Serum Homocysteine, MTHFR Gene Polymorphism, and Carotid Intimal-Medial Thickness in NIDDM Subjects Alfredo Mazza, 1 Corradino Motti, 2 Angela Nulli, 3 Anna Pastore, 4 , Felicita Andreotti, 6 Vincenzo Ammaturo, 5 Pasquale Bianco, 3 , Elena Santoro, 5 Giorgio Federici, 4 and Claudio Cortese 2 1 Department of Geriatrics and Metabolic Diseases, and 5 Institute of Medical Physiopathology, 2nd University of Naples; 3 Department of Clinical and Experimental Medicine, University “Federico II”, Naples; 4 “Bambin Gesù” Hospital, Rome; 6 Institute of Cardiology, Catholic University, Rome, 2 Department of Internal Medicine, University of Tor Vergata, Rome Italy Abstract. We assessed the contribution of serum homocys- teine levels, an independent risk factor for vascular dis- ease, and of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation to the variability of carotid inti- mal-medial thickness (IMT) in patients with non–insulin- dependent diabetes mellitus (NIDDM). Ninety-~ve patients (33 males and 62 females, mean age 53  10 years) without nephropathy or other vascular complications were enrolled. Fasting total serum homocysteine and other biochemical analytes were measured. The MTHFR polymorphism was determined by the polymerase chain reaction. Common ca- rotid IMT and plaques or stenoses in the carotid district were measured by ultrasonography. Serum total homocyste- ine concentrations were higher in subjects with the mutant (Val/Val) genotype than in those with the Ala/Val plus Ala/Ala genotypes (P  0.02). On univariate analysis, ca- rotid IMT was signi~cantly associated with age, body mass index (BMI), systolic blood pressure, and total cholesterolemia. No signi~cant association was found be- tween IMT and serum homocysteine or the MTHFR poly- morphism, although a slightly greater IMT was observed in the homozygous Val genotypes. On multiple regression analysis, only age and BMI were independently associated with IMT and explained about 40% of IMT variability. The results did not change when the analysis was restricted to the subgroups with or without atherosclerotic plaques in the carotid district. In 95 Italian NIDDM patients without nephropathy, neither basal levels of serum total homocyste- ine nor the MTHFR C677T polymorphism predicted signi~cant changes in common carotid intimal-medial thick- ness. Key Words. diabetes, homocysteine, methylenetetrahydro- folate reductase, intimal-medial thickness Homocysteine is considered to be an independent risk factor for vascular disease [1]. Subjects with inborn errors of metabolism causing severe hyperhomocyste- inemia and homocystinuria develop thrombotic and ar- teriosclerotic complications at an early age [2]. Even mild hyperhomocysteinemia seems to be associated with an increased risk of developing cardiac and pe- ripheral atherothrombosis [3]. Homocysteine is a thiol-containing amino acid de- rived from methionine. It can be catabolized to cys- tathionine and cysteine by the action of cystathionine b-synthase, in the presence of vitamin B 6 . An alterna- tive metabolic pathway consists of a remethylation process, primarily by transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine in the pres- ence of vitamin B 12 , and subsequent formation of methionine [2] This pathway is regulated by the activ- ity of 5,10-methylenetetrahydrofolate reductase (MTHFR), which, in the presence of folate, catalyzes the formation of 5-methyltetrahydrofolate [4]. Approximately 12% of the general population has a genetically determined thermolabile variant of MTHFR that shows defective enzymatic activity and is associated with mild hyperhomocysteinemia [5]. Im- portantly, this MTHFR-dependent genetic predisposi- tion to hyperhomocysteinemia can be reversed by an appropriate dietary intake of folate [6]. The variant consists of a C-to-T substitution at nucleotide 677 that converts an alanine residue to valine [7]. Con_icting results have emerged concerning the association be- tween this genetic polymorphism and cardiovascular disease [8–11]. Non–insulin-dependent diabetes mellitus (NIDDM) is associated with a high incidence of vascular compli- cations [12]. Many factors (dyslipidemia, platelet hy- peraggregability, endothelial dysfunction, impaired he- Address for correspondence: Prof. Claudio Cortese, Diparti- mento di Medicina Interna, Biochimica Clinica, Università di Roma Tor Vergata, Via di Tor Vergata 135, I-00133 Roma, Italy E-mail: cortese@uniroma2.it Received 7 December 1998; accepted in revised form 24 May 1999 207 Journal of Thrombosis and Thrombolysis 1999;8:207–212 © Kluwer Academic Publishers. Boston. Printed in the Netherlands.