ATS 2026

Joannah Kim, Isabelle Koff, Thomas Ardiles, Aamir Ali1, Brandon Brown. TrilliumBiO, Rockville, MD, United States, Grifols Shared Service North America, Research Triangle Park, NC, 3UC Riverside School of Medicine, Riverside, CA, United States

Introduction:

  • Alpha-1 Antitrypsin Deficiency (AATD) is a hereditary disorder that predisposes individuals to early-onset pulmonary disease, including emphysema and COPD.
  • AATD remains underdiagnosed due to low awareness despite multiple screening options.
  • The AlphaID™ Confirm Testing Program provides a nationwide platform for genotyping and quantitative A1AT from dried blood spots (DBS), enabling large-scale assessment of genotype–phenotype relationships in a real-world population.

Methods:

  • Retrospective study that evaluated the A1AT serum levels derived from DBS in relation to observed SERPINA1 genotype from 35,186 patients tested between January 2024 and September 2025 through AlphaID™ Confirm Testing Program to determine A1AT.
  • A1AT concentrations determined by immunoturbidimetry.
  • SERPINA1 genotypes determined by real-time PCR.
  • Quantitative A1AT levels (mg/dL) were compared across SERPINA1 genotypes, categorized as normal (MM), heterozygous, or compound heterozygous variants.
  • Descriptive and comparative statistical analyses were used to assess mean and median A1AT concentrations, interquartile variability, and distribution.

Results:

  • The M/M genotype represented the largest cohort (n = 27,553.0) with the highest median A1AT at 149.0 mg/dL. Common heterozygotes showed reductions in A1AT levels: M/S (~14% reduction; 128.0 mg/dL) and M/Z (~33% reduction; 100.0 mg/dL), while S/S homozygotes fell intermediately at 105.0 mg/dL (95% CI: 99.0–110.0) , approximately 30% below M/M yet modestly above the 90.0 mg/dL deficiency threshold (Table 1).
  • M/F (145.0 mg/dL), M/I (133.0 mg/dL), F/S (121.0 mg/dL), and F/F (143.4 mg/dL) genotypes maintained near-normal A1AT levels well above the 90.0 mg/dL threshold, with distributions closely resembling M/M (Tables 1–2, Figure).
  • The S/Z and Z/Z genotypes had the lowest median A1AT levels among common genotypes (68.5 mg/dL each), consistent with severe deficiency. Z/Z showed the widest CI for mean A1AT (66.0–109.1 mg/dL), likely reflecting inclusion of patients receiving augmentation therapy or post-liver transplant, suggesting some Z/Z values may not represent untreated baseline physiology (Table 1).
  • Among rare genotypes, Z/I (median 68.0 mg/dL; 95% CI: 60.0–75.0) reached the severe deficiency range comparable to S/Z and Z/Z, consistent with the combined burden of two low-expressing alleles. S/M Heerlen (57.0 mg/dL) and S/M Malton (63.0 mg/dL) demonstrated the lowest mean A1AT levels of all rare genotypes, with narrow distributions sharply concentrated below the 90.0 mg/dL threshold (Table 2, Figure 1).
  • Several rare genotypes produced clinically meaningful but moderate reductions: M/P Lowell (median 113.0 mg/dL; 95% CI: 106.0–127.0) and rare M variants (Heerlen, Malton, Procida; 88.0–93.5 mg/dL) showed levels comparable to M/Z; F/Z (84.0 mg/dL; 95% CI: 75.0–91.0) fell below the normal threshold; and S/I (94.0 mg/dL; 95% CI: 83.0–105.0), M/Q0 West (92.0 mg/dL; 95% CI: 62.0–105.0), and M/Q0 Clayton (91.0 mg/dL; 95% CI: 74.0–98.0) clustered around the 90.0 mg/dL normal threshold. However small sample sizes in the latter two limit interpretation (Table 2, Figure 1).

Conclusions:

  • This retrospective study–representing one of the largest reported cohorts of AATD-positive individuals–reinforces the quantitative concordance between SERPINA1 genotype and A1AT serum concentration.
  • The findings underscore that genotypes alone may underestimate clinical risk in some individuals. Improved understanding of genotype–phenotype correlations from programs such as AlphaID™ Confirm can inform precision screening, guide early intervention, and advance personalized management strategies for AATD-associated lung disease.

References:

Sandhaus, R. A., Turino, G., Brantly, M. L., Campos, M., Cross, C. E., Goodman, K., Hogarth, D. K., Knight, S. L., Stocks, J. M., Stoller, J. K.,
Strange, C., & the Alpha-1 Foundation (2016). The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic
Obstructive Pulmonary Diseases: Journal of the COPD Foundation, 3(3), 668–682. https://doi.org/10.15326/jcopdf.3.3.2015.0182

Disclosure:

TrilliumBiO partners with Grifols as the laboratory service provider for the AlphaID™ Screening Program.

Presented at the American Thoracic Society; May 15-20 2026; Orlando, FL