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This study aimed to investigate the association between residential greenness and tinnitus and the potential interaction between greenness and genetic predisposition to tinnitus. The normalized difference vegetation index (NDVI) is used to measure residential greenness. The tinnitus is defined based on self‐reported. In the cross‐sectional analyses, logistic regression models are used for the baseline sample of the United Kingdom Biobank cohort. In the secondary analysis, a Cox proportional hazard model is used for a subsample of participants who completed the tinnitus questionnaire at follow‐up. In the cross‐sectional analysis including 106471 participants, higher residential greenness is associated with lower odds of tinnitus for each interquartile range increase in continuous NDVI, with an adjusted odds ratio of 0.97 (95% confidence interval: 0.95 to 0.99) for tinnitus. A similar association is observed in the longitudinal analysis, with an adjusted hazard ratio of 0.92 (95% confidence interval: 0.86 to 0.98) for the association of NDVI increased per interquartile range with incident tinnitus. Moreover, there is a significant interaction between greenness and genetic predisposition to tinnitus (P < 0.05). This study suggested that residential greenness is negatively associated with tinnitus. Greenness and genetic predisposition to tinnitus are found to have a significant interaction. [ABSTRACT FROM AUTHOR]

Objective: Evidence on the individual and combined relationship of physical activity (PA) and fish oil supplement use on the incidence of Parkinson's disease (PD) risk remains lacking. Materials and methods: This UK population-based prospective cohort study, involving 385,275 UK Biobank participants, collected PA and fish oil supplement data via touchscreen questionnaires. Using Cox proportional hazards models and restricted cubic splines to examined the associations between use of fish oil supplements, PA and PD risk. Results: During a median 12.52-year follow-up, 2,131 participants incident PD. Analysis showed that fish oil supplement users had a lower PD risk [hazard ratio (HR), 0.89; 95% confidence interval (CI), 0.82-0.98]. The adjusted HRs for the PD incidence were 0.96 (95% CI, 0.95-0.98) for total PA; 0.93 (95% CI, 0.90-0.96) for moderate PA; 0.95 (95% CI, 0.91-0.99) for vigorous PA and 0.93 (95% CI, 0.89-0.98) for walking activity. Significant interactions were found between fish oil supplement use and total PA (P for interaction = 0.011), moderate PA (P for interaction = 0.015), and walking activity (P for interaction = 0.029) in relation to PD incidence. Conclusion: Both fish oil supplement use and PA were associated with a reduced risk of PD, and the effect of PA in reducing the risk of PD was more pronounced when fish oil supplement was used. [ABSTRACT FROM AUTHOR]

The impact of polysocial risk score (PsRS), a composite measure of multiple social risk factors, on the development of psoriasis remains unclear. Moreover, the potential modifying effects of lifestyle and genetic susceptibility on the relationship between PsRS and psoriasis risk require further exploration. This was a prospective cohort study conducted among UK Biobank. In this study, we analyzed 331,631 participants enrolled in the UK Biobank cohort. To derive the PsRS, we utilized a summative strategy, amalgamating six social determinants of health derived from three domains: socio-economic status, psychosocial factors, and neighborhood and living environment consistently linked to incident psoriasis. Cox proportional hazard models were used to assess the associations between PsRS and psoriasis incidence. Furthermore, we constructed a lifestyle score and a genetic risk score to explore the potential modifying effects of these factors on the relationship between PsRS and psoriasis risk. Compared with individuals with a low PsRS (≤1), those with intermediate PsRS (2–4) and high PsRS (≥5) had 1.20 (95% confidence interval [CI], 1.06–1.36) and 1.53 (95% CI, 1.31–1.78) times higher risks of developing psoriasis, respectively. Our findings revealed an additive interaction between PsRS and genetic susceptibility. Moreover, it was found that individuals with high PsRS and unhealthier lifestyles had a 2.60 times higher risk of developing psoriasis than those with lower PsRS and healthier ones. Our study results imply that an elevated PsRS is linked to a heightened risk of psoriasis, which is further influenced by genetic factors. Our results also indicate that greater social vulnerability and unhealthier lifestyle may synergistically contribute to the additional risk of psoriasis. [ABSTRACT FROM AUTHOR]

