Plasma adiponectin and risk of asthma: observational analysis, genetic Mendelian randomisation and meta-analysis

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2021-217675
Author(s):  
Maria Booth Nielsen ◽  
Børge G Nordestgaard ◽  
Marianne Benn ◽  
Yunus Çolak
Keyword(s):  
General Population ◽  
Population Study ◽  
Genetic Variants ◽  
Meta Analysis ◽  
High Plasma ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
General Population Study ◽  
Plasma Adiponectin ◽  
The Uk

BackgroundAdiponectin, an adipocyte-secreted protein-hormone with inflammatory properties, has a potentially important role in the development and progression of asthma. Unravelling whether adiponectin is a causal risk factor for asthma is an important issue to clarify as adiponectin could be a potential novel drug target for the treatment of asthma.ObjectiveWe tested the hypothesis that plasma adiponectin is associated observationally and causally (using genetic variants as instrumental variables) with risk of asthma.MethodsIn the Copenhagen General Population Study, we did an observational analysis in 28 845 individuals (2278 asthma cases) with plasma adiponectin measurements, and a genetic one-sample Mendelian randomisation analysis in 94 868 individuals (7128 asthma cases) with 4 genetic variants. Furthermore, in the UK Biobank, we did a genetic two-sample Mendelian randomisation analysis in 462 933 individuals (53 598 asthma cases) with 12 genetic variants. Lastly, we meta-analysed the genetic findings.ResultsWhile a 1 unit log-transformed higher plasma adiponectin in the Copenhagen General Population Study was associated with an observational OR of 1.65 (95% CI 1.29 to 2.08) for asthma, the corresponding genetic causal OR was 1.03 (95% CI 0.75 to 1.42). The genetic causal OR for asthma in the UK Biobank was 1.00 (95% CI 0.99 to 1.00). Lastly, genetic meta-analysis confirmed lack of association between genetically high plasma adiponectin and causal OR for asthma.ConclusionObservationally, high plasma adiponectin is associated with increased risk of asthma; however, genetic evidence could not support a causal association between plasma adiponectin and asthma.

scholarly journals Genetic predisposition to increased serum calcium, bone mineral density, and fracture risk in individuals with normal calcium levels: mendelian randomisation study

BMJ ◽  
2019 ◽  
pp. l4410 ◽  
Author(s):  
Agustin Cerani ◽  
Sirui Zhou ◽  
Vincenzo Forgetta ◽  
John A Morris ◽  
Katerina Trajanoska ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Serum Calcium ◽  
Genetic Predisposition ◽  
Calcium Supplementation ◽  
Meta Analysis ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
Mineral Density ◽  
The Uk

Abstract Objective To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures. Design Mendelian randomisation study. Setting Cohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics). Participants A genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed. Results A standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm 2 , 95% confidence interval −0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects. Conclusions Genetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.

scholarly journals Plasma urate, lung function and chronic obstructive pulmonary disease: a Mendelian randomisation study in 114 979 individuals from the general population

Thorax ◽  
2017 ◽  
Vol 73 (8) ◽  
pp. 748-757 ◽  
Author(s):  
Camilla J Kobylecki ◽  
Signe Vedel-Krogh ◽  
Shoaib Afzal ◽  
Sune F Nielsen ◽  
Børge G Nordestgaard
Keyword(s):  
Lung Function ◽  
General Population ◽  
Respiratory Symptoms ◽  
High Plasma ◽  
Mendelian Randomisation ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
General Population Study ◽  
Plasma Urate ◽  
Genetically Determined

BackgroundUrate is a strong antioxidant in plasma and may protect against lung function impairment. We tested the hypothesis that high plasma urate is causally associated with better lung function and low risk of respiratory symptoms and COPD.MethodsWe measured lung function and plasma urate in 114 979 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study and genotyped for SLC2A9 rs7442295 and ABCG2 rs2231142 variants, previously associated with high plasma urate, in 110 152 individuals.ResultsIn the two studies combined, multivariable-adjusted 100 µmol/L higher plasma urate was associated with −1.54% (95% CI −1.67 to −1.40) lower FEV1 % predicted and −1.57% (95% CI −1.69 to −1.44) lower FVC % predicted observationally; the corresponding estimates for genetically determined 100 µmol/L higher plasma urate were −0.46% (95% CI −1.17 to 0.25) and −0.40% (95% CI −1.03 to 0.23). High plasma urate was also associated with higher risk of respiratory symptoms; however, genetically determined high plasma urate was not associated with respiratory symptoms. Finally, we identified 14 151 individuals with COPD and found ORs of 1.08 (95% CI 1.06 to 1.11) for COPD observationally and 1.01 (95% CI 0.88 to 1.15) genetically per 100 µmol/L higher plasma urate.ConclusionHigh plasma urate was associated with worse lung function and higher risk of respiratory symptoms and COPD in observational analyses; however, genetically high plasma urate was not associated with any of these outcomes. Thus, our data do not support a direct causal relationship.

