The Journal of Rheumatology 2003; 30:10 2160 From the Servizio di Reumatologia and Laboratorio di Biologia Molecolare, Azienda Ospedaliera Arcispedale S. Maria Nuova, Reggio Emilia; Laboratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli, Bologna; and Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, University of Bologna, Bologna, Italy. L. Boiardi, MD, PhD; P. Macchioni, MD; M.G. Catanoso, MD; C. Salvarani, MD, Servizio di Reumatologia; B. Casali, MD; D. Nicoli, BD; E. Farnetti, BD; Q. Chen, MD, Laboratorio di Biologia Molecolare, Azienda Ospedaliera Arcispedale S. Maria Nuova; L. Pulsatelli, BD, Laboratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli; R. Meliconi, MD, Laboratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli and Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, University of Bologna. Address reprint requests to Dr. C. Salvarani, Servizio di Reumatologia, Arcispedale S. Maria Nuova, V. le Umberto 1 N50, 42100 Reggio Emilia, Italy. E-mail: salvarani.carlo@asmn.re.it Submitted October 17, 2002; revision accepted February 10, 2003. Giant cell arteritis (GCA) is an inflammatory vasculopathy that preferentially involves medium and large arteries. Ischemic manifestations such as visual loss, jaw claudica- tion, central nervous system ischemia, and aortic arch syndrome are the predominant clinical findings in a subgroup of patients with GCA. These manifestations are related to luminal occlusion, mainly caused by the cooccur- rence of intimal hyperplasia, neoangiogenesis, and the frag- mentation of internal elastic laminae, which are closely correlated, probably reflecting shared regulatory path- ways 1–4 . Vascular endothelial growth factor (VEGF) may play a pivotal role in mediating artery wall damage in GCA. Kaiser, et al have shown that tissue transcription of VEGF is correlated to the extent of neovascularization in the GCA arterial wall 5 . However, VEGF is not only a potent angio- genic factor, it also acts as a proinflammatory cytokine by increasing endothelial permeability and inducing adhesion molecules that bind leukocytes to endothelial cells 6,7 . Cid, et al showed that inflammation-induced angiogenesis is the main site of leukocyte-endothelial cell interactions leading to the development of inflammatory infiltrates in GCA 8 . High concentrations of circulating VEGF have been docu- mented in patients with active polymyalgia rheumatica (PMR)/GCA, and corticosteroid therapy reduces VEGF serum concentrations 9 . VEGF appears to represent an attractive candidate susceptibility gene for GCA and its production may be partially subject to genetic control. Among healthy subjects, strong interindividual variations of VEGF plasma levels, and VEGF production from stimulated peripheral blood mononuclear cells (PBMC) and VEGF gene expression have been reported 10 . A 936 C/T mutation occurring in 3’- UTR 11 and a 634 C/G mutation occurring in 5’-UTR of the Vascular Endothelial Growth Factor Gene Polymorphisms in Giant Cell Arteritis LUIGI BOIARDI, BRUNO CASALI, DAVIDE NICOLI, ENRICO FARNETTI, QINGQUAN CHEN, PIERLUIGI MACCHIONI, MARIA GRAZIA CATANOSO, LIA PULSATELLI, RICCARDO MELICONI, and CARLO SALVARANI ABSTRACT. Objective. To examine potential associations of vascular endothelial growth factor (VEGF) gene polymorphisms with giant cell arteritis (GCA) and disease expression, in particular in patients with and without ischemic complications. Methods. We enrolled 92 consecutive patients with biopsy-proven GCA residing in Reggio Emilia, Italy. Two hundred healthy blood donors from the same geographic area were selected as controls. All the GCA patients and controls were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for 936 C/T and 634 C/G mutations and for an 18 bp insertion/deletion (I/D) polymorphism in the VEGF promoter region. In vitro release of VEGF by peripheral blood mononuclear cells (PBMC) was investigated by ELISA in controls homozygous for the polymor- phisms studied. Results. The carriage rates of the alleles I and C634 were significantly more frequent in GCA patients than in controls (p = 0.025, OR 1.9, 95% CI 1.1–3.1 and p = 0.015, OR 2.1, 95% CI 1.1–3.6, respectively). The distribution of allele T936 was similar in GCA patients and controls. No signifi- cant differences in the distribution of the polymorphisms studied were observed in patients with ischemic manifestations compared to those without ischemic manifestations. Lipopolysaccharide (LPS)-stimulated VEGF production by PBMC from controls was higher in II homozygous compared to DD homozygous patients. Conclusion. Our data indicate that carriers of C634 and I alleles are associated with susceptibility to developing GCA. (J Rheumatol 2003;30:2160–4) Key Indexing Terms: GIANT CELL ARTERITIS VASCULAR ENDOTHELIAL GROWTH FACTOR POLYMORPHISMS VEGF PRODUCTION ISCHEMIC MANIFESTATIONS Personal, non-commercial use only. The Journal of Rheumatology Copyright © 2003. All rights reserved. www.jrheum.org Downloaded on January 25, 2022 from