Background: Understanding the effects of risk factor burden and genetic predisposition on the long-term risk of atrial fibrillation (AF) is important to improve public health initiatives. However, the 10-year risk of AF considering risk factor burden and genetic predisposition is unknown. Methods: A total of 348,904 genetically unrelated participants without AF at baseline from the UK were categorized into three groups: index ages 45 years (n = 84,206), 55 years (n=117,520), and 65 years (n=147,178). Optimal, borderline, or elevated risk factor burden was determined by body mass index, blood pressure, diabetes mellitus, alcohol consumption, smoking status, and history of myocardial infarction or heart failure. Genetic predisposition was estimated using the polygenic risk score (PRS), constructed using 165 predefined genetic risk variants. The combined effects of risk factor burden and PRS on the risk of incident AF in 10 years were estimated for each index age. Fine and Gray models were developed to predict the 10-year risk of AF. Results: The overall 10-year risk of AF was 0.67% (95% CI: 0.61–0.73%) for index age 45 years, 2.05% (95% CI: 1.96–2.13%) for index age 55 years, and 6.34% (95% CI: 6.21–6.46%) for index age 65 years, respectively. An optimal risk factor burden was associated with later AF onset regardless of genetic predisposition and sex (P < 0.001). Significant synergistic interactions were observed for risk factor burden with PRS at each index age (P < 0.05). Participants with an elevated risk factor burden and high PRS had the highest 10-year risk of AF in reference to those who had both an optimal risk factor burden and a low PRS. At younger ages, optimal risk burden and high PRS might also lead to later onset of AF, compared to the joint effect of elevated risk burden and low/intermediate PRS. Conclusions: Risk factor burden together with a genetic predisposition is associated with the 10-year risk of AF. Our results may be helpful in selecting high-risk individuals for primary prevention of AF and facilitating subsequent health interventions. [ABSTRACT FROM AUTHOR]

Background and Aims: Stair climbing, a straightforward and impactful form of physical activity, has shown potential in reducing risks of cardiovascular disease and mortality. However, its association with the development of atrial fibrillation (AF) remains largely unexplored., Methods and Results: 451,089 participants (mean age 56.5 years) without cardiovascular disease (year 2006-2010) were included from the UK Biobank study. Stair climbing data was collected through touchscreen questionnaire. AF cases were identified using ICD-10 code: I48 and were followed until February 1, 2022. Models adjusted for traditional cardiovascular risk factors. Over a median follow-up of 12.6 years, 23,660 (5.2 %) participants experienced new-onset AF. In multivariable-adjusted models, climbing 10-50, 60-100, 110-150, and ≥160 steps of stairs per day were associated with significant reductions in the risk of AF, compared to not climbing any stairs. The risk reduction appeared more pronounced in women than in men (P for interaction = 0.09). When compared to participants who climbed no stairs, the HRs for those who climbed 110-150 steps of stairs per day were 0.69 (95 % CI: 0.58-0.82) among those with low cardiorespiratory fitness, 0.71 (95 % CI: 0.57-0.88) among those with intermediate cardiorespiratory fitness, and 0.83 (95 % CI: 0.64-1.07) among those with high cardiorespiratory fitness., Conclusions: Climbing stairs was associated with a reduction in AF risks. Significant interaction between cardiorespiratory fitness and stair climbing associated with incident AF was observed. Findings suggest that promoting regular stair climbing could be a potential target for preventing AF onset., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The evidence regarding the relationship between different types of beverages and cardiovascular health in individuals with type 2 diabetes (T2D) is scarce., Aims: To prospectively examine the associations between individual beverage consumption, genetic predisposition, and risk of incident cardiovascular disease (CVD) among adults with T2D., Methods: We analyzed the associations of individual beverage intake with risks of CVD and ischemic heart disease (IHD) in 7315 participants with T2D, overall or stratified by genetic risk to CVD, using data from the UK Biobank study., Results: During a median follow-up of 6.1 years, 878 incident CVD cases were identified, including 517 IHD cases. Higher intakes of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and natural juices were each linearly associated with a higher CVD (Pnonlinearity > .05). Comparing the highest to lowest groups of beverage consumption, the multivariable-adjusted hazard ratios (95% confidence intervals) of CVD were 1.54 (1.14, 2.07) for SSBs, 1.34 (1.07, 1.69) for ASBs, and 1.33 (1.01, 1.76) for natural juices. Similar results were observed for incident IHD. Moreover, no significant interactions between these beverages and the CVD genetic risk score were observed. Replacing half-unit/day of SSBs or natural juices with coffee, tea, or yogurt, but not ASBs, was associated with a 20% to 46% lower risk of CVD and IHD., Interpretation: Higher intakes of SSBs, ASBs, and natural juices were each linearly associated with an increased risk of CVD among individuals with T2D, regardless of genetic predisposition. Our findings highlight the importance of selecting healthy beverage options to improve cardiovascular health in patients with T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cancer and cardiovascular disease share common lifestyle risk factors. However, it remains unclear whether cardiovascular health (CVH) evaluated by Life's Essential 8 can predict cancer risk, and attenuate the influence of genetic susceptibility on cancer., Objectives: We aimed to evaluate independent and joint associations of CVH and polygenic risk score (PRS) with risks of overall and site-specific cancers., Methods: We undertook a population-based cohort study based on the UK Biobank. The CVH score was constructed by physical activity, body mass index, nicotine exposure, sleep, diet, blood pressure, lipid profile, and blood glucose. PRSs were assessed individually for 18 cancer types by their independent single-nucleotide polymorphisms previously identified in genome-wide association studies. Multivariable Cox proportional-hazards models were applied to explore the independent and joint associations of CVH and PRS with cancer incidence risk. The results were displayed as hazard ratio (HR) and 95% confidence interval (CI)., Results: Compared with low CVH, high CVH was associated with decreased risks of overall cancer and the majority of common cancers, including digestive system [HRs (95% CI): 0.33 (0.23, 0.45)-0.66 (0.58, 0.75)], lung (HR: 0.25; 95% CI: 0.21, 0.31), renal (HR: 0.42; 95% CI: 0.32, 0.56), bladder (HR: 0.55; 95% CI: 0.44, 0.69), breast (HR: 0.83; 95% CI: 0.74, 0.92), and endometrial cancers (HR: 0.39; 95% CI: 0.30, 0.51). For overall cancer in males, there was an interaction between CVH and PRS. Notably, individuals with high CVH across all levels of PRS had lower risks of overall cancer for females and 8 site-specific cancers than those with low CVH and high PRS [HRs (95% CIs): 0.18 (0.12, 0.25)-0.79 (0.71, 0.87)]., Conclusions: High CVH was related to decreased risks of overall cancer and multiple cancers regardless of genetic predispositions. Our findings underscored the value of improving CVH for cancer prevention in the general population., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Kidney stone disease (KSD), a significant health care problem within both developed and developing countries, has been associated with genetic risk factors. An association between physical activity and KSD risk also has been hypothesized, but studies have yielded inconsistent findings. This study investigated the association between the intensity of physical activity and the incidence of KSD accounting for genetic risk., Study Design: Prospective cohort study., Setting & Participants: A total of 80,473 participants from the UK Biobank Study., Exposure: Physical activity levels, including total physical activity (TPA), moderate-to-vigorous intensity physical activity (MVPA), and light-intensity physical activity (LPA), were measured using accelerometers and quantified using a machine learning model. A polygenic risk score (PRS) for KSD was also constructed., Outcome: Individuals with KSD were identified using the International Classification of Diseases, Tenth Revision (ICD-10), and procedure codes for KSD surgery., Analytical Approach: A Fine and Gray survival model was used to estimate the associations of incident KSD with TPA, MVPA, LPA, and PRS (as categorical variables). Restricted cubic splines were used to examine potential nonlinear associations within the fully adjusted models., Results: During an average follow-up of 6.19 years, 421 participants developed KSD. Participants in the highest quartiles of TPA, MVPA, and LPA had lower adjusted rates of KSD compared with those in the lowest quartiles: HR, 0.50 (95% CI, 0.44-0.56), 0.57 (95% CI, 0.51-0.64), and 0.66 (95% CI, 