Journal Article

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

Amaral, Andre F. S., Jarvis, Debbie L., Wielscher, Matthias, Dehghan, Abbas, van der Plaat, Diana, Jarvelin, Marjo-Riitta, Sebert, Sylvain, Wain, Louise V., Herzig, Karl-Heinz, Mosen-Ansorena, David, Auvinen, Juha

2021

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Bioinformatics / Biomarkers / Biomedical and Life Sciences / Biomedicine / Blood pressure / Body Mass Index / C-reactive protein / Cancer Research / Cardiometabolic Risk Factors / Cardiovascular disease / Cardiovascular Diseases - complications / Cardiovascular Diseases - epidemiology / Chronic obstructive pulmonary disease / Coronary vessels / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - complications / Diabetes Mellitus, Type 2 - epidemiology / Disease Susceptibility / Environmental factors / Estimates / Finland - epidemiology / Genetic Association Studies / Genetic Predisposition to Disease / Genetic research / Genome-wide association studies / Genomes / Genomics / Heritability / Human Genetics / Humans / Inflammation / Inflammation Mediators / Linkage Disequilibrium / Lipoproteins / Lung - metabolism / Lung - physiopathology / Lung diseases / Lung Diseases - epidemiology / Lung Diseases - etiology / Lung diseases, Obstructive / Mediation / Medicine/Public Health / Mendelian randomisation / Metabolic syndrome / Metabolic Syndrome - complications / Metabolic Syndrome - epidemiology / Metabolism / Metabolomics / Obesity / Polymorphism, Single Nucleotide / Principal components analysis / Public Health Surveillance / Quantitative Trait Loci / Quantitative Trait, Heritable / Respiratory function / Respiratory Function Tests / Risk Assessment / Risk factors / Single-nucleotide polymorphism / Systems Biology / Triglycerides / Type 2 diabetes / UK Biobank / Womens health