BACKGROUND/ OBJECTIVE: Products of heme oxygenase 1 (HO1) possess antithrombotic properties, and impairment of HO1 activity may contribute to thrombus formation. Transcriptional activity of long GT-repeat alleles in HO1 gene (HMOX1) is lower as compared with short alleles. We hypothesize that these long alleles are associated with decreased HO1 anticoagulant activity and, thus, an increased risk of thrombosis.. DESIGN/ METHODS: In a prospective cohort study, we followed 860 patients with a first VTE, and investigated the impact of a promoter GT-dinucleotid length polymorphism in HOMX1 on the risk of recurrent venous thromboembolism (VTE). RESULTS: Allele groups short (S), medium (M) and long (L) of the promoter GT-dinucleotide length polymorphism were distinguished. L-alleles, but not M- or S-alleles, were found to be more frequent among patients with recurrence. Heterozygous carriers of L-alleles had a two-fold higher relative risk of recurrence [(RR 2.2 (95% CI: 1.4-3.4)] as compared to wild type, which was independent of other thrombotic risk factors. At five years, the cumulative probability of recurrence was 18% (95% CI: 15%-22%) in patients without an L-allele compared to 32% (95% CI: 19%-46%) in patients heterozygous for the L-allele (P = .001). CONCLUSION: Patients with first VTE and long GT-repeat alleles in HMOX1 have an increased risk of recurrence. Genetically determined alterations in HO1 function may represent a new pathomechanism in VTE.
BACKGROUND/ OBJECTIVE: Products of heme oxygenase 1 (HO1) possess antithrombotic properties, and impairment of HO1 activity may contribute to thrombus formation. Transcriptional activity of long GT-repeat alleles in HO1 gene (HMOX1) is lower as compared with short alleles. We hypothesize that these long alleles are associated with decreased HO1 anticoagulant activity and, thus, an increased risk of thrombosis.. DESIGN/ METHODS: In a prospective cohort study, we followed 860 patients with a first VTE, and investigated the impact of a promoter GT-dinucleotid length polymorphism in HOMX1 on the risk of recurrent venous thromboembolism (VTE). RESULTS: Allele groups short (S), medium (M) and long (L) of the promoter GT-dinucleotide length polymorphism were distinguished. L-alleles, but not M- or S-alleles, were found to be more frequent among patients with recurrence. Heterozygous carriers of L-alleles had a two-fold higher relative risk of recurrence [(RR 2.2 (95% CI: 1.4-3.4)] as compared to wild type, which was independent of other thrombotic risk factors. At five years, the cumulative probability of recurrence was 18% (95% CI: 15%-22%) in patients without an L-allele compared to 32% (95% CI: 19%-46%) in patients heterozygous for the L-allele (P = .001). CONCLUSION:Patients with first VTE and long GT-repeat alleles in HMOX1 have an increased risk of recurrence. Genetically determined alterations in HO1 function may represent a new pathomechanism in VTE.
Authors: Karl A Nath; Joseph P Grande; John D Belcher; Vesna D Garovic; Anthony J Croatt; Matthew L Hillestad; Michael A Barry; Meryl C Nath; Raymond F Regan; Gregory M Vercellotti Journal: Am J Physiol Heart Circ Physiol Date: 2020-01-31 Impact factor: 4.733
Authors: John A Heit; Sebastian M Armasu; Bryan M McCauley; Iftikhar J Kullo; Hugues Sicotte; Jyotishman Pathak; Christopher G Chute; Omri Gottesman; Erwin P Bottinger; Joshua C Denny; Dan M Roden; Rongling Li; Marylyn D Ritchie; Mariza de Andrade Journal: Thromb Haemost Date: 2017-02-16 Impact factor: 5.249
Authors: Michal J Tracz; Julio P Juncos; Joseph P Grande; Anthony J Croatt; Allan W Ackerman; Zvonimir S Katusic; Karl A Nath Journal: Am J Pathol Date: 2008-11-06 Impact factor: 4.307
Authors: Jeffrey A Kline; Nury M Steuerwald; John A Watts; Mark Courtney; Herbert L Bonkovsky Journal: Thromb Res Date: 2015-08-28 Impact factor: 3.944
Authors: Marie-Abele Bind; Brent Coull; Helen Suh; Robert Wright; Andrea Baccarelli; Pantel Vokonas; Joel Schwartz Journal: PLoS One Date: 2014-04-22 Impact factor: 3.240
Authors: Prakash Saha; Julia Humphries; Bijan Modarai; Katherine Mattock; Matthew Waltham; Colin E Evans; Anwar Ahmad; Ashish S Patel; Sobath Premaratne; Oliver T A Lyons; Alberto Smith Journal: Arterioscler Thromb Vasc Biol Date: 2011-03 Impact factor: 8.311