0.59-0.74), respectively. TPA, MVPA, and LPA were associated with a lower risk of KSD in participants with low and high genetic predisposition for KSD., Limitations: Selection bias as participants who provided accelerometry data may have been more adherent to health care., Conclusions: Physical activity was negatively associated with the risk of KSD, regardless of the genetic risk. Future large studies are warranted to confirm and explain the mechanisms underlying these associations., Plain-Language Summary: The association between the intensity of physical activity (PA) and the incidence of kidney stone disease (KSD) after accounting for genetic risk is unclear. We conducted a comprehensive prospective cohort study utilizing participants from the UK Biobank to assess the intensity of PA using accelerometers. Our study findings indicated that greater total PA, moderate-to-vigorous-intensity PA, and light-intensity PA were each associated with a lower risk of KSD irrespective of an individual's genetic risk. Our study informs the understanding of risk factors for KSD., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease originates in early life. We aimed to investigate the association between breastfeeding in infancy and cardiovascular disease in adult life., Methods: We followed 364,240 participants from UK Biobank aged 40-73 years from 2006 - 2010 to 2021. Information on breastfeeding in infancy was self-reported by questionnaire. Cox proportional hazard regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between breastfeeding and cardiovascular disease in middle-aged and older adulthood. The multivariable Cox models were used by adjusting for the age (used as the time scale), sex, ethnicity, assessment centre, birth weight, multiple birth status, maternal smoking during pregnancy, Townsend deprivation index, smoking status, alcohol drinker status, physical activity, and menopausal status for women. Binary and multinomial multivariable logistic regression models were used to explore the associations of breastfeeding in infancy with cardiovascular disease risk factors including obesity, body composition, metabolic and inflammatory disorders., Results: During a median of 12.6 years of follow-up, we documented 29,796 new cases of cardiovascular disease, including 24,797 coronary heart disease and 6229 stroke. The multivariable adjusted HRs for breastfed versus non-breastfed were 0.94 (95% CI: 0.91, 0.96) for cardiovascular disease, 0.94 (95% CI: 0.91, 0.96) for coronary heart disease, and 0.95 (95% CI: 0.89, 1.01) for stroke. Furthermore, the strength of observed association between breastfeeding and cardiovascular disease seems to decrease with age (P for interaction <0.001), and increase with polygenic risk for cardiovascular disease (P for interaction <0.001). Consistently, breastfeeding in infancy was associated with cardiovascular disease risk factors including lower body mass index 0.92 (95% CI: 0.89, 0.95), body fat percentage 0.85 (95% CI: 0.83, 0.87), android to gynoid fat ratio 0.89 (95% CI: 0.83, 0.96), visceral adipose tissue 0.92 (95% CI: 0.84, 1.01), as well as lower C-reactive protein level 0.95 (95% CI: 0.94, 0.97) and a lower risk of metabolic syndrome 0.89 (95% CI: 0.85, 0.92)., Conclusions: Breastfeeding in infancy was associated with a lower risk of cardiovascular disease in middle-aged and older adulthood. Promoting breastfeeding is vital not only for promoting child health, but also for halting the increasing trend of cardiovascular disease in adults., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: The American Heart Association recently introduced a novel cardiovascular health (CVH) metric, Life's Essential 8 (LE8), for health promotion. However, the relationship between LE8 and cancer mortality risk remains uncertain., Methods: We investigated 17,076 participants from US National Health and Nutrition Examination Survey (US NHANES) and 272,727 participants from UK Biobank, all free of cancer at baseline. The CVH score, based on LE8 metrics, incorporates four health behaviors (diet, physical activity, smoking, and sleep) and four health factors (body mass index, lipid, blood glucose, and blood pressure). Self-reported questionnaires assessed health behaviors. Primary outcomes were mortality rates for total cancer and its subtypes. The association between CVH score (continuous and categorical variable) and outcomes was examined using Cox model with adjustments. Cancer subtypes-related polygenic risk score (PRS) was constructed to evaluate its interactions with CVH on cancer death risk., Results: Over 141,526 person-years in US NHANES, 424 cancer-related deaths occurred, and in UK Biobank, 8,872 cancer deaths were documented during 3,690,893 person-years. High CVH was associated with reduced overall cancer mortality compared to low CVH (HR 0.58, 95% CI 0.37-0.91 in US NHANES; 0.51, 0.46-0.57 in UK Biobank). Each one-standard deviation increase in CVH score was linked to a 19% decrease in cancer mortality (HR: 0.81; 95% CI: 0.73-0.91) in US NHANES and a 19% decrease (HR: 0.81; 95% CI: 0.79-0.83) in UK Biobank. Adhering to ideal CVH was linearly associated with decreased risks of death from lung, bladder, liver, kidney, esophageal, breast, colorectal, pancreatic, and gastric cancers in UK Biobank. Furthermore, integrating genetic data revealed individuals with low PRS and high CVH exhibited the lowest mortality from eight cancers (HRs ranged from 0.36 to 0.57) compared to those with high PRS and low CVH. No significant modification of the association between CVH and mortality risk for eight cancers by genetic predisposition was observed. Subgroup analyses showed a more pronounced protective association for overall cancer mortality among younger participants and those with lower socio-economic status., Conclusions: Maintaining optimal CVH is associated with a substantial reduction in the risk of overall cancer mortality. Adherence to ideal CVH correlates linearly with decreased mortality risk across multiple cancer subtypes. Individuals with both ideal CVH and high genetic predisposition demonstrated significant health benefits. These findings support adopting ideal CVH as an intervention strategy to mitigate cancer mortality risk and promote healthy aging., (© 2024. The Author(s).)

Background: Chronic rhinosinusitis (CRS) is a prevalent upper respiratory condition that manifests in two primary subtypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). While previous studies indicate a correlation between air pollution and CRS, the role of genetic predisposition in this relationship remains largely unexplored. We hypothesized that higher air pollution exposure would lead to the development of CRS, and that genetic susceptibility might modify this association., Methods: This cohort study involving 367,298 adult participants from the UK Biobank, followed from March 2006 to October 2021. Air pollution metrics were estimated at residential locations using land-use regression models. Cox proportional hazard models were employed to explore the associations between air pollution exposure and CRS, CRSwNP, and CRSsNP. A polygenic risk score (PRS) was constructed to evaluate the joint effect of air pollution and genetic predisposition on the development of CRS., Results: We found that the risk of CRS increased under long-term exposure to PM 2.5 [the hazard ratios (HRs) with 95 % CIs: 1.59 (1.26-2.01)], PM 10 [1.64 (1.26-2.12)], NO 2 [1.11 (1.04-1.17)], and NO x [1.18 (1.12-1.25)], respectively. These effects were more pronounced among participants with CRSwNP, although the differences were not statistically significant. Additionally, we found that the risks for CRS and CRSwNP increased in a graded manner among participants with higher PRS or higher exposure to PM 2.5 , PM 10 , or NO x concentrations. However, no multiplicative or additive interactions were observed., Conclusions: Long-term exposure to air pollution increases the risk of CRS, particularly CRSwNP underscoring the need to prioritize clean air initiatives and environmental regulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Characteristics of the built environment, such as neighbourhood fast-food outlet exposure, are increasingly recognised as risk factors for unhealthy diet and obesity. Obesity also has a genetic component, with common genetic variants explaining a substantial proportion of population-level obesity susceptibility. However, it is not known whether and to what extent associations between fast-food outlet exposure and body weight are modified by genetic predisposition to obesity.Methods: We used data from the Fenland Study, a population-based sample of 12,435 UK adults (mean age 48.6 years). We derived a genetic risk score associated with BMI (BMI-GRS) from 96 BMI-associated single nucleotide polymorphisms. Neighbourhood fast-food exposure was defined as quartiles of counts of outlets around the home address. We used multivariable regression models to estimate the associations of each exposure, independently and in combination, with measured BMI, overweight and obesity, and investigated interactions.Results: We found independent associations between BMI-GRS and risk of overweight (RR = 1.34, 95% CI 1.23-1.47) and obesity (RR = 1.73, 95% CI 1.55-1.93), and between fast-food