Quantification of circulating alpha-1-antitrypsin polymers associated with different SERPINA1 genotypes
Alice M Balderacchi1, Mattia Bignotti2, Stefania Ottaviani1
1Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, UOC Pulmonology, 18631Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Clinical Chemistry and Laboratory Medicine
|February 26, 2024
Summary
Quantifying circulating polymers (CP) in alpha-1-antitrypsin deficiency (AATD) reveals disease biomarkers. Elevated CP levels in patients with specific AATD genotypes correlate with disease severity and can identify polymer-forming AAT variants.
Area of Science:
- Genetics and Molecular Biology
- Biochemistry
- Clinical Diagnostics
Background:
- Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder caused by SERPINA1 gene mutations, leading to reduced alpha-1-antitrypsin (AAT) levels.
- Low AAT levels increase emphysema risk due to uncontrolled neutrophil elastase activity.
- AAT variants, particularly the Z-AAT mutant, cause liver disease via intracellular polymer accumulation; circulating polymers (CP) may indicate this.
Purpose of the Study:
- To accurately quantify the percentage of circulating polymers (CP) in individuals with various SERPINA1 genotypes.
- To assess the potential of CP as biomarkers for intra-hepatic AAT accumulation and disease severity in AATD.
Main Methods:
- Circulating polymer (CP) concentration was measured using a sensitive sandwich ELISA.
- The assay utilized the polymer-specific 2C1 monoclonal antibody for capture.
- Measurements were performed on plasma or Dried Blood Spot (DBS) samples.
Main Results:
- CP levels were significantly elevated in patients with PI*SZ and PI*ZZ genotypes, showing considerable intra-genotype variability.
- Higher CP percentages correlated with elevated C-reactive protein levels.
- Increased CP were also observed in carriers of Mmalton, Mprocida, I, Plowell, and Mherleen variants, especially when heterozygous with Z-AAT.
Conclusions:
- CP quantification is valuable for clinical laboratories, offering insights into AATD.
- Variable CP amounts in patients with the same genotype may correlate with differing lung and liver disease severity.
- CP measurements can identify the polymerogenic potential of novel, ultrarare AAT variants.
Related Concept Videos
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
01:16Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters
The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
01:29Pharmacogenomics: Identification of New Drug Targets
Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...