PMID- 35263815 OWN - NLM STAT- MEDLINE DCOM- 20220524 LR - 20230829 IS - 1538-7836 (Electronic) IS - 1538-7933 (Print) IS - 1538-7836 (Linking) VI - 20 IP - 6 DP - 2022 Jun TI - Thrombotic risk determined by rare and common SERPINA1 variants in a population-based cohort study. PG - 1421-1427 LID - 10.1111/jth.15696 [doi] AB - 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 Malmo 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. CI - (c) 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis. FAU - Manderstedt, Eric AU - Manderstedt E AUID- ORCID: 0000-0002-8984-9697 AD - Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden. FAU - Hallden, Christer AU - Hallden C AD - Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden. FAU - Lind-Hallden, Christina AU - Lind-Hallden C AD - Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden. FAU - Elf, Johan AU - Elf J AD - Department of Clinical Sciences, Skane University Hospital, Lund University, Malmo, Sweden. FAU - Svensson, Peter J AU - Svensson PJ AD - Department of Clinical Sciences, Skane University Hospital, Lund University, Malmo, Sweden. FAU - Engstrom, Gunnar AU - Engstrom G AD - Department of Clinical Sciences, Skane University Hospital, Lund University, Malmo, Sweden. FAU - Melander, Olle AU - Melander O AD - Department of Clinical Sciences, Skane University Hospital, Lund University, Malmo, Sweden. FAU - Baras, Aris AU - Baras A AD - Regeneron Genetics Center, Tarrytown, New York, USA. FAU - Lotta, Luca A AU - Lotta LA AD - Regeneron Genetics Center, Tarrytown, New York, USA. FAU - Zoller, Bengt AU - Zoller B AUID- ORCID: 0000-0002-8250-5613 AD - Center for Primary Health Care Research, Lund University and Region Skane, Malmo, Sweden. CN - Regeneron Genetics Center AD - Regeneron Genetics Center, Tarrytown, New York, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220319 PL - England TA - J Thromb Haemost JT - Journal of thrombosis and haemostasis : JTH JID - 101170508 RN - 0 (SERPINA1 protein, human) RN - 0 (alpha 1-Antitrypsin) SB - IM MH - Aged MH - Aged, 80 and over MH - Case-Control Studies MH - Cohort Studies MH - Female MH - Genotype MH - Humans MH - Male MH - *Thrombosis/complications/genetics MH - *Venous Thromboembolism/diagnosis/epidemiology/genetics MH - alpha 1-Antitrypsin/genetics MH - *alpha 1-Antitrypsin Deficiency/complications/epidemiology/genetics PMC - PMC9314614 OTO - NOTNLM OT - SERPINA1 OT - alpha-1-antitrypsin OT - epidemiology OT - genetics OT - venous thromboembolism COIS- The authors report no conflicts of interest. FIR - Abecasis, Goncalo IR - Abecasis G FIR - Cantor, Michael IR - Cantor M FIR - Coppola, Giovanni IR - Coppola G FIR - Economides, Aris IR - Economides A FIR - Overton, John D IR - Overton JD FIR - Reid, Jeffrey G IR - Reid JG FIR - Shuldiner, Alan IR - Shuldiner A FIR - Beechert, Christina IR - Beechert C FIR - Forsythe, Caitlin IR - Forsythe C FIR - Fuller, Erin D IR - Fuller ED FIR - Gu, Zhenhua IR - Gu Z FIR - Lattari, Michael IR - Lattari M FIR - Lopez, Alexander IR - Lopez A FIR - Manoochehri, Kia IR - Manoochehri K FIR - Overton, John D IR - Overton JD FIR - Padilla, Maria Sotiropoulos IR - Padilla MS FIR - Pradhan, Manasi IR - Pradhan M FIR - Schleicher, Thomas D IR - Schleicher TD FIR - Ulloa, Ricardo H IR - Ulloa RH FIR - Widom, Louis IR - Widom L FIR - Wolf, Sarah E IR - Wolf SE FIR - Bai, Xiaodong IR - Bai X FIR - Balasubramanian, Suganthi IR - Balasubramanian S FIR - Blumenfeld, Andrew IR - Blumenfeld A FIR - Boutkov, Boris IR - Boutkov B FIR - Eom, Gisu IR - Eom G FIR - Habegger, Lukas IR - Habegger L FIR - Hawes, Alicia IR - Hawes A FIR - Khalid, Shareef IR - Khalid S FIR - Krasheninina, Olga IR - Krasheninina O FIR - Lanche, Rouel IR - Lanche R FIR - Mansfield, Adam J IR - Mansfield AJ FIR - Maxwell, Evan K IR - Maxwell EK FIR - Nafde, Mrunali IR - Nafde M FIR - O'Keeffe, Sean IR - O'Keeffe S FIR - Orelus, Max IR - Orelus M FIR - Panea, Razvan IR - Panea R FIR - Polanco, Tommy IR - Polanco T FIR - Rasool, Ayesha IR - Rasool A FIR - Reid, Jeffrey G IR - Reid JG FIR - Salerno, William IR - Salerno W FIR - Staples, Jeffrey C IR - Staples JC FIR - Jones, Marcus B IR - Jones MB FIR - Mighty, Jason IR - Mighty J FIR - Mitnaul, Lyndon J IR - Mitnaul LJ EDAT- 2022/03/10 06:00 MHDA- 2022/05/25 06:00 PMCR- 2022/07/26 CRDT- 2022/03/09 20:08 PHST- 2022/02/28 00:00 [revised] PHST- 2021/09/08 00:00 [received] PHST- 2022/02/28 00:00 [accepted] PHST- 2022/03/10 06:00 [pubmed] PHST- 2022/05/25 06:00 [medline] PHST- 2022/03/09 20:08 [entrez] PHST- 2022/07/26 00:00 [pmc-release] AID - S1538-7836(22)00191-X [pii] AID - JTH15696 [pii] AID - 10.1111/jth.15696 [doi] PST - ppublish SO - J Thromb Haemost. 2022 Jun;20(6):1421-1427. doi: 10.1111/jth.15696. Epub 2022 Mar 19.