Michael F. Leitzmann

Overweight, Obesity, and Mortality in a Large Prospective Cohort of Persons 50 to 71 Years Old

BACKGROUND Obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death, but the relation between overweight (a BMI of 25.0 to 29.9) and the risk of death has been questioned. METHODS We prospectively examined BMI in relation to the risk of death from any cause in 527,265 U.S. men and women in the National Institutes of Health-AARP cohort who were 50 to 71 years old at enrollment in 1995-1996. BMI was calculated from self-reported weight and height. Relative risks and 95 percent confidence intervals were adjusted for age, race or ethnic group, level of education, smoking status, physical activity, and alcohol intake. We also conducted alternative analyses to address potential biases related to preexisting chronic disease and smoking status. RESULTS During a maximum follow-up of 10 years through 2005, 61,317 participants (42,173 men and 19,144 women) died. Initial analyses showed an increased risk of death for the highest and lowest categories of BMI among both men and women, in all racial or ethnic groups, and at all ages. When the analysis was restricted to healthy people who had never smoked, the risk of death was associated with both overweight and obesity among men and women. In analyses of BMI during midlife (age of 50 years) among those who had never smoked, the associations became stronger, with the risk of death increasing by 20 to 40 percent among overweight persons and by two to at least three times among obese persons; the risk of death among underweight persons was attenuated. CONCLUSIONS Excess body weight during midlife, including overweight, is associated with an increased risk of death.

Meat Intake and Mortality: A Prospective Study of Over Half a Million People

BACKGROUND High intakes of red or processed meat may increase the risk of mortality. Our objective was to determine the relations of red, white, and processed meat intakes to risk for total and cause-specific mortality. METHODS The study population included the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study cohort of half a million people aged 50 to 71 years at baseline. Meat intake was estimated from a food frequency questionnaire administered at baseline. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) within quintiles of meat intake. The covariates included in the models were age, education, marital status, family history of cancer (yes/no) (cancer mortality only), race, body mass index, 31-level smoking history, physical activity, energy intake, alcohol intake, vitamin supplement use, fruit consumption, vegetable consumption, and menopausal hormone therapy among women. Main outcome measures included total mortality and deaths due to cancer, cardiovascular disease, injuries and sudden deaths, and all other causes. RESULTS There were 47 976 male deaths and 23 276 female deaths during 10 years of follow-up. Men and women in the highest vs lowest quintile of red (HR, 1.31 [95% CI, 1.27-1.35], and HR, 1.36 [95% CI, 1.30-1.43], respectively) and processed meat (HR, 1.16 [95% CI, 1.12-1.20], and HR, 1.25 [95% CI, 1.20-1.31], respectively) intakes had elevated risks for overall mortality. Regarding cause-specific mortality, men and women had elevated risks for cancer mortality for red (HR, 1.22 [95% CI, 1.16-1.29], and HR, 1.20 [95% CI, 1.12-1.30], respectively) and processed meat (HR, 1.12 [95% CI, 1.06-1.19], and HR, 1.11 [95% CI 1.04-1.19], respectively) intakes. Furthermore, cardiovascular disease risk was elevated for men and women in the highest quintile of red (HR, 1.27 [95% CI, 1.20-1.35], and HR, 1.50 [95% CI, 1.37-1.65], respectively) and processed meat (HR, 1.09 [95% CI, 1.03-1.15], and HR, 1.38 [95% CI, 1.26-1.51], respectively) intakes. When comparing the highest with the lowest quintile of white meat intake, there was an inverse association for total mortality and cancer mortality, as well as all other deaths for both men and women. CONCLUSION Red and processed meat intakes were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality.