outlet exposure and risk of obesity (highest vs lowest quartile RR = 1.58, 95% CI 1.21-2.05). There was no evidence of an interaction of fast-food outlet exposure and genetic risk on BMI (P = 0.09), risk of overweight (P = 0.51), or risk of obesity (P = 0.27). The combination of higher BMI-GRS and highest fast-food outlet exposure was associated with 2.70 (95% CI 1.99-3.66) times greater risk of obesity.Conclusions: Our study demonstrated independent associations of both genetic obesity risk and neighbourhood fast-food outlet exposure with adiposity. These important drivers of the obesity epidemic have to date been studied in isolation. Neighbourhood fast-food outlet exposure remains a potential target of policy intervention to prevent obesity and promote the public's health. [ABSTRACT FROM AUTHOR]

Key content: Lynch syndrome is an autosomal dominant condition closely associated with colorectal, endometrial and ovarian cancer.Women with Lynch syndrome are at increased risk of both endometrial and ovarian cancer and should be offered personalised counselling regarding family planning, red flag symptoms and risk‐reducing strategies.Surveillance for gynaecological cancer in women with Lynch syndrome remains controversial; more robust data are needed to determine its effectiveness.Universal testing for Lynch syndrome in endometrial cancer is being adopted by centres across Europe and is now recommended by the National Institute for Health and Care Excellence; thus, gynaecologists must become familiar with testing strategies and their results.Testing strategies involve risk stratification of cancers based on phenotypical features and definitive germline testing. Learning objectives: To define the pathogenesis of Lynch syndrome and its associated gynaecological cancers.To understand the testing strategies for Lynch syndrome in women with gynaecological cancer.To learn how best to counsel women with Lynch syndrome regarding gynaecological cancer and risk‐reducing strategies to enable informed decision‐making. Ethical issues: Offering gynaecological surveillance despite a lack of robust evidence for its clinical effectiveness may falsely reassure women and delay risk‐reducing hysterectomy.Genetic testing may yield variants of unknown significance with ill‐defined clinical implications, which can lead to confusion and anxiety.Genetic testing has implications not only for the individual, but also for the whole family, so expert counselling is crucial. [ABSTRACT FROM AUTHOR]

Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis. To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease. We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60 yr) and 1160 selected controls. Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score ≥8, n = 201) versus nonaggressive (Gleason score ≤7, n = 1048) cases. We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR] = 1.29, 95% confidence interval [CI] 1.01–1.64, p = 0.036). Gene-level analyses selected NBN (p SKAT-O = 2.4 × 10−4) for overall risk and XPC (p SKAT-O = 1.6 × 10−4) for aggressive disease, both at candidate-level significance (p < 3.1 × 10−4 and p < 3.4 × 10−4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR = 3.2, 95% CI 2.1–4.8, p ADA = 4.1 × 10−3) and four genes that increased risk of aggressive disease (OR = 11.2, 95% CI 4.6–27.7, p ADA = 5.6 × 10−3), three of which overlap the predisposition gene set. The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential. This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice. This large sequencing study assessed the rate of inherited DNA repair gene mutations in prostate cancer (PCa) patients and in disease-free men. A total of 23 genes were found to be associated with PCa predisposition or the risk of aggressive disease. These findings have predictive and prognostic potential. [ABSTRACT FROM AUTHOR]

• Reproductive risk factors have systemic effects on the risk of women's T2D. • Both reproductive and genetic risk are associated with an elevated risk of T2D. • There is a significant reproductive-genetic interaction for women's T2D risk. • Women adhering to healthy reproductive status can protect against T2D genetic risk. To assess synergistic effects of reproductive factors and gene-reproductive interaction on type 2 diabetes (T2D) risk, also the extent to which the genetic risk of T2D can be affected by reproductive risk. 84,254 women with genetic data and reproductive factors were enrolled between 2006 and 2010 in the UK Biobank. The reproductive risk score (RRS) was conducted based on 17 reproductive items, and genetic risk score (GRS) was based on 149 genetic variants. There