Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Original Paper Hum Hered 2008;66:50–60 DOI: 10.1159/000114165 Evidence of Major Genes Effects on Serum Homocysteine and Fibrinogen Levels, and Premature Ischemic Heart Disease in Italian Extended Families Mario Grassi a Aliaksei Kisialiou a Deodato Assanelli b Chiara Mozzini b Silvana Archetti c Alessandro Pezzini d a Dipartimento di Scienze Sanitarie Applicate, Sezione di Statistica Medica & Epidemiologia, Università di Pavia, Pavia, b Dipartimento di Medicina Sperimentale ed Applicata, c III Laboratorio di Analisi, Biotecnologie, e d Dipartimento di Scienze Mediche e Chirurgiche, Sezione di Neurologia Vascolare, Università di Brescia, Brescia, Italy provide evidence for a major latent gene effect influencing variation in tHcy plasma levels, which is independent on C677T MTHFR polymorphism, and significantly affecting the risk of MI. Copyright © 2008 S. Karger AG, Basel Introduction Ischemic heart disease (IHD), particularly acute myo- cardial infarction (MI), is one of the clinical manifesta- tions of arterial thrombosis, a common complex disease associated with substantial morbidity and mortality. Tra- ditional risk factors for IHD include hypertension, ciga- rette smoking, diabetes mellitus, and family history of MI among others. However, IHD sometimes occurs in individuals without any of these predisposing conditions. Thus, there is great interest in identifying other risk fac- tors that play a role in the pathogenesis of the disease. Two newly proposed of such disease markers are increased plasma levels of total homocysteine (tHcy) and fibrino- gen (FIB) [1, 2]. Variance in plasma levels of these two molecules has been proved to be influenced by environ- mental conditions as well as by a genetic background [3] . In particular, although the exact genetic mechanisms re- main largely undetermined, it might be that several genes, Key Words Segregation analysis  Mediation analysis  Cardiovascular disease  Homocysteine  Fibrinogen Abstract Objectives: The purpose of the present study was to inves- tigate the effect of novel genetic factors on plasma levels of total homocysteine (tHcy) and fibrinogen (FIB). As tHcy and FIB have been consistently associated to increased risk of ischemic heart disease (IHD) and acute myocardial infarction (MI) also genes-trait-MI mediational effects were tested. Methods: A complex segregation analysis, and a mediation analysis of a highly selected group of 44 extended families (302 subjects), each including at least one member with fatal premature ( !50 years) IHD were carried out. Results: tHcy and FIB levels turned out to be influenced by at least two major genes. A significant tHcy latent class-MI association (OR = 3.24; 95% CI, 1.37 to 7.68), and a non-significant tHcy plasma level-MI association (OR = 1.65 per 1 = log 10 mol/l, 95% CI, 0.56 to 4.81) were estimated, suggesting a direct in- fluence of the homocysteine major gene as suppressor of plasma tHcy levels effect. In contrast, FIB latent class-MI as- sociation (OR = 0.97; 95% CI, 0.31 to 3.05) and FIB level-MI association (OR = 1.32 per 1 = 70 g/l; 95% CI, 0.88 to 2.00) were not statistically significant. Conclusion: These data Received: February 26, 2007 Accepted after revision: September 4, 2007 Published online: January 28, 2008 Aliaksei Kisialiou Dipartimento di Scienze Sanitarie Applicate Via Bassi, 21 IT–27100 Pavia (Italy) Tel. +39 038 298 75 35, Fax +39 038 298 75 70, E-Mail aliaksei.kisialiou@unipv.it © 2008 S. Karger AG, Basel 0001–5652/08/0661–0050$24.50/0 Accessible online at: www.karger.com/hhe Downloaded by: Glasgow Univ.Lib. 130.209.144.239 - 9/22/2014 1:13:10 PM