A Prospective Study of Red and Processed Meat Intake in Relation to Cancer Risk

Background Red meat and processed meat have been associated with carcinogenesis at several anatomic sites, but no prospective study has examined meat intake in relation to a range of malignancies. We investigated whether red or processed meat intake increases cancer risk at a variety of sites. Methods and Findings The National Institutes of Health (NIH)-AARP (formerly the American Association for Retired Persons) Diet and Health Study is a cohort of approximately 500,000 people aged 50–71 y at baseline (1995–1996). Meat intake was estimated from a food frequency questionnaire administered at baseline. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals within quintiles of red and processed meat intake. During up to 8.2 y of follow-up, 53,396 incident cancers were ascertained. Statistically significant elevated risks (ranging from 20% to 60%) were evident for esophageal, colorectal, liver, and lung cancer, comparing individuals in the highest with those in the lowest quintile of red meat intake. Furthermore, individuals in the highest quintile of processed meat intake had a 20% elevated risk for colorectal and a 16% elevated risk for lung cancer. Conclusions Both red and processed meat intakes were positively associated with cancers of the colorectum and lung; furthermore, red meat intake was associated with an elevated risk for cancers of the esophagus and liver.

Physical Activity in Relation to Cardiovascular Disease and Total Mortality Among Men With Type 2 Diabetes

Background—The present study was conducted to examine the relationship of physical activity with risk of cardiovascular disease (CVD) and mortality among men with type 2 diabetes. CVD risk and mortality are increased in type 2 diabetes. Few epidemiological studies have investigated the effect of physical activity on these outcomes among type 2 diabetics. Methods and Results—Of the 3058 men who reported a diagnosis of diabetes at age 30 years or older in the Health Professionals’ Follow-up Study (HPFS), we excluded 255 who reported a physical impairment. In the remaining 2803 men, physical activity was assessed every 2 years; 266 new cases of CVD and 355 deaths of all causes were identified during 14 years of follow-up. Relative risks of CVD and death were estimated from Cox proportional hazards analysis with adjustment for potential confounders. The multivariate relative risks of CVD incidence corresponding to quintiles of total physical activity were 1.0, 0.87, 0.64, 0.72, and 0.67 (Ptrend=0.07). The corresponding multivariate relative risks for total mortality were 1.0, 0.80, 0.57, 0.58, and 0.58 (Ptrend=0.005). Walking was associated with reduced risk of total mortality. Relative risks across quintiles of walking were 1.0, 0.97, 0.87, 0.97, and 0.57 (Ptrend=0.002). Walking pace was inversely associated with CVD, fatal CVD, and total mortality independently of walking hours. Conclusions—Physical activity was associated with reduced risk of CVD, cardiovascular death, and total mortality in men with type 2 diabetes. Walking and walking pace were associated with reduced total mortality.

Prospective study of adiposity and weight change in relation to prostate cancer incidence and mortality

Adiposity has been linked inconsistently with prostate cancer, and few studies have evaluated whether such associations vary by disease aggressiveness.

Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer

AbstractObjective: The hormone 1,25-dihydroxyvitamin D (1,25(OH)2D) promotes prostate epithelial cell differentiation in vitro and thus, several groups have hypothesized that men who systemically have lower levels of 1,25(OH)2D may be at increased risk for prostate cancer. To address this hypothesis, we evaluated the association of circulating concentrations of 1,25(OH)2D and its precursor 25-hydroxyvitamin D (25(OH)D) with subsequent risk of prostate cancer. Methods: Prostate cancer cases were 460 men in the Health Professionals Follow-up Study who were diagnosed through 1998 after providing a blood specimen in 1993/95. 90.2% of the cases were organ confined or had minimal extraprostatic extension. An equal number of controls who had had a screening PSA test after blood draw were individually matched to cases on age, history of a PSA test before blood draw, and time of day, season, and year of blood draw. Plasma 1,25(OH)2D and 25(OH)D concentrations were determined by radio-immunosorbant assay blindly to case–control status. Odds ratios (OR) of prostate cancer and 95% confidence intervals (CI) were estimated from conditional logistic regression models mutually adjusting for quartiles of 1,25(OH)2D and 25(OH)D concentrations and for suspected prostate cancer risk factors. Quartile cutpoints were determined separately by season of blood draw using the distributions among controls. Results: Mean concentrations of 1,25(OH)2D and 25(OH)D were slightly, but not statistically significantly (p= 0.06 and 0.20, respectively), higher in cases (34.3 ± 7.1 pg/ml and 24.6 ± 7.7 ng/ml, respectively) than in controls (33.5 ± 7.1 pg/ml and 23.9 ± 8.2 ng/ml, respectively). The OR of prostate cancer comparing men in the top to bottom quartile of 1,25(OH)2D was 1.25 (95% CI: 0.82–1.90, p-trend = 0.16). For 25(OH)D the OR of prostate cancer comparing the top and bottom quartiles was 1.19 (95% CI: 0.79–1.79, p-trend = 0.59). These findings did not vary by level of the other metabolite, age at diagnosis, family history of prostate cancer, or factors that are thought to influence 25(OH)D levels. Conclusion: In this prospective study, we did not observe an inverse association between plasma concentrations of 1,25(OH)2D or 25(OH)D and incident prostate cancer, although we cannot rule out potential effects at later stages of the disease.

