Meat consumption and the risk of hip fracture in women and men: two prospective Swedish cohort studies.

PURPOSE: To study the association between meat intake (predominantly red and processed meats) and the risk of hip fracture, as well as the association between meat intake and biomarkers of inflammation, oxidative stress, bone turnover, body composition, and bone mineral density (BMD). METHODS: Data from the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men) with repeated investigations and their respective clinical sub-cohorts was utilised. Incident hip fractures were ascertained through individual linkage to registers. Associations were investigated using multivariable Cox and linear regression analyses. RESULTS: During up to 23 years of follow-up (mean 18.2 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. Each daily serving of meat intake conferred a hazard ratio (HR) of 1.03 (95% confidence interval [CI] 1.00; 1.06) for hip fracture. In quintile 5, compared to quintile 2, the HR was 1.11 (95% CI 1.01; 1.21) among all participants. In the sub-cohorts, meat intake was directly associated with circulating levels of interleukin-6, C-reactive protein, leptin, ferritin, parathyroid hormone, and calcium. CONCLUSION: A modest linear association was found between a higher meat intake and the risk of hip fractures. Our results from the sub-cohorts further suggest that possible mechanisms linking meat intake and hip fracture risk may be related to the regulation of bone turnover, subclinical inflammation, and oxidative stress. Although estimates are modest, limiting red and processed meat intake in a healthy diet is advisable to prevent hip fractures.

Risk of Cancer in Patients With Diverticular Disease: A Population-Based Cohort Study.

BACKGROUND & AIMS: Several studies have investigated the association between diverticular disease (DD) and colorectal cancer. However, whether there is an association between DD and malignancies other than those in the colorectum remains uncertain. METHODS: For the 1978-2019 period, we conducted a nationwide, population-based cohort study using national Danish health care data. We followed patients with DD for up to 20 years, beginning 1 year after the date of DD diagnosis until the first occurrence of incident cancer, emigration, death, 20 years of follow-up, or December 31, 2019. We calculated cumulative incidence proportions of cancer and standardized incidence ratios (SIRs) comparing cancer incidence among patients with DD with that in the general population. RESULTS: We identified 200,639 patients with DD, of whom 20,498 were diagnosed with cancer during the 1-20 years after their DD diagnosis. The SIRs were increased for most cancer sites except for those in the colorectum (SIR, 0.75; 95% confidence interval, 0.72-0.78). The highest SIRs were observed for cancers of the lung, bronchi, and trachea (SIR, 1.20; 95% confidence interval, 1.15-1.24) and kidney (SIR, 1.27; 95% confidence interval, 1.16-1.39). CONCLUSIONS: Our findings show an increased long-term relative risk of cancer following a diagnosis of DD. These findings are likely caused by prevalence of numerous risk factors in patients with DD that confer an increased risk of cancer. The decreased relative risk of colorectal cancer might be explained by an increased likelihood of patients with DD undergoing colonoscopy with polypectomy.

Declining hip fracture burden in Sweden 1998-2019 and consequences for projections through 2050.

We aimed to estimate the absolute and age-standardized number of hip fractures in Sweden during the past two decades to produce time trends and future projections. We used nationwide register data from 1998 to 2019 and a validated algorithm to calculate the annual absolute and age-standardized number of incident hip fractures over time. The total hip fracture burden was 335,399 incident events over the 22 years, with a change from 16,180 in 1998 to 13,929 in 2019, a 14% decrease. One decade after the index hip fracture event, 80% of the patients had died, and 11% had a new hip fracture. After considering the steady growth of the older population, the decline in the age-standardized number of hip fractures from 1998 through 2019 was 29.2% (95% CI 28.1-30.2%) in women and 29.3% (95% CI 27.5-30.7%) in men. With a continued similar reduction in hip fracture incidence, we can predict that 14,800 hip fractures will occur in 2034 and 12,000 in 2050 despite doubling the oldest old (≥ 80 years). Without an algorithm, a naïve estimate of the total number of hip fractures over the study period was 539,947, with a second 10-year hip fracture risk of 35%. We note an ongoing decline in the absolute and age-standardized actual number of hip fractures in Sweden, with consequences for future projections.

