Health Professionals Follow-up Study Research Articles

Cumulative Erythemal Ultraviolet Radiation and Risk of Cancer in 3 Large US Prospective Cohorts.

Ultraviolet radiation (UVR) exposure is the major risk factor for melanoma. However, epidemiologic studies on UVR and noncutaneous cancers have reported inconsistent results, with some suggesting an inverse relationship potentially mediated by vitamin D. To address this, we examined 3 US prospective cohorts, the Health Professionals Follow-up Study (HPFS) (1986) and Nurses' Health Study (NHS) I and II (1976 and 1989), for associations between cumulative erythemal UVR and incident cancer risk, excluding nonmelanoma skin cancer. We used a validated spatiotemporal model to calculate erythemal UVR. Participants (47,714 men; 212,449 women) were stratified into quintiles by cumulative average erythemal UVR, using the first quintile as referent, for Cox proportional hazards regression analysis. In the multivariable-adjusted meta-analysis of all cohorts, compared with the lowest quintile, risk of any cancer was slightly increased across all other quintiles (highest quintile hazard ratio (HR)=1.04, 95% confidence interval (CI): 1.01, 1.07; P for heterogeneity= 0.41). All UVR quintiles were associated with similarly increased risk of any cancer excluding melanoma. As expected, erythemal UVR was positively associated with risk of melanoma (highest quintile HR=1.17, 95% CI: 1.04, 1.31; P for heterogeneity= 0.83). These findings suggest that elevated UVR is associated with increased risk of both melanoma and noncutaneous cancers.

Associations between Types of Dietary Sugar and Risk of Coronary Heart Disease in US Men and Women

ObjectivesTo investigate the associations of dietary sugars, including total fructose equivalents (TFE) and total glucose equivalents (TGE), with coronary heart disease (CHD) risk in two prospective cohort studies, the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). We hypothesized that added sugar, TGE, and TFE intakes were positively associated with CHD risk, but that natural sugar was not associated with higher risk. MethodsWe followed 76,815 women (NHS, 1980–2020) and 39,215 men (HPFS, 1986–2016) who were free of diabetes, cardiovascular disease, and cancer and had completed a semiquantitative food frequency questionnaire (SFFQ) at baseline. Dietary sugar intake was updated every 2–4 years by SFFQs. We defined TFE as fructose monosaccharides and fructose from sucrose, and TGE as glucose monosaccharides and glucose from sucrose, maltose, lactose, and starch. CHD outcomes were ascertained through medical record review and death certificates. Cox proportional hazards models were used to quantify associations between sugar intake and CHD risk with adjustment for potential confounding factors in NHS and HPFS separately. We then pooled risk estimates from the two cohorts using fixed-effects meta-analysis. Secondarily, we examined the associations of sucrose, lactose, starch, and total, added and natural sugars with CHD risk. ResultsWe documented 9,683 incident CHD cases during up to 40 years of follow-up. Higher intake of TGE, compared with total fat, was significantly associated with higher CHD risk, whereas TFE intake was not associated with CHD risk. Comparing extreme quintiles of intake, the hazard ratios (HRs, 95% confidence interval [CI]) of CHD were 1.16 (1.06–1.25; ptrend < .001) for TGE and 1.06 (0.97–1.16; ptrend = 0.09) for TFE. Replacing 5% of energy from total fat with equivalent energy from total and added sugars were associated with estimated increases in CHD risk of 4% (HR: 1.04, 95% CI: 1.02–1.07) and 5% (HR 1.05, 95% CI: 1.01–1.09). Intakes of natural sugar, sucrose, or lactose were not significantly associated with CHD risk. Starch intake was positively associated with CHD risk (HR comparing extreme quintiles: 1.21, 95% CI: 1.11–1.31; ptrend < 0.001). ConclusionsOur findings support limiting dietary intake of starch and suggest that intake of TGE but not TFE is associated with a higher risk of CHD. Funding SourcesNIH

Prediagnosis and Postdiagnosis Diet Quality, Physical Activity, and Mortality Risk Among Individuals with Parkinson Disease: A Prospective Cohort Study

ObjectivesGreater diet quality and physical activity level are associated with a lower risk of developing Parkinson disease (PD). However, information regarding these lifestyle behaviors and survival after PD diagnosis remains limited. This study aimed to examine the association between prediagnosis and postdiagnosis diet quality, physical activity, and mortality among individuals with PD.MethodsWe included 652 men from the Health Professional Follow-up Study (1986–2012) and 599 women from the Nurses’ Health Study (1984–2012) who were diagnosed with PD and had complete baseline dietary assessments. Diet quality was assessed by the Alternative Healthy Eating Index (AHEI), and overall physical activity was assessed by metabolic-equivalent hours per week (MET-h/wk) based on questionnaires. Mortality was followed up until 2018. Cox proportional hazard models were used to estimate the association between prediagnosis and postdiagnosis diet quality/physical activity and mortality, individually and jointly, adjusting for age, total energy intake, caffeine consumption, and other lifestyle risk factors.ResultsDuring 32–34 years of follow-up, we identified 529 deaths in men and 413 deaths in women. Better diet quality was associated with lower mortality rates both before and after the diagnosis of PD (p-trend < 0.005 for both). Similar results were obtained for physical activity (p-trend < 0.005 for both before and after the PD diagnosis). In joint analyses of diet quality and physical activity before the PD diagnosis, the adjusted hazard ratio [HR] was 0.51 (95% confidence interval [CI]: of 0.36, 0.73) for individuals in the highest tertiles for both variables relative to those in the lowest tertiles. The comparable HR for diet quality and physical activity after the diagnosis was 0.35 (95% CI: 0.23, 0.52). Similar patterns were observed for PD-specific mortality.ConclusionsAdherence to a healthy dietary pattern and an active lifestyle was associated with a lower rate of mortality among individuals with PD. Reverse causation cannot be totally excluded and the results need to be interpreted with caution.Funding SourcesThis study was supported by the National Institute of Neurological Disorders and Stroke grant 1R01NS102735-01A1.

Dietary Phytoestrogens and Total and Cause-Specific Mortality: Results From Two Prospective Cohort Studies

ObjectivesEvidence regarding dietary phytoestrogens in relation to mortality remains limited and mixed. We aimed to examine associations of dietary intake of total and subclasses of phytoestrogens, specifically: isoflavones, lignans, and coumarins, with total and cause-specific mortality in US men and women.MethodsWe prospectively followed 75,981 women in the Nurses’ Health Study (1984–2018), and 44,001 men in the Health Professionals Follow-up Study (1986–2018), who were free of cardiovascular disease (CVD), diabetes, or cancer at baseline. Diet was repeatedly assessed using validated food frequency questionnaires every 2–4 years. Associations with total and cause-specific mortality (CVD, cancer, and other) were assessed using time-dependent Cox models with adjustments for demographics, dietary and lifestyle factors, and medical history.ResultsDuring 3,427,156 person-years of follow-up, we documented 50,734 deaths, including 12,492 CVD deaths, 13,726 cancer deaths, and 24,516 other deaths. In multivariable-adjusted analyses, higher total phytoestrogen intake was associated with lower total, CVD, and other mortality: comparing extreme quintiles, the pooled HRs (95%CIs) were 0.89 (0.87, 0.92) for total mortality, 0.90 (0.85, 0.96) for CVD mortality, and 0.86 (0.82, 0.90) for other mortality. Furthermore, isoflavones, lignans, and coumarins were all inversely associated with mortality. Specifically, for total mortality, comparing extreme quintiles, the pooled HRs (95%CIs) were 0.90 (0.87, 0.92) for total isoflavones, 0.93 (0.90, 0.96) for total lignans, and 0.93 (0.90, 0.95) for coumarins. These phytoestrogens were also significantly associated with lower CVD mortality or other mortality, although only coumarins were significantly associated with lower cancer mortality. Primary food sources of phytoestrogens, such as tofu, soymilk, whole grains, tea, flaxseed, and flaxseed oil, were inversely associated with total mortality.ConclusionsHigher intake of total phytoestrogens, including isoflavones, lignans, and coumarins as well as foods rich in these compounds were associated with lower total and certain cause-specific mortality in generally healthy U.S. adults. These data suggest that these phytochemicals and their dietary sources may be integrated into an overall healthy diet to achieve a longer life span.Funding SourcesNIH.

Validity and Reproducibility of FFQ in Measuring Food and Food Group Intakes

Abstract Objectives We evaluated the validity and reproducibility of a 149-item semi-quantitative Food Frequency Questionnaire (FFQ) in measuring food and food group intakes among 736 participants of the Women's Lifestyle Validation Study (WLVS) and 649 participants of the Men's Lifestyle Validation Study (MLVS). Methods The WLVS was conducted among a subset of the Nurses' Health Study (NHS) and NHSII participants aged 45–80 years in 2010. Participants of the MLVS aged 46–82 years between 2011 and 2013 were recruited from the Health Professionals Follow-up Study and members of Harvard Pilgrim Health Care. We matched 10,128 foods with unique food codes collected from the 7-day dietary records (7DDRs) to the 149 foods listed on the FFQ based on the similarity of food descriptions. After the matching, we converted gram intakes of the 7DDR-measured foods into servings using the amounts specified on the FFQ. Food group intakes were calculated as the sum of the individual component foods in servings. Validity of the FFQ compared to repeated 7DDRs measured six months apart and the reproducibility between two FFQs administered one year apart were assessed using Spearman correlations. Results Foods generally considered to be healthy were often overreported through FFQs, while those perceived unhealthy were underreported. The average 1-year reproducibility of all foods listed on the FFQ was 0.64 in both the WLVS and MLVS. Reproducibility of the food groups (mean: 0.70 among women and 0.71 among men) was generally higher than that for individual foods. Among women, the average validity correlation for individual foods was 0.59 when comparing the FFQ completed at the end of the 1-year study period with the 7DDRs and correcting for within-person variations in 7DDRs. Among men, the corresponding average validity correlation was 0.61. Food groups assessed by the FFQ had slightly higher validity correlations than did individual foods in both women (range: 0.44–0.92, mean: 0.61) and men (0.46–0.88, mean: 0.64). Conclusions This study reaffirms that the FFQ performs well in measuring foods and food groups and provides the data enabling investigators to adjust for measurement error in epidemiologic studies of foods and food groups in relation to health outcomes. Funding Sources The Women's Lifestyle Validation Study and Men's Lifestyle Validation Study were funded by National Cancer Institute.

Sugar-sweetened beverage and sugar consumption and colorectal cancer incidence and mortality according to anatomic subsite

Recent preclinical research strongly suggests that dietary sugars can enhance colorectal tumorigenesis by direct action, particularly in the proximal colon that unabsorbed fructose reaches. We aimed to examine long-term consumption of sugar-sweetened beverages (SSBs) and total fructose in relation to incidence and mortality of colorectal cancer (CRC) by anatomic subsite. We followed 121,111 participants from 2 prospective US cohort studies, the Nurses' Health Study (1984-2014) and Health Professionals Follow-Up Study (1986-2014), for incident CRC and related death. Cox proportional hazards regression was used to compute HRs and 95% CIs. During follow-up, we documented 2733 incident cases of CRC with a known anatomic location, of whom 901 died from CRC. Positive associations of SSB and total fructose intakes with cancer incidence and mortality were observed in the proximal colon but not in the distal colon or rectum (Pheterogeneity≤0.03). SSB consumption was associated with a statistically significant increase in the incidence of proximal colon cancer (HR per 1-serving/d increment: 1.18; 95% CI: 1.03, 1.34; Ptrend=0.02) and a more pronounced elevation in the mortality of proximal colon cancer (HR: 1.39; 95% CI: 1.13, 1.72; Ptrend=0.002). Similarly, total fructose intake was associated with increased incidence and mortality of proximal colon cancer (HRs per 25-g/d increment: 1.18; 95% CI: 1.03, 1.35; and 1.42; 95% CI: 1.12, 1.79, respectively). Moreover, SSB and total fructose intakes during the most recent 10 y, rather than those from a more distant period, were associated with increased incidence of proximal colon cancer. SSB and total fructose consumption were associated with increased incidence and mortality of proximal colon cancer, particularly during later stages of tumorigenesis.

Histidine Intake, Human Gut Microbiome, Plasma Levels of Imidazole Propionate, and Coronary Heart Disease Risk in US Adults

ObjectivesImidazole propionate (ImP), a microbiota metabolite from histidine, has been linked to cardiometabolic conditions in humans. The current study aimed to elucidate inter-relationships between histidine intake, gut microbial composition and functional potentials, circulating ImP levels, and the risk of coronary heart disease (CHD) in U.S. adults.MethodsA total of 896 fecal samples and 462 blood samples were collected from 298 healthy men in the Men's Lifestyle Validation Study. Multivariate Association with Linear Models 2 was used to analyze the associations between microbial features and plasma ImP levels. Associations between plasma ImP and CHD risk was examined using Cox proportional hazards regression models among 7,793 participants pooled from the Health Professionals Follow-up Study, Nurses’ Health Study (NHS), and NHSII with existing ImP measurements.ResultsThe overall microbial composition was associated with plasma ImP levels (PERMANOVA p = 0.001). Multivariable taxa-wide association analysis identified 14 bacterial species, such as Ruminococcus Obeum, Clostridium clostridioforme, C. nexile, C. symbiosum and Gordonibacter pamelaeae, that were significantly (FDR P < 0.05) associated with plasma ImP levels. A non-parametric score was derived to summarize the abundance of the 14 species. Higher intake of red meat and histidine was significantly associated with higher ImP levels among participants with a higher ImP-Species Score (for red meat, P-inter = 0.04; for histidine, P-inter = 0.01), but not among others (P > 0.05). In the pooled cohort, compared with participants in the lowest ImP tertile, the relative risk (95% CI) of CHD was 2.06 (1.96, 2.43) among those in the highest ImP tertile (P- trend = 0.0001). Histidine consumption was not associated with CHD risk in the same study population.ConclusionsWe identified multiple microbiota species that were associated with plasma ImP concentrations and collectively predicted stronger associations of histidine or red meat intake with ImP concentrations. Plasma ImP concentrations were significantly associated with an increased risk of developing CHD. These data emphasize the role of human gut microbiota in modulating the production of ImP through histidine intake.Funding SourcesThe National Institutes of Health Boston Nutrition Obesity Research Centre.

Low-Carbohydrate Diets Score and Mortality Among Adults with Incident Type 2 Diabetes

ObjectivesIt is unclear whether adherence to low carbohydrate diet (LCD) patterns is beneficial towards type 2 diabetes (T2D) patients. The present study aims to prospectively examine the association between post-diagnostic LCD patterns and mortality among T2D patients.MethodsWe included participants from the Nurses’ Health Study and Health Professionals Follow-Up Study who were diagnosed with T2D during the follow-up. An overall total low carbohydrate diet score (TLCDS) was calculated based on the percentage of energy as total carbohydrates. In addition, plant (PLCDS) and animal-based LCD scores (ALCDS) emphasizing plant or animal protein and fat consumption, respectively, healthy LCD (HLCDS) and unhealthy LCD (ULCDS) emphasizing high or low quality of carbohydrates and fats, respectively, were further derived. All LCDS were cumulative averaged since the T2D diagnosis. Cause of death was identified from death certifications or review of medical records. A multivariable-adjusted Cox models were used to assess the association between LCDS and mortality.ResultsAmong 10,101 participants with incident T2D contributing 139,417 person-years during follow-up, we documented 4,452 deaths of which 1,326 and 875 cases were attributed to cardiovascular disease (CVD) and cancer, respectively. The pooled multivariable-adjusted hazard ratios (HRs, 95% CIs) of total mortality per 10 points increment of post-diagnostic LCDS were 0.87 (0.82,0.92) for TLCDS, 0.75 (0.70,0.80) for PLCDS, and 0.78 (0.73,0.84) for HLCDS. Both PLCDS and HLCDS were also associated with significantly lower CVD and cancer mortality. Each 10 points increase of TLCDS, PLCDS, and HLCDS from pre-diagnostic to post-diagnostic period were associated with 13% (7%, 18%), 16% (20%, 31%), and 15% (20%, 31%) lower total mortality. Increasing pre-to-post-diagnostic PLCDS and HLCDS were also associated with significantly lower CVD mortality and cancer mortality. No significant associations were observed for either cumulative averaged or change of ALCDS and ULCDS.ConclusionsAmong diabetes patients, greater adherence to LCD patterns that emphasize high quality sources of macronutrients was significantly associated with lower total, cardiovascular, and cancer mortality.Funding SourcesNational Institute of Health.

Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms.

Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 (7322 proteoforms of 6596 proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses' Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r≥0.75 and 87% had an ICC/r≥0.40 in Olink compared to 44% with an ICC/r≥0.75 and 72% with an ICC/r≥0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r≥0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r>0.75) for 14.7% and poor (r<0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable.

A Healthy Lifestyle in Men at Increased Genetic Risk for Prostate Cancer

BackgroundProstate cancer is the most heritable cancer. There is a need to identify possible modifiable factors for men at an increased risk of prostate cancer due to genetic factors. ObjectiveTo examine whether men at an increased genetic risk of prostate cancer can offset their risk of disease or disease progression by adhering to a healthy lifestyle. Design, setting, and participantsWe prospectively followed 12 411 genotyped men in the Health Professionals Follow-up Study (1993–2019) and the Physicians’ Health Study (1983–2010). Genetic risk of prostate cancer was quantified using a polygenic risk score (PRS). A healthy lifestyle was defined by healthy weight, vigorous physical activity, not smoking, and a healthy diet. Outcome measurements and statistical analysisOverall and lethal prostate cancer events (metastatic disease/prostate cancer–specific death) were analyzed using time-to-event analyses estimating hazard ratios (HRs) and lifetime risks. Results and limitationsDuring 27 yr of follow-up, 3005 overall prostate cancer and 435 lethal prostate cancer events were observed. The PRS enabled risk stratification not only for overall prostate cancer, but also for lethal disease with a four-fold difference between men in the highest and lowest quartiles (HR, 4.32; 95% confidence interval [CI], 3.16–5.89). Among men in the highest PRS quartile, adhering to a healthy lifestyle was associated with a decreased rate of lethal prostate cancer (HR, 0.55; 95% CI, 0.36–0.86) compared with having an unhealthy lifestyle, translating to a lifetime risk of 1.6% (95% CI, 0.8–3.1%) among the healthy and 5.3% (95% CI, 3.6–7.8%) among the unhealthy. Adhering to a healthy lifestyle was not associated with a decreased risk of overall prostate cancer. ConclusionsOur findings suggest that a genetic predisposition for prostate cancer is not deterministic for a poor cancer outcome. Maintaining a healthy lifestyle may provide a way to offset the genetic risk of lethal prostate cancer. Patient summaryThis study examined whether the genetic risk of prostate cancer can be attenuated by a healthy lifestyle including a healthy weight, regular exercise, not smoking, and a healthy diet. We observed that adherence to a healthy lifestyle reduced the risk of metastatic disease and prostate cancer death among men at the highest genetic risk. We conclude that men at a high genetic risk of prostate cancer may benefit from adhering to a healthy lifestyle.