Sex Steroid Hormones and the Androgen Receptor Gene CAG Repeat and Subsequent Risk of Prostate Cancer in the Prostate-Specific Antigen Era

Objective: Sex steroid hormones are thought to contribute to the growth, differentiation, and progression of prostate cancer. We investigated plasma levels of sex steroid hormones and length of the androgen receptor gene CAG repeat in relation to incident prostate cancer diagnosed in the prostate-specific antigen (PSA) era. Methods: Using a nested case-control design, we included 460 prostate cancer cases diagnosed after providing a blood specimen in 1993 but before February 1998 among men in the Health Professionals Follow-up Study. Controls were 460 age-matched men without prostate cancer who had a screening PSA test after the date of providing a blood specimen. We measured plasma concentrations of total testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, estradiol, and sex hormone binding globulin (SHBG) and determined the length of the androgen receptor gene CAG repeat. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer. Results: Mean concentrations of the sex steroids adjusted for SHBG, and mean CAG repeat length did not differ significantly between the prostate cancer cases and controls. No significant associations with total prostate cancer were detected for plasma total testosterone concentration (comparing highest versus lowest quartiles: OR, 0.78; 95% CI, 0.48-1.28; Ptrend = 0.73) or the other sex hormones after adjusting for SHBG. However, plasma total testosterone concentration was positively associated with low-grade disease (Gleason sum < 7: OR, 1.91; 95% CI, 0.89-4.07; Ptrend = 0.02) and inversely associated with high-grade disease (Gleason sum ≥ 7: OR, 0.26; 95% CI, 0.10-0.66; Ptrend = 0.01). Similar patterns for grade were observed for free testosterone. Short CAG repeat length was not associated with total prostate cancer (≤ 19 versus ≥ 24: OR, 0.84; 95% CI, 0.57-1.23; Ptrend = 0.22) or grade of disease. No clear associations with regionally invasive or metastatic (≥ T3b, N1, or M1) were found for any of the hormones or the CAG repeat, although the number of these cases was small. Conclusions: The overall lack of association of prostate cancer diagnosed in the PSA era with sex steroid hormones and the androgen receptor gene CAG repeat length is consistent with the hypothesis that these factors do not substantially contribute to the development of early prostate cancer in the PSA era. The influence of plasma total and free testosterone concentrations on prostate cancer grade merits further evaluation.

Index-based Dietary Patterns and Risk of Colorectal Cancer The NIH-AARP Diet and Health Study

The authors compared how four indexes-the Healthy Eating Index-2005, Alternate Healthy Eating Index, Mediterranean Diet Score, and Recommended Food Score-are associated with colorectal cancer in the National Institutes of Health-AARP Diet and Health Study (n = 492,382). To calculate each score, they merged data from a 124-item food frequency questionnaire completed at study entry (1995-1996) with the MyPyramid Equivalents Database (version 1.0). Other variables included energy, nutrients, multivitamins, and alcohol. Models were stratified by sex and adjusted for age, ethnicity, education, body mass index, smoking, physical activity, and menopausal hormone therapy (in women). During 5 years of follow-up, 3,110 incident colorectal cancer cases were ascertained. Although the indexes differ in design, a similarly decreased risk of colorectal cancer was observed across all indexes for men when comparing the highest scores with the lowest: Healthy Eating Index-2005 (relative risk (RR) = 0.72, 95% confidence interval (CI): 0.62, 0.83); Alternate Healthy Eating Index (RR = 0.70, 95% CI: 0.61, 0.81); Mediterranean Diet Score (RR = 0.72, 95% CI: 0.63, 0.83); and Recommended Food Score (RR = 0.75, 95% CI: 0.65, 0.87). For women, a significantly decreased risk was found with the Healthy Eating Index-2005, although Alternate Healthy Eating Index results were similar. Index-based dietary patterns that are consistent with given dietary guidelines are associated with reduced risk.

