Journal of Alzheimer’s Disease 36 (2013) 733–738 DOI 10.3233/JAD-122407 IOS Press 733 Association Between Interleukin 6 Gene Haplotype and Alzheimer’s Disease: A Brazilian Case-Control Study Lucas Rasmussen a,c , Roger Delabio b , Lie Horiguchi b , Igor Mizumoto b , Carlos-Renato Terazaki b , Diego Mazzotti c , Paulo-Henrique Bertolucci c , Marcela-Augusta Pinhel d , Dorot´ eia Souza d , Henrique Krieger e , Carlos Kawamata e , Thais Minett f , Marilia Cardoso Smith c and Spencer-Luiz Pay˜ ao a,b,∗ a Universidade do Sagrado Cora¸ c˜ ao (USC), Bauru, S ˜ ao Paulo, Brazil b Faculdade de Medicina de Marilia (FAMEMA) - Hemocentro, Mar´ ılia, S ˜ ao Paulo, Brazil c Universidade Federal de S˜ ao Paulo (UNIFESP), S˜ ao Paulo, Brazil d N´ ucleo de Pesquisa em Bioqu´ ımica e Biologia Molecular da Faculdade de Medicina de S˜ ao Jos´ e do Rio Preto, Brazil e Instituto de Ciˆ encias Biom´ edicas, Universidade de S˜ ao Paulo (USP), S˜ ao Paulo, Brazil f University of Cambridge, Cambridge, UK Accepted 14 April 2013 Abstract. Alzheimer’s disease (AD) is a progressive neurodegenerative disease that takes the form of a local overexpression of cytokines and other inflammatory molecules. We investigated three single-nucleotide polymorphisms (SNP) of the interleukin 6 gene (IL-6) promoter region [-174G/C (rs 1800795), -572C/G (rs 1800796), and -597G/A (rs 1800797)] in 200 patients with late-onset AD and 165 elderly controls in a Brazilian case-control population sample. Genotyping was carried out from blood cells using PCR-RFLP techniques. Statistical analysis was performed to evaluate the Hardy-Weinberg equilibrium and to compare frequencies between groups. No association was found between any IL-6 polymorphism and AD; however the haplotype composed of the -597 A allele and the -174G allele indicated a crude odds ratio (OR) of 0.15 (p = 0.0021) and a significantly adjusted OR (adjusted for the APOE E4 allele value) of 0.15 (p = 0.00294). Linkage disequilibrium was D’ = 0.68 among the three SNPs. Our findings revealed a protective effect of AG (-597A, -174G) haplotype, which worked independently of the APOE E4 allele in our Brazilian population sample. Thus, the promoter region of IL-6 gene probably exerts an effect through gene linkage and/or gene interaction. Keywords: Association study, case-control study, haplotype, interleukin 6 gene, polymorphisms INTRODUCTION Alzheimer’s disease (AD) is one of the most com- mon neurodegenerative disorders in older adults and by 2050, the worldwide prevalence is projected to be ∗ Correspondence to: Spencer Luiz Marques Pay˜ ao, Ph.D, Labo- rat´ orio de Gen´ etica, Hemocentro, FAMEMA Rua Lourival Freire, 240, Bairro Fragata, CEP 17519-050, Mar´ ılia, S˜ ao Paulo, Brazil. Tel.: +55 14 34021856; Fax: +55 14 34330148; E-mail: slmpayao@ famema.br. more than one hundred million [1]. AD is a progressive neurodegenerative disease characterized by amyloid- deposition in neuritic plaques, neurofibrillary tangles, and a loss of neurons and synapses [2]. The activation of local inflammatory pathways also play a role in the neurodegeneration process associated with AD [2]. Although it has been established that inflammatory mediators play critical roles in the pathogenesis of AD, the exact mechanism of action is still unknown [3]. Interleukin 6 (IL-6) has been detected in amyloid- ISSN 1387-2877/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved