Which allele is associated with the highest risk of liver and lung disease in Alpha 1 Antitrypsin Deficiency?

The Z allele is primarily associated with a significantly elevated risk of liver and lung disease in individuals with Alpha-1 Antitrypsin Deficiency (AAT deficiency). This is due to the Z allele resulting in a mutated form of the alpha-1 antitrypsin protein that is less stable and more prone to aggregation. When this protein accumulates in the liver, it can lead to liver damage, including cirrhosis, and may also result in reduced levels of alpha-1 antitrypsin in the bloodstream, leading to lung diseases such as emphysema.

The other alleles—M, S, and P—are associated with different levels of AAT and various risks for disease but do not carry the same degree of risk as the Z allele for severe conditions. The M allele is considered the normal allele, while the S allele is associated with a decreased level of AAT compared to M, but neither poses the extreme risk to organs seen with the Z allele. The P allele is not commonly referenced in relation to AAT deficiency. Therefore, the Z allele is clearly indicated as the one most closely linked to severe disease outcomes in affected individuals.