Comprehensive analyses of circulating cardiometabolic proteins and objective measures of fat mass.

BACKGROUND: The underlying molecular pathways for the effect of excess fat mass on cardiometabolic diseases is not well understood. Since body mass index is a suboptimal measure of body fat content, we investigated the relationship of fat mass measured by dual-energy X-ray absorptiometry with circulating cardiometabolic proteins. METHODS: We used data from a population-based cohort of 4950 Swedish women (55-85 years), divided into discovery and replication samples; 276 proteins were assessed with three Olink Proseek Multiplex panels. We used random forest to identify the most relevant biomarker candidates related to fat mass index (FMI), multivariable linear regression to further investigate the associations between FMI characteristics and circulating proteins adjusted for potential confounders, and principal component analysis (PCA) for the detection of common covariance patterns among the proteins. RESULTS: Total FMI was associated with 66 proteins following adjustment for multiple testing in discovery and replication multivariable analyses. Five proteins not previously associated with body size were associated with either lower FMI (calsyntenin-2 (CLSTN2), kallikrein-10 (KLK10)), or higher FMI (scavenger receptor cysteine-rich domain-containing group B protein (SSC4D), trem-like transcript 2 protein (TLT-2), and interleukin-6 receptor subunit alpha (IL-6RA)). PCA provided an efficient summary of the main variation in FMI-related circulating proteins involved in glucose and lipid metabolism, appetite regulation, adipocyte differentiation, immune response and inflammation. Similar patterns were observed for regional fat mass measures. CONCLUSIONS: This is the first large study showing associations between fat mass and circulating cardiometabolic proteins. Proteins not previously linked to body size are implicated in modulation of postsynaptic signals, inflammation, and carcinogenesis.

Calcium Supplements and Risk of CVD: A Meta-Analysis of Randomized Trials.

Background: Vitamin D supplements may only be beneficial for the prevention of osteoporotic fractures when administered with calcium and in individuals with low blood levels of 25(OH)D, but possible hazards of calcium supplements on CVD cannot be excluded. Objectives: We conducted a meta-analysis of all placebo-controlled randomized trials assessing the effects of calcium supplements alone or with vitamin D on CHD, stroke, and all-cause mortality. Methods: A meta-analysis of 11 trials included 7 comparisons of calcium alone compared with control (n = 8634) and 6 comparisons of calcium plus vitamin D compared with control (n = 46,804). Aggregated study-level data were obtained from individual trials and combined using a fixed-effects meta-analysis. The main outcomes included MI, CHD death, any CHD, stroke, and all-cause mortality. Results: Among trials of calcium alone (mean daily dose 1 g), calcium was not significantly associated with any excess risk of MI (RR, 1.15; 95% CI: 0.88, 1.51; n = 219 events), CHD death (RR, 1.24; 95% CI: 0.89, 1.73; n = 142), any CHD (RR, 1.01; 95% CI: 0.75, 1.37; n = 177), or stroke (RR, 1.15; 95% CI, 0.90, 1.46, n = 275). Among 6 trials of combined treatment, supplementation with calcium plus vitamin D was not significantly associated with any excess risk of MI (RR, 1.09; 95% CI: 0.95, 1.25; n = 854), CHD death (RR, 1.04; 95% CI: 0.85, 1.27; n = 391), any CHD (RR, 1.05; 95% CI: 0.93, 1.19; n = 1061), or stroke (RR, 1.02; 95% CI: 0.89, 1.17; n = 885). Likewise, calcium alone, or with vitamin D had no significant associations with all-cause mortality. Conclusions: This meta-analysis demonstrated that calcium supplements were not associated with any significant hazard for CHD, stroke, or all-cause mortality and excluded excess risks above 0.3%-0.5% per year for CHD or stroke. Further trials of calcium and vitamin D are required in individuals with low blood levels of 25(OH)D for the prevention of fracture and other disease outcomes.

Swedish Snuff (Snus), Cigarette Smoking, and Risk of Type 2 Diabetes.