scholarly journals Plasma Ionized Calcium and Risk of Cardiovascular Disease: 106 774 Individuals from the Copenhagen General Population Study

2020 ◽  
Author(s):  
Camilla J Kobylecki ◽  
Børge G Nordestgaard ◽  
Shoaib Afzal
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Ischemic Stroke ◽  
General Population ◽  
Population Study ◽  
Reference Interval ◽  
High Plasma ◽  
Biologically Active ◽  
Ionized Calcium ◽  
General Population Study

Abstract Background Circulating total calcium or albumin-adjusted calcium is a risk factor for cardiovascular disease. As the biologically active ionized calcium is a physiologically more relevant measure and its association with cardiovascular disease is poorly understood, we tested the hypothesis that high plasma ionized calcium is associated with higher risk of myocardial infarction and ischemic stroke in individuals in the general population. Methods We included 106 774 individuals from the Copenhagen General Population Study, and defined hypocalcemia and hypercalcemia by the lowest and highest 2.5 percentiles, respectively, using the central 95% reference interval. Information on myocardial infarction and ischemic stroke was from registries and risks calculated using Cox regression and Fine and Gray competing-risks regression. Results During a median follow-up of 9.2 years, 4932 individuals received a diagnosis of either myocardial infarction or ischemic stroke. Hypercalcemia was associated with subdistribution hazard ratios of 1.67 (95%CI: 1.05–2.67) for myocardial infarction, 1.28 (0.81–2.02) for ischemic stroke, and of 1.54 (1.10–2.15) for the combined endpoint compared to individuals with plasma ionized calcium within the reference interval; hypocalcemia was not associated with cardiovascular disease. In models using plasma ionized calcium as a continuous variable, the associations were nonlinear; above the median, each 0.1 mmol/L higher plasma ionized calcium was associated with a hazard ratio of 1.31(1.02–1.68) for myocardial infarction, 1.21 (0.95–1.54) for ischemic stroke, and of 1.28 (1.08–1.53) for the combined endpoint. Conclusions High plasma ionized calcium is associated with higher risk of myocardial infarction and ischemic stroke compared to plasma ionized calcium within the reference interval.

Genetically determined risk of keratinocyte carcinoma and risk of other cancers

2020 ◽  
Author(s):  
Jean Claude Dusingize ◽  
Catherine M Olsen ◽  
Jiyuan An ◽  
Nirmala Pandeya ◽  
Upekha E Liyanage ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Epidemiological Studies ◽  
Risk Scores ◽  
Cancer Site ◽  
Uk Biobank ◽  
Individual Level ◽  
Increased Risk ◽  
The Uk

Abstract Background Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites. Methods In the first approach (one-sample), we calculated the polygenic risk scores (PRS) for KC using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-sample) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants. Results Using the one-sample approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13–1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-sample approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03–1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort. Conclusion Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites.

scholarly journals Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank

BMJ ◽  
2019 ◽  
pp. l476 ◽  
Author(s):  
Shan Luo ◽  
Shiu Lun Au Yeung ◽  
Jie V Zhao ◽  
Stephen Burgess ◽  
C Mary Schooling
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Genetic Variants ◽  
Controlled Trial ◽  
European Ancestry ◽  
Gene Region ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
1000 Genomes ◽  
The Uk

Abstract Objective To determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction. Design Two sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence. Setting Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study. Participants 3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation. Main outcome measures Thromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death. Results Of the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes. Conclusions Endogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.

scholarly journals Increased iron stores prolong the QT interval - a general population study including 20 261 individuals and meta-analysis of thalassaemia major

2016 ◽  
Vol 174 (5) ◽  
pp. 776-785 ◽  
Author(s):  
Lise Fischer Henriksen ◽  
Anne-Sofie Petri ◽  
Hans Carl Hasselbalch ◽  
Jørgen Kim Kanters ◽  
Christina Ellervik
Keyword(s):  
General Population ◽  
Population Study ◽  
Qt Interval ◽  
Meta Analysis ◽  
Thalassaemia Major ◽  
General Population Study ◽  
Iron Stores

scholarly journals Interactions Between Sugar-Sweetened Beverage Consumption and Genetic Variants in the ChREBP Locus on Lipoprotein Concentrations in the UK Biobank: A Replication Study

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1255-1255
Author(s):  
Melanie Guirette ◽  
Danielle Haslam ◽  
Gina Peloso ◽  
Achilleas Pitsillides ◽  
Caren Smith ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Meta Analysis ◽  
Density Lipoprotein ◽  
High Linkage Disequilibrium ◽  
European Ancestry ◽  
Uk Biobank ◽  
Study Objective ◽  
Sugar Sweetened Beverage ◽  
Sweetened Beverage ◽  
The Uk

