Abstract Rationale Alpha-1 Antitrypsin Deficiency (AATD) is a hereditary disorder that predisposes individuals to early-onset pulmonary disease, including emphysema and chronic obstructive pulmonary disease (COPD). AATD remains underdiagnosed due to low awareness and 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. Method 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. 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 A1AT concentrations, interquartile variability, and distribution. Results Distinct genotype-dependent differences in A1AT concentrations were observed (Table 1). The normal MM group demonstrated a median of 149 mg/dL (range: 104-216 mg/dL), while MF and MI carriers showed comparable medians of approximately 145 mg/dL and 133 mg/dL, respectively. Rare M-variants, including MM Heerlen, MM Procida, and MM Malton, exhibited reduced levels ranging from 57 mg/dL to 131 mg/dL, often overlapping with mild deficiency thresholds (110 mg/dL). Among heterozygotes, MZ individuals had a mean of 101 mg/dL and a median of 100 mg/dL (range: 69-146 mg/dL), and MS carriers averaged approximately 130 mg/dL (range: 90-185 mg/dL). Compound heterozygotes demonstrated progressively lower concentrations: SZ (mean = 69.5 mg/dL; range: 44-108 mg/dL), and ZI (mean = 69 mg/dL; range: 47-93 mg/dL). Homozygous ZZ individuals exhibited a median A1AT concentration of 68.5 mg/dL (mean = 87.5 mg/dL; range: 35-120 mg/dL) with wide interquartile variability. The upper skew likely reflects inclusion of patients receiving augmentation therapy or post-liver transplant, both of which can elevate circulating A1AT. This distribution suggests that some ZZ results may not represent untreated baseline physiology. These data reveal an allelic dose-dependent decline in A1AT levels, underscoring the genetic basis of deficiency severity and clinical significance of intermediate and rare variants. Conclusion This large-scale retrospective study 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. This abstract is funded by: None
Kim et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: