OBJECTIVE: Intraplaque hemorrhages (IPH) may predispose to unstable atherosclerotic disease and its atherothrombotic complications, ischemic stroke and coronary syndromes. However, the discriminative value of IPH has been limited in histological and imaging studies suggesting that confounding factors modulate the response to IPH. We studied whether common variants of haptoglobin (Hp), which facilitates the removal of free hemoglobin and protects tissues from heme-iron induced oxidative damage, would modify the inflammatory response to IPH and the risk of unstable carotid stenosis (CS) and major cardiovascular diseases. METHODS: We genotyped Hp polymorphism in 91 patients with a high-grade CS from Helsinki Carotid Endarterectomy Study (HeCES) and in 1417 individuals from Health 2000, a Finnish epidemiological cross-sectional health survey, and determined heme oxygenase-1 (HO1) expression in relation to Hp genotypes in carotid plaques. RESULTS: In the Health 2000 cohort, Hp genotype frequencies were 0.143 (hp1-1), 0.486 (hp1-2) and 0.371 (hp2-2) consistent with Hardy-Weinberg equilibrium and those reported from other Caucasian populations. Among patients with unstable CS, the frequency of hp2-2 genotype was higher than in the control population (0.516 vs. 0.371, P = 0.025). Hp genotypes correlated with HO1 expression in the plaque (r = 0.47, P = 0.027). In the Health 2000 cohort, hp2 allele was associated with an increased risk of major cardiovascular diseases (ischemic stroke, TIA, myocardial infarction, coronary heart disease) with an adjusted OR of 1.46 (95% CI 1.03-2.06). CONCLUSION: Common haptoglobin variants modulate the inflammatory response to IPH and associate with the risk of unstable carotid stenosis and major ischemic cardiovascular events.
OBJECTIVE: Intraplaque hemorrhages (IPH) may predispose to unstable atherosclerotic disease and its atherothrombotic complications, ischemic stroke and coronary syndromes. However, the discriminative value of IPH has been limited in histological and imaging studies suggesting that confounding factors modulate the response to IPH. We studied whether common variants of haptoglobin (Hp), which facilitates the removal of free hemoglobin and protects tissues from heme-iron induced oxidative damage, would modify the inflammatory response to IPH and the risk of unstable carotid stenosis (CS) and major cardiovascular diseases. METHODS: We genotyped Hp polymorphism in 91 patients with a high-grade CS from Helsinki Carotid Endarterectomy Study (HeCES) and in 1417 individuals from Health 2000, a Finnish epidemiological cross-sectional health survey, and determined heme oxygenase-1 (HO1) expression in relation to Hp genotypes in carotid plaques. RESULTS: In the Health 2000 cohort, Hp genotype frequencies were 0.143 (hp1-1), 0.486 (hp1-2) and 0.371 (hp2-2) consistent with Hardy-Weinberg equilibrium and those reported from other Caucasian populations. Among patients with unstable CS, the frequency of hp2-2 genotype was higher than in the control population (0.516 vs. 0.371, P = 0.025). Hp genotypes correlated with HO1 expression in the plaque (r = 0.47, P = 0.027). In the Health 2000 cohort, hp2 allele was associated with an increased risk of major cardiovascular diseases (ischemic stroke, TIA, myocardial infarction, coronary heart disease) with an adjusted OR of 1.46 (95% CI 1.03-2.06). CONCLUSION: Common haptoglobin variants modulate the inflammatory response to IPH and associate with the risk of unstable carotid stenosis and major ischemic cardiovascular events.
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Authors: William J Astle; Heather Elding; Tao Jiang; Dave Allen; Dace Ruklisa; Alice L Mann; Daniel Mead; Heleen Bouman; Fernando Riveros-Mckay; Myrto A Kostadima; John J Lambourne; Suthesh Sivapalaratnam; Kate Downes; Kousik Kundu; Lorenzo Bomba; Kim Berentsen; John R Bradley; Louise C Daugherty; Olivier Delaneau; Kathleen Freson; Stephen F Garner; Luigi Grassi; Jose Guerrero; Matthias Haimel; Eva M Janssen-Megens; Anita Kaan; Mihir Kamat; Bowon Kim; Amit Mandoli; Jonathan Marchini; Joost H A Martens; Stuart Meacham; Karyn Megy; Jared O'Connell; Romina Petersen; Nilofar Sharifi; Simon M Sheard; James R Staley; Salih Tuna; Martijn van der Ent; Klaudia Walter; Shuang-Yin Wang; Eleanor Wheeler; Steven P Wilder; Valentina Iotchkova; Carmel Moore; Jennifer Sambrook; Hendrik G Stunnenberg; Emanuele Di Angelantonio; Stephen Kaptoge; Taco W Kuijpers; Enrique Carrillo-de-Santa-Pau; David Juan; Daniel Rico; Alfonso Valencia; Lu Chen; Bing Ge; Louella Vasquez; Tony Kwan; Diego Garrido-Martín; Stephen Watt; Ying Yang; Roderic Guigo; Stephan Beck; Dirk S Paul; Tomi Pastinen; David Bujold; Guillaume Bourque; Mattia Frontini; John Danesh; David J Roberts; Willem H Ouwehand; Adam S Butterworth; Nicole Soranzo Journal: Cell Date: 2016-11-17 Impact factor: 41.582
Authors: Rabea Asleh; Alexandros Briasoulis; Elliot M Berinstein; Joshua B Wiener; Mohan Palla; Sudhir S Kushwaha; Andrew P Levy Journal: Pharmgenomics Pers Med Date: 2018-04-23
Authors: Ljubica Perisic Matic; Maria Jesus Iglesias; Mattias Vesterlund; Mariette Lengquist; Mun-Gwan Hong; Shanga Saieed; Laura Sanchez-Rivera; Martin Berg; Anton Razuvaev; Malin Kronqvist; Kent Lund; Kenneth Caidahl; Peter Gillgren; Fredrik Pontén; Mathias Uhlén; Jochen M Schwenk; Göran K Hansson; Gabrielle Paulsson-Berne; Erika Fagman; Joy Roy; Rebecka Hultgren; Göran Bergström; Janne Lehtiö; Jacob Odeberg; Ulf Hedin Journal: JACC Basic Transl Sci Date: 2018-08-01