A population-based Swedish study showed that homozygosity or compound heterozygosity for variants associated with severe alpha-1-antitrypsin deficiency (AATD) is linked to venous thromboembolism (VTE). From a total of 40 homozygous or compound heterozygous individuals, 10 had incident VTE.

The authors identified 84 SERPINA1 variants (21 synonymous, 62 missense, and 1 loss-of-function) in 28,794 individuals from the Malm diet and cancer cohort. The number of incident VTE events that occurred among individuals without prevalent VTE was 2584.

They found an overrepresentation of homozygotes for the Z variant (rs28929474) but not for the S variant among VTE patients. The number of Z variant homozygotes among individuals with and without VTE was 5 (0.19%) and 16 (0.061%), respectively, while the number of S variant homozygotes was 1 (0.039%) and 14 (0.053%).

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On the other hand, heterozygosity showed no effect in any of the variants. The number of Z variant heterozygotes among individuals with and without VTE was 151 (5.8%) and 1461 (5.6%), respectively, while the number of S variant heterozygotes was 122 (4.7%) and 1215 (4.6%).

Additionally, the authors combined rare qualifying variants (total prevalence in the population, 0.6%) with the Z variant. The resulting analysis showed that carrying 2 alleles, either ZZ genotype or compound heterozygotes (Z plus any other variant, n=5) had increased VTE risk. In contrast, carrying 1 allele did not increase VTE risk.

In addition to the Z variant, the variant rs141620200 was the only one showing different minor allele frequencies between individuals with and without VTE, showing an increase of ~0.4% in VTE individuals compared to controls. The adjusted hazard ratio for combinations of the Z variant and rare qualifying variants was 4.5 (95% CI, 2.0-10.0).


Manderstedt E, Halldén C, Lind‐Halldén C, et al. Thrombotic risk determined by rare and common SERPINA1 variants in a population‐based cohort study. J Thromb Haemost. Published online March 9, 2022. doi:10.1111/jth.15696