INTRODUCTION: Cigarette smoking is a known risk factor for Type 2 diabetes, but evidence regarding former smoking and moist snuff (snus) use and Type 2 diabetes risk is inconclusive. This study investigated the relationships of cigarette smoking and Swedish snus use with the risk of Type 2 diabetes in a cohort of middle-aged and elderly participants. METHODS: Participants (N=36,742; age range=56-95 years) were followed for incident Type 2 diabetes and death between 2009 and 2017 through linkage to the Swedish National Patient, Prescribed Drug and Death Registers. Cox proportional hazards regression was used to obtain hazard ratios and 95% CIs adjusted for potential confounders, including physical activity, education, BMI, and alcohol intake. Analyses were conducted in 2021‒2022. RESULTS: Former and current smoking was associated with an increased risk of Type 2 diabetes (hazard ratios [95% CI]=1.17 [1.07, 1.29] and 1.57 [1.36, 1.81], respectively). In those who stopped smoking, Type 2 diabetes risk remained elevated up to approximately 15 years after cessation. In participants who have never smoked, snus use was linked to a higher risk of Type 2 diabetes in the model adjusted for age and sex (hazard ratio [95% CI]=1.49 [1.04, 2.15]), but this was attenuated after multivariable adjustment (hazard ratio [95% Cl]=1.29 [0.89, 1.86]). CONCLUSIONS: This study indicates that current and former smoking are associated with an increased risk of Type 2 diabetes in middle-aged and older individuals. There was less evidence of an association of snus use with the risk of Type 2 diabetes, suggesting that compounds other than nicotine may underlie the detrimental association of smoking with the risk of Type 2 diabetes.

Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort.

BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.

Impact of Common Vitamin D-Binding Protein Isoforms on Supplemental Vitamin D3 and/or Calcium Effects on Colorectal Adenoma Recurrence Risk: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Variants in the vitamin D-binding protein (DBP) gene (GC) encode DBP isoforms that may affect vitamin D metabolism. However, whether these isoforms modify the effects of vitamin D3 and/or calcium supplementation on colorectal adenoma recurrence is unclear. We hypothesized that supplementation effects may be stronger among those with the DBP2 isoform (encoded by the rs4588*A allele), which is associated with vitamin D deficiency and modified the associations of circulating vitamin D with risk for colorectal neoplasms in observational studies. Objective: To estimate supplemental vitamin D3 and/or calcium effects on colorectal adenoma recurrence according to 3 common DBP isoforms (DBP1s, DBP1f, DBP2) encoded by 2 missense variants: rs7041 (NG_012837.3:g.57904T>G NP_001191235.1:p.Asp432Glu) and rs4588 (NG_012837.3:g.57915C>A NP_001191235.1:p.Thr436Lys). Design, Setting, and Participants: Secondary analysis of a randomized, double-blind, placebo-controlled clinical trial of 2259 participants with a recently diagnosed adenoma and no remaining polyps after complete colonoscopy in the US from July 1, 2004, to August 31, 2013. The current analyses were performed from August 12, 2019, to July 16, 2022. Interventions: Daily vitamin D3 (1000 IU), calcium (1200 mg), both, or placebo. Main Outcomes and Measures: One or more adenomas diagnosed during 3 to 5 years of follow-up. Treatment effects were estimated according to DBP isoform as risk ratios (RRs) and 95% CIs using Poisson regression analysis. Results: Of the 2259 participants randomized (mean [SD] age, 58 [6.8] years; 1033 [64%] men), 1604 non-Hispanic White participants (chosen to avoid population stratification bias) were included in the analysis. Among those with the DBP2 isoform (rs4588*AC or AA), the RRs (95% CI) for adenoma recurrence were 0.84 (0.72-1.00) with vitamin D3 relative to no vitamin D3, 0.83 (95% CI, 0.70-0.99) with calcium relative to no calcium, and 0.76 (95% CI, 0.59-0.98) with both agents relative to neither agent. Conversely, among those without DBP2 (rs4588*CC), the corresponding values were 1.08 (95% CI, 0.93-1.26; P = .03 for interaction) with vitamin D3 relative to no vitamin D3, 0.98 (95% CI, 0.84-1.14; P = .37 for interaction) with calcium relative to no calcium, and 1.09 (0.88-1.36; P = .03 for interaction) with both agents relative to neither agent. Among DBP2 homozygotes (rs4588*AA), the RR for adenoma recurrence was 0.57 (95% CI, 0.31-1.08) with both agents relative to neither agent. Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that individuals with the DBP2 isoform-encoding rs4588*A allele may particularly benefit from vitamin D3 and/or calcium supplementation for colorectal adenoma prevention. Trial Registration: ClinicalTrials.gov Identifier: NCT00153816.

