Abstract
BackgroundAssociations 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.MethodsWe 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).ResultsWe 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.ConclusionsThe 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.
Highlights
Associations of low lung function with features of poor cardio-metabolic health have been reported
Applying several Mendelian randomisation (MR) techniques, we found a consistent association between type 2 diabetes (T2D)-specific Single nucleotide polymorphism (SNP) and forced vital capacity (FVC) and Forced expiratory volume in second one (FEV1)/FVC (Fig. 3)
We discovered consistent associations between FEV1/FVC-specific SNPs and diastolic blood pressure (DBP), systolic blood pressure (SBP) as well as pulse pressure (PP) suggesting a causal effect of FEV1/FVC on blood pressure (Fig. 3B, Additional File 1: Fig. S10-S13)
Summary
Associations of low lung function with features of poor cardio-metabolic health have been reported. It is, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors. There is a growing literature on the association of obesity with lung function and chronic lung disease, the underlying pathways and potential mediators are not well understood. Several observational studies have reported an association between low lung function and cardio-metabolic traits, including obesity [2,3,4,5]. It is not possible to infer whether associations such as those seen in NFBC1966, and in the other studies, are causal as most studies were not able to control for all known potential confounders or residual confounding by unknown factors
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