scholarly journals Genetically downregulated interleukin-6 signaling is associated with a favorable cardiometabolic profile: a phenome-wide association study

2020 ◽  
Author(s):  
Marios K. Georgakis ◽  
Rainer Malik ◽  
Xue Li ◽  
Dipender Gill ◽  
Michael G. Levin ◽  
...  
Keyword(s):  
Association Study ◽  
Clinical Outcomes ◽  
Interleukin 6 ◽  
Lower Risk ◽  
Bacterial Infections ◽  
Interleukin 4 ◽  
Uk Biobank ◽  
The Uk ◽  
Tract Infections ◽  
Cardiometabolic Profile

AbstractBackgroundInterleukin-6 (IL6) signaling is a key inflammatory pathway widely implicated in the pathogenesis of multiple diseases including autoimmune, vascular, and metabolic disorders. While IL6-receptor (IL6R) inhibitors are already in use for the treatment of autoimmune diseases, their repurposing potential and safety profile is still debated.MethodsWe used 7 genetic variants at the IL6R locus as proxies for IL6 signaling downregulation and explored their effects on 1,428 clinical outcomes in a phenome-wide association study (PheWAS) using data from the UK Biobank (339,256 unrelated individuals). Significant associations were meta-analyzed with data from the Penn Medicine (10,244 individuals) and BioMe (9,054 individuals) Biobanks for validation. We further investigated associations between genetically downregulated IL6 signaling and 366 biomarkers and endophenotypes of human disease in the UK Biobank and other phenotype-specific consortia. All associations were examined by Mendelian randomization (MR) analyses scaled to the effects of tocilizumab, a monoclonal antibody targeting IL6R.ResultsThe PheWAS-MR analyses showed significant associations with 16 clinical outcomes and 17 biomarkers following correction for multiple comparisons. Genetically downregulated IL6 signaling was associated with a lower risk of several atherosclerotic phenotypes including ischemic heart disease (OR: 0.84, 95%CI: 0.77-0.90) and abdominal aortic aneurysm (OR: 0.44, 95%CI: 0.29-0.67). We further found significant associations with lower risk of type 2 diabetes (OR: 0.80, 95%CI: 0.73-0.88), lower glycated hemoglobin A1c (HbA1c) levels (beta: −0.07, 95%CI: −0.08 to −0.05), and higher HDL-cholesterol levels (beta: 0.04, 95%CI: 0.02-0.06). In accord with clinical trials examining pharmacological IL6 blockade, genetically downregulated IL6 signaling was associated with higher risk of neutropenia and bacterial infections (cellulitis and urinary tract infections) and with higher hemoglobin concentrations. We further found significant associations with higher risk of atopic dermatitis and higher levels of the pro-allergic cytokine interleukin-4.ConclusionsGenetic IL6 signaling downregulation associates with a lower risk of vascular outcomes and a more favorable cardiometabolic profile. These findings further support a repurposing of IL6R blockade for lowering cardiovascular risk while also informing on potential side effects.

scholarly journals Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse

2021 ◽  
Author(s):  
Mengyao Yu ◽  
Sergiy Kyryachenko ◽  
Stephanie Debette ◽  
Philippe Amouyel ◽  
Jean-Jacques Schott ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Cardiac Development ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Additional Risk ◽  
Genome Wide ◽  
The Uk

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study have identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank. Methods: We reanalyzed 1007/479 cases from the MVP-France study, 1469/862 controls from the MVP-Nantes study for reimputation genotypes using HRC and TOPMed panels. We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used FUMA for post-genome-wide association study annotations and MAGMA for gene-based and gene-set analyses. Results: We found TOPMed imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1 . We identified an additional risk locus on Chr1 ( SYT2 ) and 2 suggestive risk loci on chr8 ( MSRA ) and chr19 ( FBXO46 ), all driven by common variants. Gene-based association using MAGMA revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

Diet and Risk of Incident Lung Cancer: A Large Prospective Cohort Study in UK Biobank

