Volume 27 Number 2, 2005
ISSN: 0895–8696
JOURNAL OF
Molecular Neuroscience Editor-in-Chief: ILLANA GOZES, PhD In This Issue The Biological Clock Alzheimer’s Immunization Signal Transduction/ Neuroprotection/ Polymorphism
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Journal of Molecular Neuroscience Copyright © 2005 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/05/27:213–218/$30.00 DOI:10.1385/JMN:27:02:213
ORIGINAL ARTICLE
Monoamine Oxidase A Polymorphism in Brazilian Patients Risk Factor for Late-Onset Alzheimer’s Disease?
Agnes L. Nishimura,1 Camila Guindalini,1 João R. M. Oliveira,3 Ricardo Nitrini,2 Valéria S. Bahia,2 Paulo R. de Brito-Marques,3 Paulo A. Otto,1 and Mayana Zatz*,1 1
Human Genome Research Center, Biology Department, Institute of Biosciences, São Paulo University (IBUSP), São Paulo, Brazil; 2Neurology Department of Medical School, São Paulo University, São Paulo, Brazil; and 3Behavioral Neurology Unit, Department of Neurology, Faculty of Medical Sciences, University of Pernambuco, Recife, Brazil Received December 8, 2004; Accepted March 30, 2005
Abstract Different studies have attempted to find polymorphisms involved in the serotonergic pathway that could be involved in mood disorders and late-onset Alzheimer’s disease (LOAD) symptoms. Here, we compared the frequency of two polymorphisms: monoamine oxidase A (MAOA) and serotonin transporter in LOAD patients versus controls. No evidence of association was observed when these polymorphisms were compared separately; however, the combination of the MAOA allele 1 + the short allele of 5-HTTLPR + ApoE-ε4 was significantly more frequent in patients than in controls. It reinforces the hypothesis that different genes acting together might play a role in AD susceptibility. Based on these data, we suggest replicating these studies in larger samples of LOAD patients belonging to different ethnic groups. DOI:10.1385/JMN:27:02:213 Index Entries: Alzheimer’s disease; monoamine oxidase A; polymorphisms; serotonergic pathway; Brazilian population.
Introduction Alzheimer ’s disease (AD), the most common mental disorder in the elderly, leads to cognitive impairment, progressive loss of memory, and other symptoms such as depression and mood alteration. It is characterized by two histopathological hallmarks: neurofibrillary tangles, caused by hyperphosphorylation of the Tau protein, and β-amyloid deposits. Mutations in three genes have been associated with the familial form of AD: presenilin 1, presenilin 2, and the amyloid precursor protein (APP), localized at 14q24.3, 1q31–q42, and 21q21,
respectively. In addition, the ε4 allele of Apolipo protein E (ApoE-ε4) polymorphic locus is the most important associated with late-onset AD (LOAD) sporadic cases. Because depression and mood disorders are observed in patients with AD, different studies have explored whether genes of the serotonergic pathway might be involved with these symptoms (Collier et al., 1996; Lesch et al.; 1996, Li et al., 1997). Serotonin (5-HT) is an important neurotransmitter in the central and peripheral nervous systems, implicated in the control of mood, appetite, sleep, pain, and behavior. Mutations in this gene
*Author to whom all correspondence and reprint requests should be addressed. E-mail:
[email protected]
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214 or polymorphisms related to the serotonin pathway, such as the serotonin transporter (5-HTT), could be associated with mood disorders (Wenham et al., 1991; Collier et al., 1996; Lesch et al., 1996; Li et al., 1997; Oliveira et al., 1998; Kunugi et al., 2000). The short allele of the 5-HTT gene-linked polymorphic region (5-HTTLPR), involved in the activity of the serotonin transporter gene, has been studied in several mood disorders, including AD, bipolar, and unipolar disease. Some reports suggest that the 5-HT uptake function is reduced in these disorders (Collier et al., 1996; Lesch et al., 1996; Li et al., 1997; Kunugi et al., 2000). The search for other polymorphisms associated with AD has been undertaken by many groups of investigators around the world. Several putative candidate loci have been suggested, but most studies have shown controversial results when replicated in different populations, including the 5-HTTLPR polymorphism (Wenham et al., 1991; Collier et al., 1996; Lesch et al., 1996; Li et al., 1997; Oliveira et al., 1998; Kunugi et al., 2000). Monoamine oxidase A (MAOA) is a mitochondrial enzyme that catalyzes the degradation of different amines, including neurotransmitters like dopamine, norepinephrine, and serotonin. Several studies have shown that MAOAplays an important role in human behavior and physiology, being associated with mild mental retardation and impulsive aggressive behavior, mood disorders, and alcoholism with antisocial personality (Deckert et al., 1999; Furlong et al., 1999; Kunugi et al., 1999, 2000; Samochowiec et al., 1999; Schuback et al., 1999; Koller et al., 2003; Gutierrez et al., 2004). A functional polymorphism located upstream of this gene was described and consists of a 30-bp repeated sequence and the alleles 2 or 3, which were found to be transcribed 2–10 times more efficiently than others (Sabol et al., 1998). Moreover, the longer alleles (2, 3, and 4) were more frequent in panic disorder patients from German and Italian population than in controls. However, this association was observed only in females, which might be explained because it is an X-linked gene (Deckert et al., 1999). In contrast, no association between any MAOA polymorphic allele and mood disorders was reported by other researchers in the Japanese population, suggesting ethnic differences for association studies with this locus (Kunugi et al., 1999). Taking into account these controversial results, we have undertaken the present study in the Brazil-
Journal of Molecular Neuroscience
Nishimura et al. ian population, aiming to verify (1) whether MAOA polymorphisms are involved in LOAD, and (2) whether the short allele of 5-HTTLPR associated with MAOA polymorphism increases the risk for developing LOAD.
Patients and Methods A total of 128 LOAD patients (46 males and 82 females; mean age, 70.72 ± 8.99) were selected and diagnosed according to NINCDS-ADRDA criteria. To classify the cognitive impairment, neurological and neuropsychological testing, including MiniMental State Exam (MMSE) and Clinical Dementia Rating (CDR), were performed. The age/ethnicmatched control group (45 males and 81 females; mean age, 70.90 ± 9.08) was selected based on the MMSE and/or Blessed Scale, sociocultural and ethnic background. Informed consent was obtained from all subjects included in this study. Genomic DNAwas isolated from peripheral blood according to standard procedures. Analyses of MAOA, 5-HTTLPR, and ApoE polymorphisms were based on previous studies (Wenham et al., 1991; Lesch et al., 1996; Sabol et al., 1998) comparing LOAD patients and healthy controls. The Hardy-Weinberg equilibrium, as well as genotypic and allelic frequencies comparing LOAD patients and controls, was analyzed using χ2 tests, Fisher ’s exact test, and contingency tables. Differences were considered statistically significant at p < 0.05.
Results There were no significant deviations from the Hardy-Weinberg equilibrium for any of the polymorphisms studied. The allele and genotype distribution of the MAOA polymorphism is shown in Table 1. No allele distribution association was observed when the genders were analyzed separately comparing LOAD patients and controls (χ2 = 6.16, df = 3, p = 0.10 for males, and χ2 = 8.69, df = 7, p = 0.27 for females). However, a significant association was observed when both sexes were analyzed together (χ2 = 12.54, df = 4, p = 0.01). Interestingly, allele