were 2300 (2.8 %) T2D cases during an average follow-up of 4.49 years. We found a significant increase in T2D risk across RRS categories (P trend < 0.001). Compared with low reproductive risk, high-mediate (adjusted hazard ratio [aHR] 1.38, 95 % CI 1.20–1.58) and high (aHR 1.84, 95 % CI 1.54–2.19) reproductive risk could increase the risk of T2D. We further observed a significant additive interaction between reproductive risk and genetic predisposition. In the situation of high genetic predisposition, women with low reproductive risk had lower risk of T2D than those with high reproductive risk (aHR 0.47, 95 % CI 0.30–0.76), with an absolute risk reduction of 2.98 %. Our novo developed RRS identified high reproductive risk is associated with elevated risk of women's T2D, which can be magnified by gene-reproductive interaction. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mashed and fried potato intake was associated with a higher risk of T2D. • Genetic risk score was associated with higher risk of T2D. • Potato intake was positively associated with T2D risk regardless of genetic risk. • Replacing potatoes with equivalent vegetables was associated with lower T2D risk. Whether the consumption of different processed potatoes is detrimental to type 2 diabetes (T2D) is highly debated. This study aimed to assess the relations between potato consumption and the risk of T2D and whether the relationship was modified by the genetic predisposition to T2D. We included 174,665 participants from the UK Biobank at baseline. Potato consumption was evaluated using the 24-hour dietary questionnaire. The genetic risk score (GRS) was calculated based on 424 variants associated with T2D. After adjustment for demographic, lifestyle, and dietary factors, the consumption of total potatoes was significantly and positively associated with T2D risk [hazard ratio (HR) comparing two or more servings/day with non-consumers was 1.28 (95% CI: 1.13–1.45)]. HRs (95% CIs) of T2D for each 1-SD increment in boiled/baked potatoes, mashed potatoes, and fried potatoes were 1.02 (0.99–1.05), 1.05 (1.02–1.08), and 1.05 (1.02–1.09), respectively. There were no significant interactions between the consumption of total or different processed potatoes and overall GRS on T2D risk. Theoretically, replacing one serving/day of total potatoes with the same amount of non-starchy vegetables was related to a 12% (95% CI: 0.84–0.91) lower T2D risk. These results showed the positive associations of the consumption of total potatoes, mashed potatoes or fried potatoes and genetic risk with higher incident T2D. An unhealthy potato-based diet is associated with higher diabetes risk regardless of genetic risk. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased., Methods: In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0-18 years, 19-30 years and 31-50 years., Results: DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5-18 years OR 0.16 (95% CI 0.08, 0.31); age 19-30 years OR 0.10 (0.04, 0.23); and age 31-50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes., Conclusions/interpretation: HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life., (© 2021. The Author(s).)

Study Objectives: To prospectively investigate the association between sleep traits and lung cancer risk, accounting for the interactions with genetic predisposition of lung cancer., Methods: We included 469 691 individuals free of lung cancer at recruitment from UK Biobank, measuring sleep behaviors with a standardized questionnaire and identifying incident lung cancer cases through linkage to national cancer and death registries. We estimated multivariable-adjusted hazard ratios (HRs) for lung cancer (2177 incident cases) across four sleep traits (sleep duration, chronotype, insomnia, and snoring) and examined the interaction and joint effects with a lung cancer polygenic risk score., Results: A U-shaped association was observed for sleep duration and lung cancer risk, with an 18% higher risk (95% confidence interval [CI]: 1.07 to 1.30) for short sleepers and a 17% higher risk (95% CI: 1.02 to 1.34) for long sleepers compared with normal sleepers (7-8 h/day). Evening preference was associated with elevated lung cancer risk compared with morning preference (HR: 1.25; 95% CI: 1.07 to 1.46), but no association was found for insomnia or snoring. Compared with participants with favorable sleep traits and low genetic risk, those with both unfavorable sleep duration (<7 hours or >8 hours) or evening preference and high genetic risk showed the greatest lung cancer risk (HRsleep duration: 1.83; 95% CI: 1.47 to 2.27; HRchronotype: 1.85; 95% CI: 1.34 to 