Z variant heterozygosity in alpha-1 antitrypsin deficiency: disease risk and treatment implications

BACKGROUND: Individuals heterozygous for alpha-1 antitrypsin deficiency (AATD) have one copy of the normal "M" allele and one copy of an abnormal allele ("Z", "S", or another variant) in the SERPINA1 gene. Historically, evidence has been lacking to support the concept that heterozygotes are at increased risk for liver and/or lung complications compared to individuals homozygous for the M allele. However, growing evidence suggests that inheritance of a single Z allele increases the risk of disease in some individuals. The Alpha-1 Foundation convened a workshop on October 27, 2023, in Bethesda, Maryland that included stakeholders from the research, pharmaceutical, and patient communities. The focus of the meeting was to describe and assess what is known about the relative risks of liver and/or lung disease for heterozygotes and to identify future avenues of research into disease mechanisms and clinical phenotypes in MZ heterozygotes. RESULTS: Population-based and family studies of individuals heterozygous for the AATD Z risk allele demonstrate that a proportion of these individuals have relatively higher risk for lung or liver disease than do individuals harboring no variants in SERPINA1. Included are studies identifying increased rates of chronic obstructive pulmonary disease (COPD) among MZ and SZ smokers compared to MM individuals with similar histories of smoke exposure. Evidence collected from human macrophages, cellular and mouse models of AATD, and explanted tissue from...