Thrombotic risk determined by rare and common SERPINA1 variants in a population‐based cohort study. (19th March 2022)

• Record Type: Journal Article
• Authors: Manderstedt, Eric; Halldén, Christer; Lind‐Halldén, Christina; Elf, Johan; Svensson, Peter J.; Engström, Gunnar; Melander, Olle; Baras, Aris; Lotta, Luca A.; Zöller, Bengt
• Other Names: Abecasis Goncalo investigator.; Cantor Michael investigator.; Coppola Giovanni investigator.; Economides Aris investigator.; Overton John D. investigator.; Reid Jeffrey G. investigator.; Shuldiner Alan investigator.; Beechert Christina investigator.; Forsythe Caitlin investigator.; Fuller Erin D. investigator.; Gu Zhenhua investigator.; Lattari Michael investigator.; Lopez Alexander investigator.; Manoochehri Kia investigator.; Overton John D. investigator.; Padilla Maria Sotiropoulos investigator.; Pradhan Manasi investigator.; Schleicher Thomas D. investigator.; Ulloa Ricardo H. investigator.; Widom Louis investigator.; Wolf Sarah E. investigator.; Bai Xiaodong investigator.; Balasubramanian Suganthi investigator.; Blumenfeld Andrew investigator.; Boutkov Boris investigator.; Eom Gisu investigator.; Habegger Lukas investigator.; Hawes Alicia investigator.; Khalid Shareef investigator.; Krasheninina Olga investigator.; Lanche Rouel investigator.; Mansfield Adam J. investigator.; Maxwell Evan K. investigator.; Nafde Mrunali investigator.; O'Keeffe Sean investigator.; Orelus Max investigator.; Panea Razvan investigator.; Polanco Tommy investigator.; Rasool Ayesha investigator.; Reid Jeffrey G. investigator.; Salerno William investigator.; Staples Jeffrey C. investigator.; Jones Marcus B. investigator.; Mighty Jason investigator.; Mitnaul Lyndon J. investigator.;
• Is Part Of: Journal of thrombosis and haemostasis. Volume 20:Number 6(2022)
• Page Start: 1421
• Page End: 1427
• Publication Date: 2022-03-19
• Subjects: alpha‐1‐antitrypsin -- epidemiology -- genetics -- SERPINA1 -- venous thromboembolism; Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.15696
• Languages: English
• ISSNs: 1538-7933

Abstract

Abstract: Background: Severe alpha‐1‐antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case‐control study. Objectives: This 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/Methods: The 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. Results: Resequencing 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. Conclusions: The SERPINA1 ZZ genotype and compound heterozygotes for severe AATD are rare but associated with VTE in a population‐based Swedish study.