The Relationship between Plasma Alpha-1-Antitrypsin Polymers and Lung or Liver Function in ZZ Alpha-1-Antitrypsin-Deficient Patients

Abstract

Alpha-1-Antitrypsin (AAT) is a protein of the SERPINA1 gene. A single amino acid mutation (Lys342Glu) results in an expression of misfolded Z-AAT protein, which has a high propensity to intra- and extra-cellular polymerization. Here, we asked whether levels of circulating Z-AAT polymers are associated with the severity of lung disease, liver disease, or both. We obtained cross sectional data from the Dutch part of the Alpha1 International Registry of 52 ZZ-AAT patients who performed a pulmonary function test and donated a blood sample on the same day. From the Alpha-1 Liver Aachen Registry, we obtained a cohort of 40 ZZ-AAT patients with available data on their liver function. The levels of plasma Z-AAT polymers were determined using a LG96 monoclonal antibody-based sandwich ELISA. In a Dutch cohort, the median plasma level of Z-AAT polymers of patients diagnosed for pulmonary disease was 947.5 µg/mL (733.6–1218 µg/mL (95% CI)), which did not correlate with airflow obstruction or gas transfer value. In the Alpha-1 liver patient cohort, the median polymer level was 1245.9 µg/mL (753–2034 µg/mL (95% CI)), which correlated with plasma gamma-glutamyl transferase (GGT, rs = 0.57, p = 0.001), glutamate dehydrogenase (GLDH, rs = 0.48, p = 0.002) and triglycerides (TG, rs = 0.48, p = 0.0046). A Wilcoxon rank test showed higher Z-AAT polymer values for the liver over the lung group (p < 0.0001). These correlations support a possible link between plasma Z-AAT polymers and the liver function.

Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy to treat murine liver diseases

“…Engraftment of these functional cells reduces misfolded Z-AAT protein burden in liver tissue and sera, and ALT levels are significantly reduced indicating restoration of overall liver function. There is a growing body of evidence that demonstrates a correlation between circulating Z-AAT polymers and overall liver disease in AATD patients, thus, reducing serum Z-AAT is promising for overall patient outcomes 49,50 . Approximately 34 million individuals worldwide carry disease alleles for AATD, with no existing cure for associated liver disease other than liver transplantation 51 .…”

Serum a‐1 antitrypsin as a novel biomarker in chronic heart failure

“…AAT is a 52‐kDa glycoprotein which is encoded by SERPINA1 gene and acts as an antiprotease 25,26 . The main target of AAT is neutrophil elastase (NE) 27 .…”

“…AAT is a 52‐kDa glycoprotein which is encoded by SERPINA1 gene and acts as an antiprotease. 25 , 26 The main target of AAT is neutrophil elastase (NE). 27 Previous studies suggest that both AAT and NE are related to inflammation, and the imbalance between AAT and NE is considered as a possible mechanism for atherosclerotic plaque and aneurysm formation.…”

Tracing genetic diversity captures the molecular basis of misfolding disease

“…These results further suggest that GRP94 ATPase inhibition increases the tolerance of the ER for AAT folding in a manner that can differentially impact the monomer secretion and the NE inhibitory activity on a residue-by-residue basis. We next explored the impact of these changes on intracellular polymer accumulation-the hallmark of liver disease 32,[70][71][72] .…”