Abstract Objectives A meta-analysis of 11 CHARGE cohorts (N = 63,599) suggested that genetic variants within or near the CHREBP locus may modify the associations between sugar sweetened beverage (SSB) consumption and high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. The study objective was to replicate these findings in a large independent cohort. Methods Blood lipids and 24-hour recalls were available for 57,794 adults of European ancestry in the UK Biobank (2006-‘10). SSBs included “squash” and “fizzy” drinks derived from a single 24-hr recall. A total of 875 SNPs within or near the CHREBP locus were identified and included in this analysis. Associations between these SNPs and HDL-C and TG concentrations were quantified among participants who did not report SSB consumption (non-consumers, n = 45,866), reported ≥0.5 servings/day of SSB (consumers, n = 11,928), and a subset of consumers who reported ≥2 servings/day of SSB (high consumers, n = 3742). Interaction between SSB and selected SNPs on HDL-C and TG concentrations was evaluated by examining the difference in beta coefficients between strata. Results were considered statistically significant at a Bonferroni-corrected pinteract < 0.0001 (0.05/499 effective tests). Results A significant interaction between SSB consumption and TBL2-rs71556729 on HDL-C concentration previously observed in the meta-analysis was replicated in UK Biobank. However, we observed a stronger interaction for a SNP in high linkage disequilibrium (R2 = 0.93) FZD9-rs34821369 (MAF = 0.03, pinteract = 8.2E-05) with TBL2-rs71556729 (MAF = 0.03, pinteract = 0.0004). Among only SSB consumers, each additional minor G allele at FZD9-rs34821369 was associated with mean HDL-C concentrations 1.63 mg/dL (SE = 0.53, P = 0.002) higher than those with the major T allele. Conclusions Our results suggest that adults with the minor allele at FZD9-rs34821369 may be protected against SSB-induced low HDL-C concentrations. These results are consistent the findings from a prior meta-analysis of 11 cohorts. Funding Sources NIH, AHA, USDA-ARS. This research has been conducted using the UK Biobank Resource (Application Number 35,835).

scholarly journals Causal Relationship between Plasma Adiponectin and Body Mass Index: One- and Two-Sample Bidirectional Mendelian Randomization Analyses in 460 397 Individuals

2020 ◽  
Vol 66 (12) ◽  
pp. 1548-1557
Author(s):  
Maria Booth Nielsen ◽  
Yunus Çolak ◽  
Marianne Benn ◽  
Børge Grønne Nordestgaard
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
High Plasma ◽  
General Population Study ◽  
Plasma Adiponectin ◽  
Genetically Determined ◽  
Randomization Analysis ◽  
High Bmi

Abstract Background Adiponectin is a protein hormone produced by adipocytes that may play an important role in obesity. However, the causal interrelation between plasma adiponectin and body mass index (BMI) is still uncertain. We tested the hypotheses that (a) plasma adiponectin and BMI are inversely associated observationally, (b) genetically high BMI is associated with lower plasma adiponectin, and (c) genetically high plasma adiponectin is associated with lower BMI. Methods Information on 108 896 individuals from the Copenhagen General Population Study was used in observational and bidirectional one-sample Mendelian randomization analyses, using 5 genetic variants for BMI and 3 for adiponectin. For independent confirmation, information on 322 154 individuals from the GIANT consortium, and 29 347 individuals from the ADIPOGen consortium was used in bidirectional two-sample Mendelian randomization analysis, using 68 genetic variants for BMI and 14 for adiponectin. Results In observational analyses, a 1 kg/m2 increase in BMI was associated with −0.44 µg/mL (95% confidence interval: −0.46, −0.42) in plasma adiponectin, whereas a 1 µg/mL increase in plasma adiponectin was associated with −0.11 kg/m2 (−0.12, −0.11) in BMI. In causal genetic analyses, no associations were observed between BMI and plasma adiponectin and vice versa. In one-sample Mendelian randomization analyses, a 1 kg/m2 genetically determined increase in BMI was associated with −0.13 µg/mL (−0.53, 0.28) in plasma adiponectin, whereas a 1 µg/mL genetically determined increase in plasma adiponectin was associated with 0.01 kg/m2 (−0.05, 0.07) in BMI. Corresponding estimates in the two-sample Mendelian randomization analyses were 0.03 µg/mL (−0.02, 0.07) and 0.03 kg/m2(−0.02, 0.07), respectively. Conclusions Observationally, plasma adiponectin and BMI are inversely associated. In contrast, genetically high plasma adiponectin is unlikely to influence BMI, and genetically high BMI is unlikely to influence plasma adiponectin.

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