2.56)., Conclusions: Both unfavorable sleep duration and evening chronotype were associated with increased lung cancer incidence, especially for those with low to moderate genetic risk. These results indicate that sleep behaviors as modifiable risk factors may have potential implications for lung cancer risk., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Epidemiologic studies have suggested an inverse association between circulating concentrations of long-chain ω-3 PUFAs and fracture risk. However, whether supplementation of long-chain ω-3 PUFA (i.e. fish oil) is associated with fracture risk, and whether the association is modified by genetic predisposition to fracture risk remain unclear., Objectives: To evaluate the associations of habitual fish oil supplement use with fracture risk, and to explore the potential effect modification by genetic predisposition., Methods: This study included 492,713 participants from the UK Biobank who completed a questionnaire on habitual fish oil supplement use between 2006 and 2010. HRs and 95% CIs for fractures were estimated from multivariable Cox proportional hazards models. A weighted fracture-genetic risk score (GRS) was derived from 14 validated single nucleotide polymorphisms., Results: During a median follow-up of 8.1 y, 12,070 incident fractures occurred among participants free of fracture at baseline (n = 441,756). Compared with nonuse, habitual use of fish oil supplements was associated with a lower risk of total fractures (HR = 0.93; 95% CI: 0.89, 0.97), hip fractures (HR = 0.83; 95% CI: 0.75, 0.92), and vertebrae fractures (HR = 0.85; 95% CI: 0.72, 0.99). The inverse association for total fractures was more pronounced among participants having a higher fracture-GRS than among those with a lower fracture-GRS (P-interaction <0.001). Among participants with a history of fracture at baseline (n = 50,957), fish oil use was associated with a lower risk of total recurrent fractures (HR = 0.88; 95% CI: 0.82, 0.96) and vertebrae recurrent fractures (HR = 0.64; 95% CI: 0.46, 0.88) but not with hip fracture recurrence., Conclusions: Our findings suggest that habitual fish oil supplement use is associated with lower risks of both incident and recurrent fractures. The inverse associations of fish oil use with total fractures appeared to be more pronounced among individuals at higher genetic risk of fractures than those with lower genetic risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background & Aims: People with a higher genetic risk for obesity are more likely to develop cardiovascular disease (CVD), and healthy plant-based dietary patterns may be associated with decreased risks of obesity and cardiovascular events. We investigated whether adherence to healthy plant-foods-rich dietary patterns might attenuate risks of obesity and related cardiovascular abnormalities for people at genetically higher risk of obesity., Methods: This study included 121,799 middle-aged adults in UK Biobank who were initially free of metabolic diseases and cancer. We calculated a healthful plant-based diet index (hPDI) based on 17 major food groups as well as a genetic risk score (GRS) for obesity consisting of body mass index (BMI)-associated variants. The incidence of cardiovascular events (myocardial infarction, MI, or stroke) was prospectively followed during a mean (SD) 5.1 (0.9) years., Results: We found significant interactions between GRS and hPDI on adiposity (P interaction <0.0001); adherence to hPDI was more strongly associated with lower levels of adiposity among participants with higher GRS than those with lower GRS. Further, we found a similar pattern of GRS-hPDI interactions on untreated hypertension (P interaction  = 0.0036). When we tested GRS-hPDI interactions on cardiovascular events, adherence to hPDI was more strongly associated with a decreased risk of MI among people with high GRS (above median) than those with low GRS (P interaction  = 0.006). Among participants with high GRS, high adherence to hPDI (the top tertile of hPDI) was associated with an HR 0.54 (95% CI: 0.39, 0.74) for MI, as compared to low adherence., Conclusions: Adherence to healthy plant-based dietary patterns significantly attenuated risks of cardiovascular abnormalities for people at genetically higher risk of obesity. Our results support the precision medicine strategies considering genetics and dietary habits to modify cardiovascular health for people at higher risk of genetically determined obesity., Competing Interests: Conflict of interest The authors declare no conflict of interest associated with this publication., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)