified by body mass index or physical activity but seemed to be slightly stronger among never smokers than ever smokers. Fasting C-peptide and insulin were not related to pancreatic cancer; however, we observed a strong linear association for nonfasting C-peptide and pancreatic cancer (OR, 4.24; 95% CI, 1.30-13.8, highest versus lowest quartile, P(trend) < 0.001). CONCLUSIONS: Based on our finding of a strong positive association with nonfasting C-peptide levels, we propose that insulin levels in the postprandial state may be the relevant exposure for pancreatic carcinogenesis; however, other studies will need to examine this possibility.

Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts.

Folate deficiency induces DNA breaks and may alter cellular capacity for mutation and epigenetic methylation. Few studies have examined the influence of one-carbon nutrients on pancreatic cancer risk, although recent studies suggest a potential protective effect for one-carbon nutrients from food sources, but not from supplements. We conducted a prospective nested case-control study to examine plasma concentrations of folate, vitamin B6 [whose main circulating form is pyridoxal-5'-phosphate (PLP)], vitamin B12, and homocysteine in relationship to pancreatic cancer, using four large prospective cohorts. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. All statistical tests were two sided. Among 208 cases and 623 controls, we observed no association between folate, PLP, vitamin B12, or homocysteine and pancreatic cancer risk. Comparing the highest to lowest quartiles of plasma concentration, the ORs were 1.20 (95% CI, 0.76-1.91) for folate, 0.80 (95% CI, 0.51-1.25) for B6, 0.91 (95% CI, 0.57-1.46) for B12, and 1.43 (95% CI, 0.90-2.28) for homocysteine. In analyses restricted to nonusers of multivitamins, we observe a modest inverse trend between folate, PLP, and B12 and pancreatic cancer risk. In contrast, no such inverse associations were observed among study subjects who reported multivitamin supplement use. Among all participants, plasma levels of folate, B6, B12, and homocysteine were not associated with a significant reduction in the risk of pancreatic cancer. Among participants who obtain these factors exclusively through dietary sources, there may be an inverse relation between circulating folate, B6, and B12 and risk.

Genetic variation in the HSD17B1 gene and risk of prostate cancer.

Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.

Depressive symptoms and prospective incidence of colorectal cancer in women.

The authors examined depressive symptoms and prospective incidence of colorectal cancer and distal colorectal adenomas in 81,612 women without prior cancer from the Nurses' Health Study; 400 cases of colorectal cancer and 680 distal colorectal adenomas accrued between 1992 and the year 2000. Depressive symptoms were assessed in 1992 and 1996 with the five-question Mental Health Index (MHI-5), a subscale of the Short-Form 36 health status survey. Scores ranged from 0 to 100, and women with scores between 0 and 52 were defined as having significant depressive symptomatology. The authors also created four categories across the range of Mental Health Index scores: 0-52, 53-75, 76-85, and 86-100 (referent). Cox proportional hazards models were used to analyze the extent of depressive symptoms and colorectal events. Analyses were stratified by body mass index. In multivariate analyses with updated exposure, women with the highest levels of depressive symptoms had an elevated risk of incident colorectal cancer (hazard ratio = 1.43, 95% confidence interval: 0.97, 2.11) compared with women with the lowest levels of symptoms (p(trend) = 0.04). Associations appeared stronger in overweight women. However, depressive symptoms were unrelated to risk of colorectal adenomas. Associations are consistent with a possible role in late promotion of the disease.

Sugar-sweetened soft drink consumption and risk of pancreatic cancer in two prospective cohorts.

BACKGROUND: A history of diabetes mellitus and a diet high in glycemic load are both potential risk factors for pancreatic cancer. Sugar-sweetened soft drinks are a prevalent source of readily absorbable sugars and have been associated with an increased risk of obesity and diabetes. We investigated whether higher consumption of sugar-sweetened soft drinks increases the risk of pancreatic cancer. METHODS: We examined the relation between consumption of sugar-sweetened soft drinks and the development of pancreatic cancer in the Nurses' Health Study and the Health Professionals Follow-up Study. Among 88,794 women and 49,364 men without cancer at baseline, we documented 379 cases of pancreatic cancer during up to 20 years of follow-up. Soft drink consumption was first assessed at baseline (1980 for the women, 1986 for the men) and updated periodically thereafter. RESULTS: Compared with participants who largely abstained from sugar-sweetened soft drinks, those who consumed more than three sugar-sweetened soft drinks weekly experienced overall a multivariate relative risk (RR) of pancreatic cancer of 1.13 [95% confidence interval (95% CI), 0.81-1.58; P for trend = 0.47]. Women in the highest category of sugar-sweetened soft drink intake did experience a significant increase in risk (RR, 1.57; 95% CI, 1.02-2.41; P for trend = 0.05), whereas there was no association between sweetened soft drink intake and pancreatic cancer among men. Among women, the risk associated with higher sugar-sweetened soft drink was limited to those with elevated body mass index (>25 kg/m(2); RR, 1.89; 95% CI, 0.96-3.72) or with low physical activity (RR, 2.02; 95% CI, 1.06-3.85). In contrast, consumption of diet soft drinks was not associated with an elevated pancreatic cancer risk in either cohort. CONCLUSION: Although soft drink consumption did not influence pancreatic cancer risk among men, consumption of sugar-sweetened soft drinks may be associated with a modest but significant increase in risk among women who have an underlying degree of insulin resistance.