Healthcare system engagement and algorithm-identified cancer incidence following initiation of a new medication.

PURPOSE: Implausibly high algorithm-identified cancer incidence within a new user study after medication initiation may result from increased healthcare utilization (HU) around initiation ("catch-up care") that increases diagnostic opportunity. Understanding the relationships between HU prior to and around initiation and subsequent cancer rates and timing is important to avoiding protopathic bias. METHODS: We identified a cohort of 417 458 Medicare beneficiaries (2007-2014) aged ≥66 initiating an antihypertensive (AHT) after ≥180 days of non-use. Initiators were stratified into groups of 0, 1, 2-3, and ≥4 outpatient visits (OV) 60-360 days before initiation. We calculated algorithm-identified colorectal cancer (aiCRC) rates stratified by OVs and time since AHT initiation: (0-90, 91-180, 181-365, 366-730, and 731+ days). We summarized HU -360/+60 days around AHT initiation by aiCRC timing: (0-29, 30-89, 90-179, and ≥180 days). RESULTS: AiCRC incidence (311 per 100 000 overall) peaked in the first 0-90 days, was inversely associated with HU before initiation, and stabilized ≥180 days after AHT initiation. Catch-up care was greatest among persons with aiCRCs identified <30 days in follow-up. Catch-up care magnitude decreased as time to the aiCRC date increased, with aiCRCs identified ≥180 days after AHT initiation exhibiting similar HU compared with the full cohort. CONCLUSION: Lower HU before-and increased HU around AHT initiation-seem to drive excess short-term aiCRC incidence. Person-time and case accrual should only begin when incidence stabilizes. When comparison groups within a study differ by HU, outcome-detection bias may exist. Similar observations may exist in other settings when typical HU is delayed (e.g., cancer screening during SARS-CoV-2).

Anger frequency and risk of cardiovascular morbidity and mortality.

Aims: Anger may increase the risk of cardiovascular diseases (CVDs) but previous findings are inconclusive and large prospective studies are needed. We investigated whether frequency of strong anger is associated with the incidence of specific CVDs and CVD mortality, and if sex, age, and cardiometabolic risk factors modify these associations. Methods and results: We used data from a population-based cohort of 47 077 Swedish adults (56-94 years of age) who completed questionnaires regarding their experience of anger, lifestyle habits, and health characteristics. Participants were followed for incident cardiovascular outcomes and death up to 9 years through linkage to the Swedish National Patient and Death Registers. Hazard ratios and confidence intervals adjusted for potential confounders were assessed.In multivariable analyses, frequent episodes of strong anger were associated with an increased risk of heart failure, atrial fibrillation, and CVD mortality [hazard ratios (95% confidence intervals) = 1.19 (1.04-1.37), 1.16 (1.06-1.28), and 1.23 (1.09-1.40), respectively]. The link between anger frequency and heart failure was more pronounced in men and participants with a history of diabetes. No evidence of an independent association of anger frequency with risk of myocardial infarction, aortic valve stenosis, and abdominal aortic aneurysm was found. Conclusion: Our findings indicate that anger may contribute to the development of specific CVDs and CVD mortality, especially heart failure in men and in those with diabetes.

Self-reported symptoms of sleep-disordered breathing and risk of cardiovascular diseases: Observational and Mendelian randomization findings.