0698 Genetic susceptibility to elevated C-reactive protein and risk of obstructive sleep apnea in US men and women

Abstract Introduction Obstructive sleep apnea (OSA) may trigger inflammation. However, growing evidence suggests a role for inflammation in predisposing OSA through increased upper airway size/collapsibility and altered ventilatory control. Inflammation also promotes sleep disturbance and excessive daytime sleepiness (EDS). Genetic analysis may provide further insights into the causal relationship between chronic inflammation and OSA incidence. Methods In 33,171 participants of European ancestry from the Nurses’ Health Study (NHS), NHS2 and the Health Professionals Follow-up Study, we quantified genetic predisposition to inflammation using a weighted polygenic risk score (PRS) based on 51 loci identified for C-reactive protein (CRP) in a recent genome-wide association meta-analysis. OSA was determined using self-reported diagnoses, which were demonstrated to reliably indicate moderate-to-severe OSA in these cohorts. EDS was defined based on self-reports of disrupted daily activities due to sleepiness ≥4 days/week. Multivariable logistic regression was used to estimate the odds ratio (OR) for OSA risk according to the number of risk alleles, adjusted for age, sex, BMI, genotyping platforms and 10 genetic principal components. Mendelian randomization using individual-level participant data was performed to evaluate the association between genetically determined CRP levels and OSA risk. Results A total of 3,163 participants (9.5%) had clinically diagnosed OSA (575 with EDS). While the CRP PRS (explained 5.0% variance in circulating levels) was not associated with OSA risk overall (OR per increment of 5 risk alleles: 1.00; 95% CI: 0.96, 1.04; p=0.96), a significant positive association was observed for OSA with concurrent EDS (Comparable OR: 1.13; 95% CI: 1.04, 1.23; p=0.003). In contrast, among participants without clinically diagnosed OSA, there was no association between the PRS and EDS (Comparable OR for EDS: 1.02; 95% CI: 0.98, 1.06; p=0.28). In Mendelian randomization, each doubling of genetically elevated CRP was associated with 44% higher odds of OSA with EDS (95% CI: 1.13, 1.82). Conclusion Chronic inflammation (characterized by elevated CRP levels) may be casually associated with risk of developing symptomatic OSA with EDS, but not OSA or EDS alone. To confirm our findings, future investigations are needed to evaluate the genetic associations with objective measures of OSA severity across diverse populations and elucidate mechanisms driven by specific inflammatory mediators. Support (If Any) NIH grants UM1CA186107, U01CA176726, U01CA167552, K01HL143034, R35HL135818

Regular, Long-Duration Multivitamin Use and Risk of Overall and Aggressive Prostate Cancer in the Health Professionals Follow-Up Study.

Multivitamin supplement is commonly used among older adults in the United States. Evidence on multivitamin use and prostate cancer risk is limited, and some suggested potential risk for clinically important subtypes of cancer. A total of 48,137 men from the Health Professionals Follow-up Study were followed from 1986 to 2017. Multivitamin use and frequency were self-reported at baseline and updated biennially. Clinical features of prostate cancer included advanced, lethal and high-grade outcomes. Cox proportional hazards models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) of multivitamin use and incidence of prostate cancer. The median followup for men without prostate cancer diagnosis or death was 30.7 years. We documented 7,108 incident prostate cancer cases including 564 advanced and 1,065 lethal. Overall, we observed a null association between multivitamin use and risk of prostate cancer. Compared to never-users, men who used multivitamin 10 or more tablets per week had similar risk of advanced (HR: 1.14, 95% CI: 0.77-1.70, Ptrend=0.46) or lethal (HR: 1.07, 95% CI: 0.80-1.44, Ptrend=0.59) prostate cancer, and multivitamin use of 15 years or more was not associated with risk of advanced (HR: 1.10, 95% CI: 0.80-1.50, Ptrend=0.46) or lethal (HR: 1.04, 95% CI: 0.83-1.31, Ptrend=0.13) prostate cancer. Regular or long-duration multivitamin use among older, generally well-nourished men was not associated with either increased or lower risk of overall or aggressive prostate cancer.

MP43-10 IMPACT OF FAMILY HISTORY AND GERMLINE GENETIC RISK VARIANTS ON LONG-TERM OUTCOMES OF ACTIVE SURVEILLANCE-ELIGIBLE PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022MP43-10 IMPACT OF FAMILY HISTORY AND GERMLINE GENETIC RISK VARIANTS ON LONG-TERM OUTCOMES OF ACTIVE SURVEILLANCE-ELIGIBLE PROSTATE CANCER Florian Rumpf, Anna Plym, Jane Vaselkiv, Mark Preston, Adam Kibel, Lorelei Mucci, and Keyan Salari Florian RumpfFlorian Rumpf More articles by this author , Anna PlymAnna Plym More articles by this author , Jane VaselkivJane Vaselkiv More articles by this author , Mark PrestonMark Preston More articles by this author , Adam KibelAdam Kibel More articles by this author , Lorelei MucciLorelei Mucci More articles by this author , and Keyan SalariKeyan Salari More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002609.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A family history of prostate cancer (PCa) and BRCA/DNA repair gene-associated cancers are risk factors for developing prostate cancer. In the last decade, >260 PCa-associated single nucleotide polymorphisms (SNPs) have been identified through large-scale genome-wide association studies that strongly stratify lifetime risk of prostate cancer. Few studies have examined the prognostic value of family history or PCa germline risk variants in patients with favorable-risk PCa eligible for active surveillance (AS). Here, we evaluate the impact of a positive family history and germline risk SNPs on outcomes on AS-eligible patients. METHODS: In a prospective cohort of 39,427 U.S. men in the Health Professionals Follow-up Study, 1,367 were diagnosed with clinically favorable-risk (NCCN very low-, low-, or favorable intermediate-risk) PCa from 1986 to 2016 and underwent genome-wide SNP genotyping. During the 30-year follow-up, 263 patients experienced disease recurrence and 52 patients died of PCa. A polygenic risk score was derived from 269 SNPs associated with development of PCa. Two loci associated with PCa survival were also assessed. Multivariable Cox proportional hazards models were used to estimate the association between family history of prostate, breast, or pancreatic cancer, germline risk SNPs, and PCa recurrence or death through 2019. RESULTS: The median follow up time from diagnosis was 14.1 years. A family history of prostate, breast, or pancreatic cancer was observed in 494 (36%) patients. Men with a positive family history had an 83% greater risk of PCa-specific death (95% CI 1.06-3.17, p=0.03), and greater than that of men with a family history of PCa alone. The polygenic risk score was not associated with either PCa recurrence or death. However, focusing on 2 loci on 8q24 and 19q13 with the strongest evidence in the literature for association with PCa aggressiveness, we observed a significant association between rs2735839 on 19q13 and PCa-specific death (HR 1.81, 95% CI 1.04-3.17, p=0.037). Using a risk score giving one point each to a positive family history and rs2735839 risk allele, each point of the heritable risk score was associated with a 72% increased risk of PCa-specific death (95% CI 1.16-2.54, p=0.006). CONCLUSIONS: Our study found that patients with AS-eligible PCa with a family history of prostate, breast, or pancreatic cancer or a 19q13 germline risk allele had elevated risks of PCa-specific death. These findings have implications for how germline genetic risk should be factored into AS selection criteria. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e744 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Florian Rumpf More articles by this author Anna Plym More articles by this author Jane Vaselkiv More articles by this author Mark Preston More articles by this author Adam Kibel More articles by this author Lorelei Mucci More articles by this author Keyan Salari More articles by this author Expand All Advertisement PDF DownloadLoading ...

