Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program.

BACKGROUND: Genetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group. METHODS: This was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer. RESULTS: A total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P < .001). Comparing men in the highest 20% of PHS290 with those in the lowest 20% (based on percentiles from an independent training cohort), the hazard ratio for fatal prostate cancer was 4.42 (95% confidence interval = 3.91 to 5.02). When accounting for guideline-recommended risk factors (family history, race, and ethnicity), PHS290 remained a strong independent predictor of any, metastatic, and fatal prostate cancer. CONCLUSIONS: PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

Circulating Estrogen Levels and Self-Reported Health and Mobility Limitation in Community-Dwelling Men of the Framingham Heart Study.

BACKGROUND: Self-rated health is a commonly used global indicator of health status. Few studies have examined the association of self-rated health and mobility with estrone and estradiol in men. Accordingly, we determined the cross-sectional, incident, and mediating relations between circulating estrone and estradiol levels with self-rated health, mobility limitation, and physical performance in community-dwelling men. METHODS: The cross-sectional sample included 1,148 men, who attended Framingham Offspring Study Examinations 7 and 8. Estrone and estradiol levels were measured using liquid chromatography tandem mass spectrometry at Examination 7. Self-reported mobility limitation and self-rated health were assessed at Examinations 7 and 8. Additionally, short physical performance battery, usual walking speed, and grip strength were assessed at Examination 7. RESULTS: In incident analysis, estradiol levels at Examination 7 were associated with increased odds of fair or poor self-rated health at Examination 8, after adjusting for age, body mass index, comorbidities, and testosterone levels; in an individual with 50% greater estradiol than other, the odds of reporting "fair or poor" self-rated health increased by 1.78 (95% confidence interval: 1.25-2.55; p = .001). Neither estrone nor estradiol levels were associated with any physical performance measure at baseline. CONCLUSIONS: Higher circulating levels of estradiol are associated with increased risk of incident fair/poor self-rated health in community-dwelling men. The mechanisms by which circulating levels of estradiol are related to self-rated health in men need further investigation.

Circulating estrone levels are associated prospectively with diabetes risk in men of the Framingham Heart Study.

OBJECTIVE: In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS). RESEARCH DESIGN AND METHODS: Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998-2001) in FHS generation 2 men (n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography-tandem mass spectrometry, and free estradiol and estrone were calculated. RESULTS: In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02-1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8. CONCLUSIONS: Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than is estradiol.

Age trends in estradiol and estrone levels measured using liquid chromatography tandem mass spectrometry in community-dwelling men of the Framingham Heart Study.

BACKGROUND: Age trends in estradiol and estrone levels in men and how lifestyle factors, comorbid conditions, testosterone, and sex hormone-binding globulin affect these age trends remain poorly understood, and were examined in men of the Framingham Heart Study. METHODS: Estrone and estradiol concentrations were measured in morning fasting samples using liquid chromatography tandem mass spectrometry in men of Framingham Offspring Generation. Free estradiol was calculated using a law of mass action equation. RESULTS: There were 1,461 eligible men (mean age [±SD] 61.1±9.5 years and body mass index [BMI] 28.8±4.5kg/m(2)). Total estradiol and estrone were positively associated with age, but free estradiol was negatively associated with age. Age-related increase in total estrone was greater than that in total estradiol. Estrone was positively associated with smoking, BMI, and testosterone, and total and free estradiol with diabetes, BMI, testosterone, and comorbid conditions; additionally, free estradiol was associated negatively with smoking. Collectively, age, BMI, testosterone, and other health and behavioral factors explained only 18% of variance in estradiol, and 9% of variance in estrone levels. Men in the highest quintile of estrone levels had significantly higher age and BMI, and a higher prevalence of smoking, diabetes, and cardiovascular disease than others, whereas those in the highest quintile of estradiol had higher BMI than others. CONCLUSIONS: Total estrone and estradiol levels in men, measured using liquid chromatography tandem mass spectrometry, revealed significant age-related increases that were only partially accounted for by cross-sectional differences in BMI, diabetes status, and other comorbidities and health behaviors. Longitudinal studies are needed to confirm these findings.

Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts.

CONTEXT: Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men. METHODS: TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study. RESULTS: In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes. CONCLUSION: Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.

Early cigarette use and psychological distress as predictors of obesity risk in adulthood.

The study examined the simultaneous longitudinal relationships of cigarette use in adolescence to continuing cigarette use, psychological distress, physical activity, subjective rating of health in emerging adulthood and, finally, to body mass index (BMI) in early adulthood. The study utilized data (N=414) from a drug abuse prevention trial, Midwestern Prevention Project, with subjects participating from ages 11-34 years. Structural equation modeling showed that cigarette use in early adolescence had direct paths to distress in the beginning of emerging adulthood, which in turn had significant relationships to cigarette use, physical activity, and subjective rating of health in mid-emerging adulthood. Finally, both cigarette use and physical activity had significant negative relationships to BMI in early adulthood. Results suggest that prevention programs that have been previously applied to either cigarette use or distress prevention might be re-examined for their potential to also affect obesity risk in adulthood.

Influences affecting adolescent smoking behavior in China.

This study examined multiple influences on the use of tobacco by adolescents in China. Using the theory of triadic influences as a guide, we selected interpersonal, attitudinal/cultural, and intrapersonal constructs from baseline data to predict adolescent smoking 1 year later. We used prospective data from middle and high school students (N = 11,583) and their parents from the China Seven Cities Study, a longitudinal study that is evaluating the effects of changing economic and social factors on health behaviors including tobacco use. A multilevel regression analysis provided some support that each of the influences in the theory of triadic influences affects adolescent smoking in China. After adjusting for important confounders including age, gender, socioeconomic status, and smoking behaviors (lifetime and past 30-day) at baseline, we found significant risk factors within each of the three categories, including interpersonal influences (parental monitoring, good friend smoking, and peer smoking), attitudinal/cultural influences (school academic ranking, initial liking of smoking, and the meaning of smoking), and intrapersonal influences (susceptibility to smoking, and low self-confidence to quit smoking). Results suggest that the etiology of smoking among adolescents in China might be similar to that observed in western countries and that some of the techniques used successfully in prevention programs in those countries might be useful guides when developing prevention programs in China.

Translation in tobacco and drug abuse prevention research.

The purpose of this article is to describe the translation of research on tobacco and drug abuse prevention from basic science to program development to large-scale program dissemination, and from animal to human studies. Where relevant, continuity of translation is discussed by referring to two variables that have been studied for their potential relationship to drug use risk in both animals and humans: sensation and novelty seeking and low impulse control. Review of the research indicates relatively slow translation until the early 1990s. The authors recommend several mechanisms to promote more rapid translation across types of research that encourage reciprocal rather than unidirectional transmission of knowledge to expedite the development and diffusion of more timely, targeted drug abuse prevention programs.