Sleep-disordered breathing may increase the risk of cardiovascular diseases, but observational findings are inconclusive. We investigated whether sleep-disordered breathing-related symptoms are associated with risk of several cardiovascular diseases using data from a cohort study and by performing Mendelian randomization analyses. The cohort study included 43,624 adults (56-94 years old) who completed questionnaires regarding symptoms of snoring and cessation of breathing, lifestyle habits and health characteristics. Participants were followed up for incident cardiovascular diseases and death over 8 years through linkage to the Swedish National Patient and Death Registers. The Mendelian randomization analyses were conducted using single-nucleotide polymorphisms robustly associated with sleep apnea in a recent genome-wide association study and summary-level data for major cardiovascular diseases from large-scale consortia. In the cohort study, an increased risk of atrial fibrillation was observed in participants who reported both snoring and cessation of breathing (hazard ratio [95% confidence interval] = 1.16 [1.03-1.30]) compared with those without sleep-disordered breathing symptoms. There was no association between sleep-disordered breathing symptoms and risk of myocardial infarction, heart failure, aortic valve stenosis or abdominal aortic aneurysm in multivariable analyses. Mendelian randomization analyses showed no association of genetic liability to sleep apnea with myocardial infarction, heart failure or atrial fibrillation, but revealed a suggestive association with coronary artery disease (odds ratio [95% confidence interval] = 1.24 [1.02-1.52]).

Plasma Metabolomics Analysis of Aspirin Treatment and Risk of Colorectal Adenomas.

Despite substantial observational and experimental evidence that aspirin use can provide protection against the development of colorectal neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of aspirin. Associations between levels of metabolic features in plasma and aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of aspirin (81 or 325 mg/day) and were linked to risk of colorectal adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with aspirin treatment included linoleate and glycerophospholipid metabolism for the 81-mg dose and carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day aspirin treatment and were also associated with decreased risk of adenomas during follow-up included certain forms of lysophosphatidylcholine and lysophosphatidylethanolamine as well as trihydroxyoctadecenoic acid, which is a derivative of linoleic acid and is upstream of cyclooxygenase inhibition by aspirin in the linoleate and arachidonic acid metabolism pathways. In conclusion, our findings regarding lysophospholipids and metabolites in the linoleate metabolism pathway may provide novel insights into the chemopreventive effects of aspirin in the colorectum, although they should be considered hypothesis-generating at this time. PREVENTION RELEVANCE: This research used metabolomics, an innovative discovery-based approach, to identify molecular changes in human blood that may help to explain how aspirin use reduces the risk of colorectal neoplasia in some individuals. Ultimately, this work could have important implications for optimizing aspirin use in the prevention of colorectal cancer.

Predictors of Incident Serrated Polyps: Results from a Large Multicenter Clinical Trial.

BACKGROUND: Serrated polyps (SP) are important colorectal cancer precursors, yet their epidemiology is incompletely understood. We measured risk factors for incident sessile-serrated lesions (SSL) and microvesicular (MVHP) and goblet-cell rich (GCHP) hyperplastic polyp subtypes. METHODS: We conducted a cohort study of patients undergoing colonoscopic surveillance nested within a chemoprevention trial. Outcomes of interest were ≥1 SPs, including SSLs, MVHPs, and GCHPs specifically. Multivariable generalized estimating equation models were used to estimate adjusted risk ratios (RR) and 95% confidence intervals (CI) for different polyp types. RESULTS: Among 2,102 participants, a total of 1,615 SPs (including 212 SSLs) were found among 758 participants during follow-up. Prior history of SPs was strongly associated with subsequent occurrence of SPs. There was no apparent association between age, sex, or education and risk of SPs. Black participants were at lower risk of SSLs and MVHPs, but higher risk of GCHPs compared with white participants [RR, 0.40; 95% CI, 0.16-0.99); RR, 0.63 (95% CI, 0.42-0.96); and RR, 1.83 (95% CI, 1.23-2.72) respectively]. Alcohol and smoking exposure were also associated with SPs, including hyperplastic polyp subtypes in particular. CONCLUSIONS: In this prospective study, the risk of SP subtypes differed by race, alcohol, and smoking status, and prior history of SPs. Risk factor associations for SPs differ from risk factors for conventional adenomas, supporting the concept of etiologic heterogeneity of colorectal cancer. IMPACT: These findings allow for better risk stratification of patients undergoing colorectal cancer screening and could inform screening test selection.

Association of demographic and health characteristics with circulating oxysterol concentrations.