2021 ◽  
Author(s):  
Xiaoxia Wei ◽  
Chen Zhu ◽  
Mengmeng Ji ◽  
Jingyi Fan ◽  
Junxing Xie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dietary Fiber ◽  
Dietary Patterns ◽  
Lower Risk ◽  
Red Meat ◽  
Processed Meat ◽  
Uk Biobank ◽  
High Intake ◽  
Breakfast Cereals ◽  
The Uk

ABSTRACT Background Epidemiological evidence remains conflicting regarding diet and risk of lung cancer. Objectives We sought to systematically investigate whether dietary factors are associated with the risk of incident lung cancer in the UK Biobank. Methods A total of 416,588 participants (54% women) from the UK Biobank were included in the present study. Based on baseline data from FFQs, 3 main dietary patterns were identified by using principal component analysis. Cox proportional hazards models were used to investigate the association of individual food groups and dietary patterns with lung cancer risk. Results During a median follow-up of 7.13 y, 1782 incident lung cancer cases were documented. The association analysis showed high intake of red meat and processed meat was associated with an increased risk of lung cancer (HRper 50 g/d: 1.36; 95% CI: 1.13, 1.65 for red meat; HRper 25 g/d: 1.30; 95% CI: 1.10, 1.53 for processed meat). However, the consumption of fruits (HRper 100 g/d: 0.90; 95% CI: 0.84, 0.95), vegetables (HRper 100 g/d: 0.89; 95% CI: 0.81, 0.99), breakfast cereals (HRper 50 g/d: 0.81; 95% CI: 0.74, 0.89), and dietary fiber (HRper 5 g/d: 0.76; 95% CI: 0.69, 0.84) was inversely associated with the risk of lung cancer. For the dietary pattern analysis [quartile (Q) comparison], high adherence to the Prudent pattern (HRQ4 compared with Q1: 0.84; 95% CI: 0.73, 0.96) was associated with a lower risk of lung cancer, whereas the Western pattern (HRQ4 compared with Q1: 1.27; 95% CI: 1.11, 1.46) was associated with a higher risk of lung cancer. Conclusions Our study indicated that a diet characterized by high intake of fruits, vegetables, breakfast cereals, and dietary fiber, as well as low intake of red meat and processed meat, was associated with a lower risk of lung cancer.

Associations of BMI and Serum Urate with Developing Dementia: A Prospective Cohort Study

2020 ◽  
Vol 105 (12) ◽  
pp. e4688-e4698
Author(s):  
Zhi Cao ◽  
Chenjie Xu ◽  
Hongxi Yang ◽  
Shu Li ◽  
Fusheng Xu ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Cohort Study ◽  
Lower Risk ◽  
Serum Urate ◽  
Healthy Weight ◽  
Uk Biobank ◽  
Health Records ◽  
Increased Risk ◽  
The Uk

Abstract Context Recent studies have suggested that a higher body mass index (BMI) and serum urate levels were associated with a lower risk of developing dementia. However, these reverse relationships remain controversial, and whether serum urate and BMI confound each other is not well established. Objectives To investigate the independent associations of BMI and urate, as well as their interaction with the risk of developing dementia. Design and Settings We analyzed a cohort of 502 528 individuals derived from the UK Biobank that included people aged 37–73 years for whom BMI and urate were recorded between 2006 and 2010. Dementia was ascertained at follow-up using electronic health records. Results During a median of 8.1 years of follow-up, a total of 2138 participants developed dementia. People who were underweight had an increased risk of dementia (hazard ratio [HR] = 1.91, 95% confidence interval [CI]: 1.24–2.97) compared with people of a healthy weight. However, the risk of dementia continued to fall as weight increased, as those who were overweight and obese were 19% (HR = 0.81, 95%: 0.73–0.90) and 22% (HR = 0.78, 95% CI: 0.68–0.88) were less likely to develop dementia than people of a healthy weight. People in the highest quintile of urate were also associated with a 25% (HR = 0.75, 95% CI: 0.64–0.87) reduction in the risk of developing dementia compared with those who were in the lowest quintile. There was a significant multiplicative interaction between BMI and urate in relation to dementia (P for interaction = 0.004), and obesity strengthens the protective effect of serum urate on the risk of dementia. Conclusion Both BMI and urate are independent predictors of dementia, and there are inverse monotonic and dose-response associations of BMI and urate with dementia.

