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

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.

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 AATD patients provides clues to the disease mechanisms associated with Z heterozygosity. Early-stage research is focused on identifying the proportion of MZ individuals who might be at increased risk of disease and determining whether treatment strategies in current use or under investigation for ZZ patients might be appropriate and beneficial for Z heterozygotes. Participants discussed clinical trials design and infrastructure needed to study the AATD heterozygous population.

Evidence at this time suggests modest increased risk among Z heterozygotes as a result of carrying a single Z gene. Associated risk of this population to develop either liver or lung disease is modified by genetic and environmental factors. Focused clinical trials are needed before using treatments beneficial for homozygous Z individuals in this population.

Not applicable.