BACKGOUND: Circulating oxysterols, cholesterol metabolites with important signaling functions, are increasingly being recognized as candidate biomarkers for several diseases, but associations with demographic and health characteristics remain poorly described. OBJECTIVE: This study aims to characterize associations of major circulating oxysterols with sex, age, race/ethnicity, body mass index (BMI), lifestyle factors, and use of common medications. METHODS: We measured plasma concentrations of 27-hydroxycholesterol (27-OHC), 25-hydroxycholesterol (25-OHC), 24(S)-hydroxycholesterol (24(S)-OHC), 7ɑ-hydroxycholesterol (7ɑ-OHC), and 4ß-hydroxycholesterol (4ß-OHC) from 1,440 participants of a completed clinical trial for the chemoprevention of colorectal adenomas. Adjusted percent difference in means were calculated using linear regression. RESULTS: Women had 18% (95% CI, 14%, 22%) lower 27-OHC and 21% (15%, 27%) higher 4ß-OHC than men. Blacks had 15% (7%, 23%) higher 4ß-OHC than Non-Hispanic Whites, and Asian or Pacific Islanders had 19% (2%, 35%) higher 7ɑ-OHC than Non-Hispanic Whites. Individuals of BMI ≥35 kg/m2 had 33% (25%, 41%) lower 4ß-OHC than those <25 kg/m2. Current smokers had 15% (5%, 24%) higher 7ɑ-OHC than never smokers, and daily alcohol drinkers had 17% (10%, 24%) higher 7ɑ-OHC than never drinkers. Statin use was associated with lower concentrations of all 5 oxysterols. Differences in mean <15% were found for characteristics such as age, total dietary energy intake, physical activity, diabetes, and anti-inflammatory drug use. CONCLUSION: Circulating oxysterols are uniquely associated with multiple demographic and health characteristics.

The impact and causal directions for the associations between diagnosis of ADHD, socioeconomic status, and intelligence by use of a bi-directional two-sample Mendelian randomization design.

BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder (ADHD) and lower socioeconomic status and intelligence. We aimed to evaluate the causal directions and strengths for these associations by use of a bi-directional two-sample Mendelian randomization (MR) design. METHODS: We used summary-level data from the largest available genome-wide association studies (GWAS) to identify genetic instruments for ADHD, intelligence, and markers of socioeconomic status including the Townsend deprivation index, household income, and educational attainment. Effect estimates from individual genetic variants were combined using inverse-variance weighted regression. RESULTS: A genetically predicted one standard deviation (SD) increment in the Townsend deprivation index conferred an odds ratio (OR) of 5.29 (95% confidence interval (CI) 1.89-14.76) for an ADHD diagnosis (p<0.001). A genetically predicted one SD higher education level conferred an OR of 0.30 (95% CI 0.25-0.37) (p<0.001), and a genetically predicted one SD higher family income provided an OR of 0.35 (95% CI 0.25-0.49; p<0.001). The associations remained after adjustment for intelligence whereas the lower odds of an ADHD diagnosis with higher intelligence did not persist after adjustment for liability to greater educational attainment (adjusted OR 1.03, 95% CI 0.68-1.56; p=0.87). The MR analysis of the effect of ADHD on socioeconomic markers found that genetic liability to ADHD was statistically associated with each of them (p<0.001) but not intelligence. However, the average change in the socioeconomic markers per doubling of the prevalence of ADHD corresponded only to 0.05-0.06 SD changes. CONCLUSIONS: Our results indicate that an ADHD diagnosis may be a direct and strong intelligence-independent consequence of socioeconomic related factors, whereas ADHD appears to lead only to modestly lowered socioeconomic status. Low intelligence seems not to be a major independent cause or consequence of ADHD.

Sleep-disordered breathing-related symptoms and risk of stroke: cohort study and Mendelian randomization analysis.