Polygenic scores, diet quality, and type 2 diabetes risk: An observational study among 35,759 adults from 3 US cohorts.

Both genetic and lifestyle factors contribute to the risk of type 2 diabetes, but the extent to which there is a synergistic effect of the 2 factors is unclear. The aim of this study was to examine the joint associations of genetic risk and diet quality with incident type 2 diabetes. We analyzed data from 35,759 men and women in the United States participating in the Nurses' Health Study (NHS) I (1986 to 2016) and II (1991 to 2017) and the Health Professionals Follow-up Study (HPFS; 1986 to 2016) with available genetic data and who did not have diabetes, cardiovascular disease, or cancer at baseline. Genetic risk was characterized using both a global polygenic score capturing overall genetic risk and pathway-specific polygenic scores denoting distinct pathophysiological mechanisms. Diet quality was assessed using the Alternate Healthy Eating Index (AHEI). Cox models were used to calculate hazard ratios (HRs) for type 2 diabetes after adjusting for potential confounders. With over 902,386 person-years of follow-up, 4,433 participants were diagnosed with type 2 diabetes. The relative risk of type 2 diabetes was 1.29 (95% confidence interval [CI] 1.25, 1.32; P < 0.001) per standard deviation (SD) increase in global polygenic score and 1.13 (1.09, 1.17; P < 0.001) per 10-unit decrease in AHEI. Irrespective of genetic risk, low diet quality, as compared to high diet quality, was associated with approximately 30% increased risk of type 2 diabetes (Pinteraction = 0.69). The joint association of low diet quality and increased genetic risk was similar to the sum of the risk associated with each factor alone (Pinteraction = 0.30). Limitations of this study include the self-report of diet information and possible bias resulting from inclusion of highly educated participants with available genetic data. These data provide evidence for the independent associations of genetic risk and diet quality with incident type 2 diabetes and suggest that a healthy diet is associated with lower diabetes risk across all levels of genetic risk.

Association of animal and plant protein intakes with biomarkers of insulin and insulin-like growth factor axis

Insulin and insulin-like growth factor (IGF)-1 signaling is a proposed mechanism linking dietary protein and major chronic diseases. However, it is unclear whether animal and plant proteins are associated with biomarkers of insulin and IGF axis. We analyzed a total of 14,709 participants from Nurses' Health Study and Health Professionals Follow-up Study who had provided a blood sample. Detailed dietary information was assessed using validated food frequency questionnaires. We assessed C-peptide, insulin, IGF-1, and IGF binding proteins (BP). Multivariable-adjusted linear regressions were used to examine associations of animal and plant protein intake with biomarkers after adjusting for confounders. The medians (5th-95th percentiles) of animal and plant protein intake (% of total energy) were 13% (8-19%) and 5% (4-7%), respectively. Compared to participants in the lowest quintile, those in the highest quintile of animal protein had 4.8% (95% CI: 1.9, 7.9; P-trend<0.001) higher concentration of IGF-1 and -7.2% (95% CI:-14.8, 1.1; P for trend=0.03) and-11.8% (95% CI:-20.6,-1.9; P-trend<0.001) lower concentration of IGFBP-1 and IGFBP-2, respectively, after adjustment for major lifestyle factors and diet quality. In contrast, no association was observed between animal protein intake and C-peptide, insulin and IGFBP-3. The associations were restricted to participants with at least one unhealthy lifestyle risk factor (i.e., overweight/obese, physical inactivity, smoking, and heavy alcohol intake). Plant protein tended to be strongly associated with numerous biomarkers in age-adjusted analyses but these became largely attenuated or non-significant in multivariable adjustment. Plant protein intake remained positively associated with IGF-1 (P-trend=0.002) and possibly IGFBP-1 (P-trend=0.02) after multivariable adjustment. Substitution of plant protein with animal protein sources was associated with lower IGFBP-1. In additional analysis, IGF-1 and IGFBPs were estimated to mediate approximately 5-20% of the association between animal protein and type 2 diabetes. Higher animal protein intake was associated with higher IGF-1 and lower IGFBP-1 and IGFBP-2, whereas higher plant protein intake was associated with higher IGF-1 and IGFBP-1.