scholarly journals Incidence of Microbial Infections in English UK Biobank Participants: Comparison with the General Population

2020 ◽  
Author(s):  
Bridget Hilton ◽  
Daniel Wilson ◽  
Anne-Marie O’Connell ◽  
Dean Ironmonger ◽  
Justine K Rudkin ◽  
...  
Keyword(s):  
General Population ◽  
Bacterial Infections ◽  
Older Individuals ◽  
Uk Biobank ◽  
Microbial Isolation ◽  
Serious Infection ◽  
Microbial Infections ◽  
Serious Bacterial Infections ◽  
Rate Ratios ◽  
The Uk

AbstractUnderstanding the genetic and environmental risk factors for serious bacterial infections in ageing populations remains incomplete. Utilising the UK Biobank (UKB), a prospective cohort study of 500,000 adults aged 40-69 years at recruitment (2006-2010), could help address this.We assess the feasibility of linking an England-wide dataset of microbiological isolations to UKB participants, to enable characterisation of microbial infections within the UKB Cohort. Microbiological infections occurring in patients in England, as recorded in the Public Health England Second Generation Surveillance System (SGSS), were linked to UKB participants using pseudonymised identifiers. By January 2015, ascertainment of laboratory reports from UKB participants by SGSS was estimated at 98%. 4.5% of English UKB participants had a positive microbiological isolate in 2015. Half of UKB isolates came from 12 laboratories, and 70% from 21 laboratories. Incidence rate ratios for microbial isolation, which is indicative of serious infection, from the UKB cohort relative to the comparably aged general population ranged from 0.6 to 1, compatible with the previously described healthy participant bias in UKB.Data on microbial isolations can be linked to UKB participants from January 2015 onwards. This linked data would offer new opportunities for research into infectious disease in older individuals.

scholarly journals Diet-quality and its association with cardiovascular diseases and cancer incidence and all-cause mortality: a prospective cohort study from UK Biobank

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Fanny Petermann-Rocha ◽  
Stuart R. Gray ◽  
Jill Pell ◽  
Carlos Celis-Morales
Keyword(s):  
Cancer Incidence ◽  
Diet Quality ◽  
Lower Risk ◽  
Quality Score ◽  
Confounding Factors ◽  
Uk Biobank ◽  
Healthy Group ◽  
Oily Fish ◽  
All Cause Mortality ◽  
The Uk

AbstractIntroductionNewly available data from big scale studies conducted in the UK, such as the UK Biobank, offers the possibility to further explore the prospective association between a diet-quality score and health outcomes after accounting for the effect of important confounding factors. The aim of this work, therefore, was to investigate the association between a diet-quality score, with the incidence of cardiovascular diseases (CVDs), cancer and all-cause mortality.Material and methodsThis study includes 345,343 participants (age range: 39–73, 55.1% women) from the UK Biobank, a prospective population-based study. Using 21 standardised variables of diet (alcohol, bread, bread type, cereal, dried fruit, water, coffee, tea, cheese, oily fish, non-oily fish, salt added to food, spread type, fresh fruit, cooked vegetable, raw vegetables, milk type, poultry, beef, lamb, and pork) we created a diet-quality score (very healthy, healthy, unhealthy and very unhealthy) using principal-component factor analysis. Associations between the dietary-quality score (very unhealthy individuals were the reference group) and health outcomes (all-cause mortality, CVD and cancer incidence) were investigated using Cox-proportional hazard models. All analyses were performed using STATA 14 statistical software.ResultsIn comparison to individuals with a very unhealthy diet, those with a better diet-quality had a lower risk of all-cause mortality and cancer as well as incidence of CVD and cancer. For example, individuals classified in the very healthy group had a 12% lower risk of all-cause mortality (HR: 0.88 [95% CI: 0.82 to 0.95]), 12% lower risk of CVD incidence (HR: 0.88 [95% CI: 0.80 to 0.98]), 17% of all-cancer mortality (HR: 0.83 [95% CI: 0.75 to 0.93]), and 10% lower risk all-cancer incidence (HR: 0.90 [95% CI: 0.85 to 0.94]). Those in the healthy group had a 12% lower risk of all-cause (HR: 0.88 [95% CI: 0.83 to 0.93]) and 15% lower risk of all-cancer mortality (HR: 0.85 [95% CI: 0.78 to 0.93]). There was no significant association between CVD mortality and any diet-quality group. These findings were independent of major confounding factors including socio-demographic covariates, prevalent of diseases and lifestyle factors.DiscussionOur findings indicate that individuals with a healthy diet in the UK biobank cohort are associated with a lower risk of premature mortality, and incidence of CVDs and cancer independently of major confounding factors.