BACKGROUND: Sleep-disordered breathing (SDB) may contribute to development of stroke. However, findings are inconclusive. We investigated whether SDB-related symptoms are associated with incidence of stroke and its types in a general community sample of adult men and women as well as to perform Mendelian randomization (MR) analysis. METHODS: We used data from a cohort of 41,742 Swedish adults (56-94 years of age) who completed questionnaires regarding snoring, cessation of breathing, lifestyle and health characteristics. Participants were followed up for incident stroke and death over 8 years through linkage to the Swedish Registers. Hazard ratios, adjusted for potential confounders, were estimated by Cox proportional hazards regression. MR analyses were performed using single-nucleotide polymorphisms associated with sleep apnea at the genome-wide significance level and summary-level data for stroke and its subtypes from consortia and a meta-analysis of Genome-Wide Association Studies. RESULTS: In the cohort study, symptoms of disturbing snoring and/or cessation of breathing were associated with increased risk of total stroke (hazard ratio 1.12, 95% confidence interval 1.02-1.24) and intracerebral hemorrhage (hazard ratio 1.59, 95% confidence interval 1.23-2.05) but not with ischemic stroke or subarachnoid hemorrhage. MR analyses showed no association of genetic liability to sleep apnea with the risk of overall stroke or any specific types of stroke or ischemic stroke subtypes. CONCLUSIONS: SDB-related symptoms were associated with increased risk of total stroke, specifically intracerebral hemorrhage, in the observational analyses but not in the MR analyses. There was limited evidence of an association of SDB with ischemic stroke and subarachnoid hemorrhage.

Circulating Sex Hormones and Risk of Colorectal Adenomas and Serrated Lesions in Men.

BACKGROUND: Sex hormones have been implicated in the etiology of colorectal neoplasia in women for over 40 years, but there has been very little investigation of the role of these hormones in men. METHODS: Using data from an adenoma chemoprevention trial, we conducted a secondary analysis to examine serum hormone levels [testosterone, androstenedione, DHEA sulfate (DHEAS), and sex hormone binding globulin (SHBG)] and risk of colorectal precursors in 925 men. Multivariable logistic regression models were fit to evaluate adjusted associations between hormone levels and risk of "low-risk" (single tubular adenoma < 1 cm) and "high-risk" lesions (advanced adenoma or sessile serrated adenoma or right-sided serrated polyp or >2 adenomas of any size). RESULTS: Overall, levels of free testosterone, total testosterone, androstenedione, DHEAS, or SHBG were not associated with either "low-risk" or "high-risk" early precursor lesions in the colorectum. CONCLUSIONS: These findings do not support the role of sex hormones in early colorectal neoplasia among men. IMPACT: This large prospective study address a missing gap in knowledge by providing information on the role of sex hormones in colorectal neoplasia in males.

Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.

Proliferation, apoptosis and their regulatory protein expression in colorectal adenomas and serrated lesions.

BACKGROUND: Adenomas and serrated lesions represent heterogeneous sets of early precursors in the colorectum with varying malignant potential. They are often distinguished by their histopathologic differences, but little is known about potential differences in regulation of epithelial proliferation and apoptosis. METHODS: We conducted a protein expression analysis using tissue microarrays of 625 colorectal adenomas and 142 serrated lesions to determine potential differences in regulation of epithelial proliferation and apoptosis. We quantitated proliferation with Ki-67; apoptosis with activated caspase-3 (CASP3); up- and down-regulators of proliferation with cyclin D1, p16INK2, and p21Cip1; and apoptosis regulators with BAX, BCL2, and survivin. Linear mixed effects models and circos diagrams were used to determine relationships among expression and lesion characteristics. RESULTS: Adenomas had a significantly higher CASP-3 labeling index (LI) than serrated lesions, resulting in a lower net growth ratio (Ki-67 LI/activated CASP-3 LI, p-value<0.0001). Cyclin D1 LI, p16 LI and p21 LI were lower in adenomas compared to serrated lesions, while expression of both BCL2 and BAX were higher (p <0.001). Among adenomas, cyclin D1 LI and p16 LI levels increased with greater villous component, and the highest BAX expression was detected in adenomas larger than 2 cm (both p<0.0001). Right-sided adenomas had higher CASP3 LI than left colorectal adenomas (p = 0.008). Significant differences in cyclin D1 LI, p21 LI and survivin LI were also observed across histopathologic subtypes of serrated lesions. CONCLUSIONS: Our findings demonstrate different patterns of regulatory protein expression in adenomas than serrated lesions, especially involving apoptosis. ClinicalTrials.gov Identifier: NCT00272324.