Genetic association of inflammatory marker GlycA with lung function and respiratory diseases

Abstract

Association of circulating glycoprotein acetyls (GlycA), a systemic inflammation biomarker, with lung function and respiratory diseases remain to be investigated. We examined the genetic correlation, shared genetics, and potential causality of GlycA (N = 115,078) with lung function and respiratory diseases (N = 497,000). GlycA showed significant genetic correlation with FEV1 (r_g = -0.14), FVC (r_g = -0.18), asthma (r_g = 0.21) and COPD (r_g = 0.31). We consistently identified ten shared loci (including chr3p21.31 and chr8p23.1) at both SNP and gene level revealing potential shared biological mechanisms involving ubiquitination, immune response, Wnt/β-catenin signaling, cell growth and differentiation in tissues or cells including blood, epithelium, fibroblast, fetal thymus, and fetal intestine. Genetically elevated GlycA was significantly correlated with lung function and asthma susceptibility (354.13 ml decrement of FEV1, 442.28 ml decrement of FVC, and 144% increased risk of asthma per SD increment of GlycA) from MR analyses. Our findings provide insights into biological mechanisms of GlycA in relating to lung function, asthma, and COPD.

Fig. 1. Whole genome genetic correlations of inflammatory biomarkers with lung function parameters (FEV1, FVC, FEV1/FVC ratio, and PEF), asthma, and COPD using linkage disequilibrium score regression (LDSC).

Colors represent the magnitude of genetic correlation of each inflammatory biomarkers with lung function parameters (FEV1, FVC, FEV1/FVC ratio, and PEF), asthma, and COPD using LDSC, red for positive genetic correlation and blue for negative genetic correlation. Numbers represent the genetic correlation at nominal significance level (P < 0.05); ** represent significant genetic correlation after controlling for multiple testing (P < 0.05/30). Abbreviations: GlycA glycoprotein acetyls, hsCRP high sensitivity C-reactive protein, WBC white blood cell, FEV1 forced expired volume in 1 s, FVC forced vital capacity, PEF peak expiratory flow, COPD chronic obstructive pulmonary diseases. All P values are two-side.

Fig. 2. Partitioned genetic correlations of GlycA with lung function parameters (FEV1, FVC, FEV1/FVC ratio, and PEF), asthma, and COPD according to 11 functional categories using linkage disequilibrium score regression (LDSC).

Colors represent the magnitude of genetic correlation of GlycA with lung function parameters (FEV1, FVC, FEV1/FVC ratio, and PEF), asthma, and COPD at each functional category using LDSC, red for positive genetic correlation and blue for negative genetic correlation. Numbers represent the genetic correlation at nominal significance level (P < 0.05); * represent significant genetic correlation after controlling for multiple testing (P < 0.05/ [30 × 11]). Abbreviations: GlycA glycoprotein acetyls, FEV1 forced expired volume in 1 s, FVC forced vital capacity, PEF peak expiratory flow, COPD chronic obstructive pulmonary diseases. All P values are two-side.

Fig. 3. GARFIELD enrichment wheel plots in DNase I–hypersensitive sites (hotspots) for traits (FEV1, FVC, asthma, and COPD) significantly genetically correlated with GlycA.

A GARFIELD enrichment wheel plots for FEV1; B GARFIELD enrichment wheel plots for FVC; C GARFIELD enrichment wheel plots for asthma; D GARFIELD enrichment wheel plots for COPD. Radial lines show OR values at eight GWAS P value thresholds (T) for all ENCODE and Roadmap Epigenomics DHS cell lines, sorted by tissue on the outer circle. Dots in the inner ring of the outer circle denote significant GARFIELD enrichment (if present) at T < 10⁻⁵ (outermost) to T < 10⁻⁸ (innermost) after multiple-testing correction for the number of effective annotations and are colored with respect to the tissue cell type tested (font size of tissue labels reflect the number of cell types from that tissue). GlycA glycoprotein acetyls, FEV1 forced expired volume in 1 s, FVC forced vital capacity, COPD chronic obstructive pulmonary diseases.