Serum IgA isotypes are associated with percent emphysema, wall thickness and lung function decline

Abstract

Rationale: Immunoglobulin A (IgA) deficiency, a rare, highly heritable trait, is associated with frequent pulmonary infections, emphysema, airway changes and low lung function; however, it is unclear if reduced IgA levels may affect lung structure and function.

Methods: Serum IgA, IgA1 and galactose-deficient IgA1 (Gd-IgA1) levels were measured in the population-based Multi-Ethnic Study on Atherosclerosis (MESA). The MESA Lung Study measured percent emphysema on cardiac CT and airway dimensions on chest CT, and performed spirometry. Regression models were evaluated after adjustment for demographic and CT factors. Mendelian randomisation (MR) analyses were conducted using genetic variants from the Trans-Omics for Precision Medicine (TOPMed) programme. A replication analysis was performed in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS).

Measurements and main results: Among 5497 participants, lower log-normalised serum IgA levels were associated with greater percent emphysema (β=-0.084; 95% CI -0.14 to -0.026; p=0.005), which was confirmed on MR (β=-0.79; 95% CI -1.4 to -0.18; p=0.011). Greater log-normalised serum Gd-IgA1 levels were associated with airway wall thickness (β=0.0079; 95% CI 0.0017 to 0.014; p=0.012; n=2580) and decline in the forced expiratory volume in one second (FEV1) (β=-0.012; 95% CI -0.021 to -0.0036; p=0.0055; n=2778) and FEV1/forced vital capacity (FVC) ratio (β=-0.0028; 95% CI -0.0048 to -0.00084; p=0.0054; n=2778).

Conclusion: Lower serum IgA levels were associated with greater percent emphysema. Additionally, higher Gd-IgA1 levels were associated with airway wall thickness and lung function decline. These findings support a protective role of IgA in emphysema pathogenesis and possible deleterious role of Gd-IgA1 in airway diseases.

Keywords: Emphysema; Forced Expiratory Volume; Imaging/CT MRI etc.

Figure 1.. Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 1–6 (2000–2018) with serum immunoglobulin A (IgA), percent emphysema on cardiac CT, airway measurements on full-lung CT and lung function).

The blue colored boxes describe the number of participants used for the cross-sectional and subsequent MR emphysema analyses. The orange-colored boxes describe the number of participants used for the cross-sectional and MR spirometry analyses. The green colored boxes describe the number of participants used for the cross-sectional and MR segmental airways analyses. Longitudinal analyses of spirometry measures were conducted on participants with at least 2 measures across exams 3/4, 5, and 6.

Figure 2.. Mendelian randomization (MR) analysis of serum IgA levels with percent emphysema and of serum Gd-IgA1 with airway wall thickness and lung function decline.

A) MR analysis of serum IgA levels on percent emphysema was conducted utilizing 19 variants found to be associated with IgA. These variants were used to create an instrumental variable (IV) for analysis. This analysis showed a potentially causal association between serum IgA levels and percent emphysema. Confounding bias was observed (p< 0.016) but corrected for in these analyses. B) A similar MR analysis of serum Gd-IgA1 levels on segmental airway wall thickness was conducted using 3 variants found to be associated with Gd-IgA1.This analysis showed no association between serum Gd-IgA1 levels and airway wall thickness. C) An MR analysis of serum Gd-IgA1 levels on FEV1 was conducted using 3 variants found to be associated with Gd-IgA1. This analysis showed no association between serum Gd-IgA1 levels and FEV1 decline. D) Lastly, an MR analysis of serum Gd-IgA1 levels on FEV1/FVC ratio decline was conducted using 3 variants found to be associated with Gd-IgA1. No association was seen between serum Gd-IgA1 levels and FEV1/FVC ratio.