Leveraging Population Genomics for Individualized Correction of the Hallmarks of Alpha-1 Antitrypsin Deficiency.

Deep medicine is rapidly moving towards a high-definition approach for therapeutic management of the patient as an individual given the rapid progress of genome sequencing technologies and machine learning algorithms. While considered a monogenic disease, alpha-1 antitrypsin (AAT) deficiency (AATD) patients present with complex and variable phenotypes we refer to as the "hallmarks of AATD" that involve distinct molecular mechanisms in the liver, plasma and lung tissues, likely due to both coding and non-coding variation as well as genetic and environmental modifiers in different individuals. Herein, we briefly review the current therapeutic strategies for the management of AATD. To embrace genetic diversity in the management of AATD, we provide an overview of the disease phenotypes of AATD patients harboring different AAT variants. Linking genotypic diversity to phenotypic diversity illustrates the potential for sequence-specific regions of AAT protein fold design to play very different roles during nascent synthesis in the liver and/or function in post-liver plasma and lung environments. We illustrate how to manage diversity with recently developed machine learning (ML) approaches that bridge sequence-to-function-to-structure knowledge gaps based on the principle of spatial covariance (SCV). SCV relationships provide a deep understanding of the genotype to phenotype transformation initiated by AAT variation in the population to address the role of genetic and environmental modifiers in the individual. Embracing the complexity of AATD in the population is critical for risk management and therapeutic intervention to generate a high definition medicine approach for the patient.