scholarly journals Accelerometer measured physical activity and the incidence of cardiovascular disease: Evidence from the UK Biobank cohort study

PLoS Medicine ◽  
2021 ◽  
Vol 18 (1) ◽  
pp. e1003487
Author(s):  
Rema Ramakrishnan ◽  
Aiden Doherty ◽  
Karl Smith-Byrne ◽  
Kazem Rahimi ◽  
Derrick Bennett ◽  
...  
Keyword(s):  
Physical Activity ◽  
Cardiovascular Disease ◽  
Lower Risk ◽  
Cox Regression ◽  
Moderate Intensity ◽  
Inverse Association ◽  
Uk Biobank ◽  
Reverse Causality ◽  
Vigorous Intensity ◽  
The Uk

Background Higher levels of physical activity (PA) are associated with a lower risk of cardiovascular disease (CVD). However, uncertainty exists on whether the inverse relationship between PA and incidence of CVD is greater at the highest levels of PA. Past studies have mostly relied on self-reported evidence from questionnaire-based PA, which is crude and cannot capture all PA undertaken. We investigated the association between accelerometer-measured moderate, vigorous, and total PA and incident CVD. Methods and findings We obtained accelerometer-measured moderate-intensity and vigorous-intensity physical activities and total volume of PA, over a 7-day period in 2013–2015, for 90,211 participants without prior or concurrent CVD in the UK Biobank cohort. Participants in the lowest category of total PA smoked more, had higher body mass index and C-reactive protein, and were diagnosed with hypertension. PA was associated with 3,617 incident CVD cases during 440,004 person-years of follow-up (median (interquartile range [IQR]): 5.2 (1.2) years) using Cox regression models. We found a linear dose–response relationship for PA, whether measured as moderate-intensity, vigorous-intensity, or as total volume, with risk of incident of CVD. Hazard ratios (HRs) and 95% confidence intervals for increasing quarters of the PA distribution relative to the lowest fourth were for moderate-intensity PA: 0.71 (0.65, 0.77), 0.59 (0.54, 0.65), and 0.46 (0.41, 0.51); for vigorous-intensity PA: 0.70 (0.64, 0.77), 0.54 (0.49,0.59), and 0.41 (0.37,0.46); and for total volume of PA: 0.73 (0.67, 0.79), 0.63 (0.57, 0.69), and 0.47 (0.43, 0.52). We took account of potential confounders but unmeasured confounding remains a possibility, and while removal of early deaths did not affect the estimated HRs, we cannot completely dismiss the likelihood that reverse causality has contributed to the findings. Another possible limitation of this work is the quantification of PA intensity-levels based on methods validated in relatively small studies. Conclusions In this study, we found no evidence of a threshold for the inverse association between objectively measured moderate, vigorous, and total PA with CVD. Our findings suggest that PA is not only associated with lower risk for of CVD, but the greatest benefit is seen for those who are active at the highest level.

scholarly journals A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

2020 ◽  
Vol 29 (8) ◽  
pp. 1396-1404 ◽  
Author(s):  
Weihua Meng ◽  
Brian W Chan ◽  
Cameron Harris ◽  
Maxim B Freidin ◽  
Harry L Hebert ◽  
...  
Keyword(s):  
Association Study ◽  
Shoulder Pain ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Significant Locus ◽  
The Uk

Abstract Background Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. Methods A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. Results We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10−11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10−10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10−8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). Conclusions We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

scholarly journals Genome-wide association study of medication-use and associated disease in the UK Biobank

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yeda Wu ◽  
Enda M. Byrne ◽  
Zhili Zheng ◽  
Kathryn E. Kemper ◽  
Loic Yengo ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Medication Use ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
The Uk

scholarly journals Consumption of coffee and tea and risk of developing stroke, dementia, and poststroke dementia: A cohort study in the UK Biobank

PLoS Medicine ◽  
2021 ◽  
Vol 18 (11) ◽  
pp. e1003830
Author(s):  
Yuan Zhang ◽  
Hongxi Yang ◽  
Shu Li ◽  
Wei-dong Li ◽  
Yaogang Wang
Keyword(s):  
Cohort Study ◽  
Lower Risk ◽  
Smoking Status ◽  
Density Lipoprotein ◽  
Tea Consumption ◽  
Uk Biobank ◽  
Daily Consumption ◽  
History Of ◽  
Poststroke Dementia ◽  
The Uk

Background Previous studies have revealed the involvement of coffee and tea in the development of stroke and dementia. However, little is known about the association between the combination of coffee and tea and the risk of stroke, dementia, and poststroke dementia. Therefore, we aimed to investigate the associations of coffee and tea separately and in combination with the risk of developing stroke and dementia. Methods and findings This prospective cohort study included 365,682 participants (50 to 74 years old) from the UK Biobank. Participants joined the study from 2006 to 2010 and were followed up until 2020. We used Cox proportional hazards models to estimate the associations between coffee/tea consumption and incident stroke and dementia, adjusting for sex, age, ethnicity, qualification, income, body mass index (BMI), physical activity, alcohol status, smoking status, diet pattern, consumption of sugar-sweetened beverages, high-density lipoprotein (HDL), low-density lipoprotein (LDL), history of cancer, history of diabetes, history of cardiovascular arterial disease (CAD), and hypertension. Coffee and tea consumption was assessed at baseline. During a median follow-up of 11.4 years for new onset disease, 5,079 participants developed dementia, and 10,053 participants developed stroke. The associations of coffee and tea with stroke and dementia were nonlinear (P for nonlinear <0.01), and coffee intake of 2 to 3 cups/d or tea intake of 3 to 5 cups/d or their combination intake of 4 to 6 cups/d were linked with the lowest hazard ratio (HR) of incident stroke and dementia. Compared with those who did not drink tea and coffee, drinking 2 to 3 cups of coffee and 2 to 3 cups of tea per day was associated with a 32% (HR 0.68, 95% CI, 0.59 to 0.79; P < 0.001) lower risk of stroke and a 28% (HR, 0.72, 95% CI, 0.59 to 0.89; P = 0.002) lower risk of dementia. Moreover, the combination of coffee and tea consumption was associated with lower risk of ischemic stroke and vascular dementia. Additionally, the combination of tea and coffee was associated with a lower risk of poststroke dementia, with the lowest risk of incident poststroke dementia at a daily consumption level of 3 to 6 cups of coffee and tea (HR, 0.52, 95% CI, 0.32 to 0.83; P = 0.007). The main limitations were that coffee and tea intake was self-reported at baseline and may not reflect long-term consumption patterns, unmeasured confounders in observational studies may result in biased effect estimates, and UK Biobank participants are not representative of the whole United Kingdom population. Conclusions We found that drinking coffee and tea separately or in combination were associated with lower risk of stroke and dementia. Intake of coffee alone or in combination with tea was associated with lower risk of poststroke dementia.

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