Genetic correlation and causal relationships between cardio-metabolic traits and lung function impairment

Genome Medicine

Karl-Heinz Herzig¹  Sylvain Sebert²  Juha Auvinen²  Marjo-Riitta Jarvelin³  Abbas Dehghan³  Matthias Wielscher³  David Mosen-Ansorena³  Louise V. Wain⁴  Andre F. S. Amaral⁵  Diana van der Plaat⁵  Debbie L. Jarvis⁵ 

[1] Biocenter of Oulu, University of Oulu;Center for Life Course Health Research, Faculty of Medicine, University of Oulu;Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London;Genetic Epidemiology Group, Department of Health Sciences, George Davies Centre, University of Leicester;National Heart and Lung Institute (NHLI), Imperial College London;

关键词: Mendelian randomisation;    Metabolic syndrome;    Obesity;    Chronic obstructive pulmonary disease;    UK Biobank;   

DOI  :  10.1186/s13073-021-00914-x

来源: DOAJ

【 摘 要 】

Abstract Background Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. Methods We performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000). Results We observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure. Conclusions The present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

【 授权许可】

Unknown