Association analysis between K and À116A variants of butyrylcholinesterase and Alzheimer’s disease in a Brazilian population Daiane Priscila Simão-Silva a , Paulo Henrique Ferreira Bertolucci b , Roger William de Labio c , Spencer Luiz Marques Payão c , Lupe Furtado-Alle a , Ricardo Lehtonen Rodrigues Souza a,⇑ a Department of Genetics, Federal University of Paraná, Curitiba, Brazil b Department of Behavioral Neurology, Federal University of São Paulo, São Paulo, Brazil c Department of Genetic and Molecular Biology of Hemocentro, School of Medicine of Marília, São Paulo, Brazil article info Article history: Available online 27 September 2012 Keywords: Alzheimer’s disease BCHE Butyrylcholinesterase abstract In Alzheimer’s disease (AD) a reduction in acetylcholinesterase (AChE) and an increase in butyrylcholin- esterase (BChE) activity are observed. K variant (539T) is the most common variant of the BCHE gene and, although controversial, several studies reported association between K variant and AD. Previous results showed that the K variant alone is not capable of diminishing BChE activity, depending on the presence of the À116A variant. Considering that, we conducted a case-control association study using a clinically well defined group of AD patients (n = 82) and age and sex matched control subjects (EC; n = 78) in order to test the association with these variations of BCHE gene in a Brazilian population. The allele, genotype and haplotype frequencies of the K and the À116A variants of BCHE gene were not significantly different between cases and controls. Although not reaching statistical significance, the results suggested that the presence of À116A variant may have a protective effect against AD. The association of the K variant with AD in a controversial manner in different surveys is probably caused by its linkage disequilibrium with À116A that, by reducing BChE activity, potentially increases cholinergic transmission in comparison with usual genotypes. Ó 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction In Alzheimer’s disease (AD, OMIM 104300) a significant reduc- tion in Acetylcholinesterase (AChE, EC 3.1.1.7) and an increase in Butyrylcholinesterase (BChE, EC 3.1.1.8) activity are observed. These changes are especially found in the hippocampus, suggesting a relationship with the loss of episodic memory in AD [1,2], and in the temporal cortex, where the increased level of BChE is associated with cognitive decline in dementias [3].The acetylcholine hydrolyz- ing enzyme BChE is linked to the neurofibrillary tangles and amy- loid plaques characteristic of AD [4]. BChE activity was related to the transformation of neurotoxic plaques from benign diffuse state to the compact malignant form associated with dystrophic neurites, degeneration and dementia in AD [5,6]. Other studies ascertain that BChE is able to facilitate the suppression of amyloid formation and the presence of BChE in amyloid plaques implies that BChE incorpo- rates into Ab-fibrils at a late phase of their formation [7,8]. Based in the biochemical evidences supporting a role of BChE in the pathophysiology of AD, studies have been conducted about the BCHE gene and AD. Over 65 genetic variants were described for BCHE gene [9], but AD association studies are restricted to the most common variant of the coding region of BCHE gene, the K variant (rs1803274, A539T). This mutation does not affect hydrolytic activ- ity of BChE, but destabilizes and impairs its capacity to attenuate fibrils formation [7,8] and is a long-debated risk factor for AD. The presence of the K variant was associated with 30% decrease in enzymatic activity of BChE in serum [10] but the K variant alone is not associated with decreased BChE activity, being the 5 0 UTR À116A variant necessary for this decrease [11]. This variant is pres- ent in the non-coding exon 1 of BCHE at À116 nt (rs1126680), being À116A preferentially found in cis with the K variant [12] with described frequency for Caucasian population among 5.0–9.3% [11,13]. Considering the linkage disequilibrium between variants of exons 1 and 4 of the BCHE gene, and the effect of the presence of À116A variant on the BChE activity, we conducted this case-con- trol study in order to test the association among AD and À116 and K variants in a Brazilian population. 2. Materials and methods 2.1. Population samples Samples were obtained from 160 Brazilian individuals, being 82 AD patients (mean age 74.5 ± 8.52) from the Behavioral Neurology 0009-2797/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cbi.2012.09.008 ⇑ Corresponding author. Address: P.O. Box 19071, 81531-980 Curitiba, PR, Brazil. Tel.: +55 41 33611554; fax: +55 41 32662042. E-mail address: ricardo.lehtonen@gmail.com (R.L.R. Souza). Chemico-Biological Interactions 203 (2013) 358–360 Contents lists available at SciVerse ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint