Thrombotic risk determined by rare and common SERPINA1 variants in a population‐based cohort study

Abstract

BackgroundSevere alpha‐1‐antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case‐control study. ObjectivesThis study aimed to determine the genetic variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population‐based cohort study. Patients/MethodsThe coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Individuals were followed from baseline until the first event of VTE, death, or 2018. ResultsResequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss‐of‐function variant. Kaplan‐Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty‐one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non‐benign (PolyPhen‐2) missense variants with minor allele frequency (MAF) <0.1%. Combining the rare qualifying variants with the Z variant showed that carrying two alleles (ZZ or compound heterozygotes) showed increased risk. Cox regression analysis revealed an adjusted hazard ratio of 4.5 (95% confidence interval 2.0–10.0) for combinations of the Z variant and rare qualifying variants. One other variant (rs141620200; MAF = 0.002) showed an increased risk of VTE. ConclusionsThe SERPINA1 ZZ genotype and compound heterozygotes for severe AATD are rare but associated with VTE in a population‐based Swedish study.