Plasma metabolite profiles related to plant-based diets and the risk of type 2 diabetes.

Plant-based diets, especially when rich in healthy plant foods, have been associated with a lower risk of type 2 diabetes. However, whether plasma metabolite profiles related to plant-based diets reflect this association was unknown. The aim of this study was to identify the plasma metabolite profiles related to plant-based diets, and to evaluate the associations between the identified metabolite profiles and the risk of type 2 diabetes. Within three prospective cohorts (Nurses' Health Study, Nurses' Health Study II and Health Professionals Follow-up Study), we measured plasma metabolites from 10,684 participants using high-throughput LC MS. Adherence to plant-based diets was assessed by three indices derived from the food frequency questionnaire: an overall Plant-based Diet Index (PDI), a Healthy Plant-based Diet Index (hPDI), and an Unhealthy Plant-based Diet Index (uPDI). Multi-metabolite profiles related to plant-based diet were identified using elastic net regression with a training/testing approach. The prospective associations between metabolite profiles and incident type 2 diabetes were evaluated using multivariable Cox proportional hazards regression. Metabolites potentially mediating the association between plant-based diets and type 2 diabetes risk were further identified. We identified multi-metabolite profiles comprising 55 metabolites for PDI, 93 metabolites for hPDI and 75 metabolites for uPDI. Metabolite profile scores based on the identified metabolite profiles were correlated with the corresponding diet index (Pearson r = 0.33-0.35 for PDI, 0.41-0.45 for hPDI, and 0.37-0.38 for uPDI, all p<0.001). Metabolite profile scores of PDI (HR per 1 SD higher = 0.81 [95% CI 0.75, 0.88]) and hPDI (HR per 1 SD higher = 0.77 [95% CI 0.71, 0.84]) showed an inverse association with incident type 2 diabetes, whereas the metabolite profile score for uPDI was not associated with the risk. Mutual adjustment for metabolites selected in the metabolite profiles, including trigonelline, hippurate, isoleucine and a subset of triacylglycerols, attenuated the associations of diet indices PDI and hPDI with lower type 2 diabetes risk. The explainable proportion of PDI/hPDI-related diabetes risk by these metabolites ranged between 8.5% and 37.2% (all p<0.05). Plasma metabolite profiles related to plant-based diets, especially a healthy plant-based diet, were associated with a lower risk of type 2 diabetes among a generally healthy population. Our findings support the beneficial role of healthy plant-based diets in diabetes prevention and provide new insights for future investigation.

Insulin Resistance, Hyperglycemia, and Risk of Developing Obstructive Sleep Apnea in Men and Women in the United States.

Rationale: Recent prospective studies suggest diabetes as a risk factor for the development of obstructive sleep apnea (OSA). However, the extent to which diabetes-related traits, such as hyperglycemia and insulin resistance, are related to OSA risk remains uncertain. Objectives: To examine the risk of developing OSA according to baseline concentrations of fasting insulin and hemoglobin A1c (HbA1c). Methods: Participants from four prospective U.S. cohorts were included: NHS (Nurses' Health Study; 2002-2012), NHSII (Nurses' Health Study II; 1995-2013), HPFS (Health Professionals Follow-up Study; 1996-2012), and MESA (Multi-Ethnic Study of Atherosclerosis; 2000-2012). OSA was assessed by self-reported clinical diagnosis in NHS/NHSII/HPFS and at-home polysomnography in MESA (defined as Apnea-Hypopnea Index ⩾30). Results: Of 9,283 participants with fasting insulin data, 790 (8.5%) developed OSA over 10 to 18 years of follow-up. After adjusting for sociodemographic, lifestyle, and comorbidity factors, the odds ratio for incident OSA comparing the extreme quintiles of fasting insulin was 3.59 (95% confidence interval, 2.67-4.82; P-trend < 0.0001). Of 6,342 participants with HbA1c data, 715 (11.3%) developed OSA. The comparable odds ratio for HbA1c was 2.21 (95% confidence interval, 1.69-2.89; P-trend < 0.0001). Additional adjustment for body mass index and waist circumference attenuated the associations for fasting insulin (P-trend = 0.005) and HbA1c (P-trend = 0.03). In the fully adjusted model simultaneously including both biomarkers, only fasting insulin but not HbA1c was associated with OSA risk. Conclusions: Independent of obesity, insulin resistance may play a more important role than hyperglycemia in the pathogenesis of OSA. Given the limitation of using self-reported diagnosis to exclude baseline prevalent OSA cases, additional studies are needed to further establish the temporal relationship and assess whether improving insulin resistance may reduce OSA risk.

Avocado Consumption and Risk of Cardiovascular Disease in US Adults.

BackgroundEpidemiologic studies on the relationship between avocado intake and long‐term cardiovascular disease (CVD) risk are lacking.Methods and ResultsThis study included 68 786 women from the NHS (Nurses’ Health Study) and 41 701 men from the HPFS (Health Professionals Follow‐up Study; 1986–2016) who were free of cancer, coronary heart disease, and stroke at baseline. Diet was assessed using validated food frequency questionnaires at baseline and then every 4 years. Cox proportional hazards regressions were used to estimate hazard ratios and 95% CIs. A total of 14 274 incident cases of CVD (9185 coronary heart disease events and 5290 strokes) were documented over 30 years of follow‐up. After adjusting for lifestyle and other dietary factors, compared with nonconsumers, those with analysis‐specific higher avocado intake (≥2 servings/week) had a 16% lower risk of CVD (pooled hazard ratio, 0.84; 95% CI, 0.75–0.95) and a 21% lower risk of coronary heart disease (pooled hazard ratio, 0.79; 95% CI, 0.68–0.91). No significant associations were observed for stroke. Per each half serving/day increase in avocado intake, the pooled hazard ratio for CVD was 0.80 (95% CI, 0.71–0.91). Replacing half a serving/day of margarine, butter, egg, yogurt, cheese, or processed meats with the equivalent amount of avocado was associated with a 16% to 22% lower risk of CVD.ConclusionsHigher avocado intake was associated with lower risk of CVD and coronary heart disease in 2 large prospective cohorts of US men and women. The replacement of certain fat‐containing foods with avocado could lead to lower risk of CVD.

Healthy Lifestyle Score Including Sleep Duration and Cardiovascular Disease Risk

Although insufficient or prolonged sleep duration is associated with cardiovascular disease, sleep duration is not included in most lifestyle scores. This study evaluates the relationship between a lifestyle score, including sleep duration and cardiovascular disease risk. A prospective analysis among 67,250 women in the Nurses' Health Study and 29,114 men in Health Professionals Follow-up Study (1986-2016) was conducted in 2021. Lifestyle factors were updated every 2-4 years using self-reported questionnaires. The traditional lifestyle score was defined as not smoking, having a normal BMI, being physically active (≥30 minutes/day of moderate physical activity), eating a healthy diet, and drinking alcohol in moderation. Low-risk sleep duration, defined as sleeping ≥6 to <8 hours/day, was included as an additional component in the updated lifestyle score. Cox proportional hazard regression models were used to estimate cardiovascular disease risk. The likelihood-ratio test and C-statistics were used to compare both scores. A total of 11,710 incident cardiovascular disease cases during follow-up were documented. The multivariable-adjusted hazard ratios comparing 6 with 0 low-risk factors in the healthy lifestyle score including sleep duration were 0.17 (95% CI=0.12, 0.23) for cardiovascular disease, 0.14 (95% CI=0.10, 0.21) for coronary heart disease, and 0.20 (95% CI=0.12, 0.33) for stroke. Approximately 66% (95% CI=56%, 75%) of cardiovascular disease, 67% (95% CI=54%, 77%) of coronary heart disease, and 62% (95% CI=42%, 76%) of stroke cases were attributable to poor adherence to a healthy lifestyle including sleep. Adding sleep duration to the score slightly increased the C-statistics from 0.64 (95% CI=0.63, 0.64) to 0.65 (95% CI=0.64, 0.65) (p<0.001). Adopting a healthy lifestyle including sleep recommendations could substantially reduce the risk of cardiovascular disease in U.S. adults.

5-Alpha Reductase Inhibitors and Prostate Cancer Mortality among Men with Regular Access to Screening and Health Care.

How 5-alpha reductase inhibitor (5-ARI) use influences prostate cancer mortality is unclear. The objective of this study was to determine whether men taking 5-ARIs with regular health care access have increased prostate cancer mortality. We undertook two analyses in the Health Professionals Follow-up Study examining 5-ARI use, determined by biennial questionnaires, and prostate cancer. A cohort analysis followed 38,037 cancer-free men for prostate cancer incidence from 1996 through January 2017 and mortality through January 2019. A case-only analysis followed 4,383 men with localized/locally advanced prostate cancer for mortality over a similar period. HRs and 95% confidence intervals (CI) were calculated for prostate cancer incidence and mortality. Men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Over 20 years of follow-up, 509 men developed lethal disease (metastases or prostate cancer death). Among men initially free from prostate cancer, 5-ARI use was not associated with developing lethal disease [HR, 1.02; 95% confidence interval (CI), 0.71-1.46], but was associated with reduced rates of overall and localized disease (HR, 0.71; 0.60-0.83). Among men diagnosed with prostate cancer, there was no association between 5-ARI use and cancer-specific (HR, 0.78; 95% CI, 0.48-1.27) or overall survival (HR, 0.88; 95% CI, 0.72-1.07). Men using 5-ARIs were less likely to be diagnosed with low-risk prostate cancer, without increasing long-term risk of lethal prostate cancer or cancer-specific death after diagnosis. Our results provide evidence that 5-ARI use is safe with respect to prostate cancer mortality in the context of regular health care access. See related commentary by Hamilton, p. 1259.