A Prospective Study of Serum C-Reactive Protein and Colorectal Cancer Risk in Men

Chronic inflammation has been implicated in the etiology of colorectal cancer. C-reactive protein (CRP), a sensitive marker of inflammation, has been investigated with regard to colorectal cancer in only three previous studies, and the results from these investigations were inconsistent. We examined serum CRP levels in relation to colorectal cancer incidence in a nested case-control study within the Alpha Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study, a cohort of 29,133 Finnish males enrolled from 1985 to 1988 with follow-up through April 2002. Colorectal cancer cases were ascertained by the Finnish Cancer Registry; this analysis included 130 cases of colorectal cancer (with available blood), which occurred between 1990 and April 30, 2002, and 260 matched controls. Baseline median CRP levels were approximately 25% higher among colorectal cancer cases (3.4 mg/L) than controls (2.6 mg/L; P = 0.04). Relative to men in the lowest quartile of CRP concentration, men in the highest quartile had an odds ratio of 2.9 (95% confidence interval, 1.4-6.0) for developing colorectal cancer with a dose-response relationship supported (P(trend) = 0.006). The relation between CRP and incident colorectal cancer was modified by body mass index such that the association was stronger among lean individuals than in heavier individuals (P(interaction) = 0.018). These results support the notion that chronic low-grade inflammation is a marker for increased risk of colorectal cancer.

Cigarette smoking and subsequent risk of lung cancer in men and women: analysis of a prospective cohort study

BACKGROUND Whether women are more susceptible than men to lung cancer caused by cigarette smoking has been controversial. To address this question, we aimed to compare incidence rates of lung cancer by stratum of smoking use in men and women of the National Institutes of Health (NIH)-AARP cohort. METHODS Participants in the NIH-AARP Diet and Health study responded to a postal questionnaire between Oct 13, 1995, and May 6, 1996, and were followed up until Dec 31, 2003. The questionnaire asked participants about their past and current smoking status, demographics, alcohol intake, tobacco smoking, physical activity, and included a food-frequency questionnaire of 124 items. Incident lung cancers were identified by linkage to individual state cancer registries. We present age-standardised incidence rates for cancer and multivariate hazard ratios (HRs) adjusted for potential confounders, with 95% CIs. This study conforms to the STROBE guidelines. FINDINGS 279 214 men and 184 623 women from eight states in the USA aged 50-71 years at study baseline were included in this analysis. During follow-up, lung cancers occurred in 4097 men and 2237 women. Incidence rates were 20.3 (95% CI 16.3-24.3) per 100 000 person-years in men who had never smoked (99 cancers) and 25.3 (21.3-29.3) in women who had never smoked (152 cancers); for this group, the adjusted HR for lung cancer was 1.3 (1.0-1.8) for women compared with men. Smoking was associated with increased risk of lung cancer in men and women. The incidence rate of current smokers who smoked more than two packs per day was 1259.2 (1035.0-1483.3) in men and 1308.9 (924.2-1693.6) in women. In current smokers, in a model adjusted for typical smoking dose, the HR was 0.9 (0.8-0.9) for women compared with men. For former smokers, in a model adjusted for years of cessation and typical smoking dose, the HR was 0.9 (0.9-1.0) for women compared with men. Incidence rates of adenocarcinoma, small-cell carcinoma, and undifferentiated tumours were similar in men and women; incidence rates of squamous tumours in men were about twice that in women. INTERPRETATION Our findings suggest that women are not more susceptible than men to the carcinogenic effects of cigarette smoking in the lung. In smokers, incidence rates tended to be higher in men than women with comparable smoking histories, but differences were modest; smoking was strongly associated with lung cancer risk in both men and women. Future studies should confirm whether incidence rates are indeed higher in women who have never smoked than in men who have never smoked.