Blood Eosinophil Count and Metabolic, Cardiac and Pulmonary Outcomes: A Mendelian Randomization Study

Amini, Marzyeh; Vonk, Judith M.; Abbasi, Ali; Prins, Bram P.; Bruinenberg, Marcel; Franke, Lude; Harst, Pim van der; Navis, Gerjan; Koppelman, Gerard H.; Wolffenbuttel, Bruce H. R.; Boezen, H. Marike; Snieder, Harold; Chasman, Daniel I.; Alizadeh, Behrooz Z.

doi:10.1017/thg.2018.6

Cited by 11 publications

(12 citation statements)

References 56 publications

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“…MR analysis helps to evaluate the causal relationship of WBC subtypes with lung function. To our knowledge, only one MR study investigated the association of circulating eosinophil counts with FEV 1 by using Netherlands LifeLines cohort data (n ¼ 13,301) and they did not find causal association [38], which was consistent with the current results. However, we found that genetically elevated total WBC and neutrophil counts were associated with decreased FVC and FEV 1 among the Asian population.…”

Section: Discussionsupporting

confidence: 89%

Circulating white blood cells and lung function impairment: the observational studies and Mendelian randomization analysis

Wang

et al. 2021

Annals of Medicine

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Background: Circulating white blood cell (WBC) counts have been related to lung function impairment, but causal relationship was not established. We aimed to evaluate independent effects and causal relationships of WBC subtypes with lung function. Methods: The 19,159 participants from NHANES 2011-2012 (n ¼ 3570), coke-oven workers (COW, n ¼ 1762) and Dongfeng-Tongji (DFTJ, n ¼ 13,827) cohorts were included in the observational studies. The associations between circulating counts of WBC subtypes and prebronchodilator lung function were evaluated by linear regression models and LASSO regression was used to select effective WBC subtypes. Summary statistics for WBC-associated SNPs were extracted from literature, and Mendelian randomization (MR) analysis with inverse-variance weighted (IVW) method was applied to estimate the causal effects of total WBC and subtypes on lung function among 4012 subjects from COW (n ¼ 1126) and DFTJ cohorts (n ¼ 2886). Results: Total WBC counts were negatively associated with lung function among three populations and their pooled analysis indicated that per 1 Â 10 9 cells/L increase in total WBC was associated with 36.13 (95% CI: 30.35, 41.91) mL and 25.23 (95% CI: 19.97, 30.50) mL decrease in FVC and FEV 1 , respectively. Independent associations with lung function were found for neutrophils, monocytes, eosinophils and basophils (all p < .05), except lymphocytes. Besides, IVW MR analysis showed that genetically predicted total WBC and neutrophil counts were associated with reduced FVC (p ¼ .017 and .021, respectively) and FEV 1 (p ¼ .048 and .043, respectively). Conclusions: WBC subtypes were independently associated with lower lung function except lymphocytes. Our findings suggest that circulating neutrophils may be causal factors in lung function impairment. KEY MESSAGESWhite blood cell (WBC) subtypes were negatively associated with lung function level except lymphocytes in the observational studies. Associations of WBC subtypes with lung function may be modified by sex and smoking. Mendelian randomization analysis shows that neutrophils may be causal factors in lung function impairment.

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Section: Discussionsupporting

confidence: 89%

Circulating white blood cells and lung function impairment: the observational studies and Mendelian randomization analysis

Wang

et al. 2021

Annals of Medicine

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“…We are aware of one other MR study of eosinophil counts in relation to asthma, COPD, FEV 1 and FEV 1 /FVC, conducted entirely within the LifeLines cohort (N=13,301, 5 SNPs used as IVs). 16 In that study, confidence intervals for causal estimates of eosinophils were consistent with the null, albeit point estimates were consistent with a harmful effect for FEV 1 /FVC, asthma and COPD. Here, we used the largest eosinophil count GWAS to date (N=172,275) 14 to derive IVs, and found evidence for causality of eosinophils in reducing FEV 1 /FVC, the lung function trait in which impairment is the key feature of COPD diagnosis, and FEV 1 , the trait used to grade airflow limitation in COPD.…”

Section: Discussionmentioning

confidence: 68%

“…15 However, causality of these associations has yet to be established, with the only previous MR of lung function being of small sample size, with imprecise effect estimates precluding confident inference. 16 Moreover, causal effects of eosinophils on other respiratory phenotypes, such as asthma-COPD overlap (ACO), and respiratory infections are yet to be investigated. Diagnosis of COPD is made by spirometry if the ratio of the forced expiratory volume in one second (FEV 1 ) to the forced vital capacity (FVC), FEV 1 /FVC, is <0.7, with airflow obstruction being graded according to predicted values of FEV 1 .…”

Section: Introductionmentioning

confidence: 99%

Mendelian randomisation analyses of eosinophils and other blood cell types in relation to lung function and disease

Guyatt

John

Williams

et al. 2020

Preprint

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Background: Eosinophils are granulocytes associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled by interleukin-5: anti-interleukin-5 agents reduce asthma and COPD exacerbation frequency, and response correlates with baseline eosinophil counts. However, causal relationships between eosinophils and other respiratory phenotypes are less studied. Methods: We investigated causality between eosinophils and: lung function, acute exacerbations of COPD (AECOPD), asthma-COPD overlap (ACO), moderate-to-severe asthma, and respiratory infections. We performed Mendelian randomization (MR) using 151 genetic variants from genome-wide association studies of blood eosinophil counts in UK Biobank/INTERVAL, and respiratory data from UK Biobank, using MR methods relying on different assumptions for validity. Multivariable MR using eight blood cell type exposures was performed for outcomes showing evidence of causation by eosinophils. Findings: There was evidence that higher eosinophils reduce FEV1/FVC and FEV1 (weighted median estimator, SD change FEV1/FVC per SD eosinophils: -0.054 [95%CI -0.078,-0.029]. There was also evidence that eosinophils cause ACO (weighted median OR 1.44 [95%CI 1.19,1.74]), and asthma (weighted median OR 1.50 [95%CI 1.23,1.83]). Multivariable MR for FEV1/FVC, FEV1, ACO and asthma suggested that eosinophils were the cell type with the most important effect. Causal estimates of individual variants were heterogeneous, which may arise from pleiotropy. Interpretation: We found evidence that eosinophils reduce lung function, and increase ACO and asthma risk, on average over the set of genetic variants studied. Eosinophils appear to be causal determinants of fixed airflow obstruction among individuals with features of both asthma and COPD.

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“…We have previously demonstrated a potential causal effect of low surfactant protein D (SPD) in increasing COPD risk and progression using the MR framework. [12] Other molecules associated with COPD outcomes in epidemiological studies, such as C-reactive protein, [13] interleukin-6 [14] and blood eosinophil count, [15] do not yield evidence of causality when subjected to analysis by MR. Therefore, .…”

Section: Introductionmentioning

confidence: 99%

Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study

Milne

Cordero

et al. 2020

Thorax

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BackgroundThe anti-inflammatory pneumoprotein club cell secretory protein-16 (CC-16) is associated with the clinical expression of chronic obstructive pulmonary disease (COPD). We aimed to determine if there is a causal effect of serum CC-16 level on the risk of having COPD and/or its progression using Mendelian randomisation (MR) analysis.MethodsWe performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study (LHS), n=3850 and ECLIPSE, n=1702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) as instrumental variables in MR analysis to identify a causal effect of serum CC-16 on ‘COPD risk’ (ie, case status in the International COPD Genetics Consortium/UK-Biobank dataset; n=35 735 COPD cases, n=222 076 controls) and ‘COPD progression’ (ie, annual change in forced expiratory volume in 1 s in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1111 lung tissue samples from the Lung Expression Quantitative Trait Locus Study.ResultsWe identified seven SNPs independently associated (p<5×10–8) with serum CC-16 levels; six of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (MR estimate (SE) −0.11 (0.04), p=0.008) and progression (LHS only, MR estimate (SE) 7.40 (3.28), p=0.02). Five of the SNPs were also associated with gene expression in lung tissue (at false discovery rate <0.1) of several genes, including the CC-16-encoding gene SCGB1A1.ConclusionWe have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on the risk of having COPD and its progression, the biological basis of which warrants further investigation.

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Blood Eosinophil Count and Metabolic, Cardiac and Pulmonary Outcomes: A Mendelian Randomization Study

Cited by 11 publications

References 56 publications

Circulating white blood cells and lung function impairment: the observational studies and Mendelian randomization analysis

Circulating white blood cells and lung function impairment: the observational studies and Mendelian randomization analysis

Mendelian randomisation analyses of eosinophils and other blood cell types in relation to lung function and disease

Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study

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