Abstract of online articleEstrogen receptor alpha gene variants are associated with Alzheimer's disease
Introduction
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that starts with mild memory deficit and cognitive decline that ultimately leads to severe dementia in a few years. It is the most prevalent neurodegenerative disorder in the elderly and affects more than 10% of the population older than 65 years (Evans et al., 1997, Rapp et al., 2003). With the increasing aging of the population AD represents 1 of the more severe health challenges for the near future.
It is well established that AD symptoms are due to severe synaptic transmission impairment in the brain as a consequence of a progressive neuronal cell loss in the central nervous system (CNS).
Late onset AD (LOAD) is considered a complex trait disease in which multiple genetic and nongenetic factors must work together to produce the clinical phenotype. The apolipoprotein E [APOE] ε4 allele is the only well established major genetic risk factor involved in LOAD (Crutcher, 2004). In addition to APOE gene, other loci may be associated with LOAD. For instance, 2 recent large genome-wide association studies (GWAS) have identified genetic variants within the CLU, PICALM and CR1 loci as risk factors for AD (Harold et al., 2009, Lambert et al., 2009).
Several lines of evidence suggest that AD could be an estrogen-related disease (ERD). Estrogen concentrations in post mortem brains from AD women are reduced compared with controls (Yue et al., 2005). The physiological activities of 17-β-estradiol and estrogen receptors in the brain are not restricted to reproductive-related areas of the central nervous system but they also influence the development and differentiation of several neuronal populations; they modulate synapsis plasticity, neurotransmission, neurite sprouting, and axonal growth (Morissette et al., 2008).
The ESR1 gene encodes for estrogen receptor alpha, 1 of the 2 subtypes of estrogen receptors. Some estrogen receptor alpha (ESR1) polymorphisms have been associated with risk of developing cognitive impairment in older women (Olsen et al., 2006, Yaffe et al., 2002) and with smaller gray matter volumes of the cerebral and cerebellar cortex (Boccardi et al., 2008). Furthermore, ESR1 markers have been widely studied in LOAD in multiple populations with discordant results (www.alzforum.org). In spite of this cumulative information, reduced sample size and heterogeneity of studied samples make the interpretation of these results controversial and difficult.
The aim of the present study is to assess the effect of 3 ESR1 polymorphisms on LOAD in a large sample representative of the Spanish population (n = 2343). The rs2234693 (PvuII) polymorphism has been extensively studied in AD but no conclusive results have been reached (www.alzforum.org). The rs3844508 has been proposed as a protective factor for AD in a recent genome-wide association study of Alzheimer's disease (Li et al., 2008). The ESR1 noncoding deletion 1 (ESR1-NCD1) is a 2244 base pair (bp) interstitial deletion that was characterized by our group and it seems to be a risk factor for idiopathic male infertility, and other estrogen-related disease (Galan et al., 2008). We also developed molecular analyses on this deletion to asses its potential effect over estrogen receptor alpha function.
Our results clearly support the involvement of ESR1 gene in AD in Spanish population and point to the existence of sexual dimorphism for ESR1 markers. In addition, our results also suggest that ESR1-NCD1 deletion could provoke an ESR1 receptor overresponse to estradiol action.
Section snippets
Study population
This study comprises 1113 unrelated sporadic AD patients (69.98% females; mean age, 78.81 ± 7.84). These samples were consecutively recruited at the Fundació ACE-Institut Català de Neurociències Aplicades, (Barcelona, Spain); Hospital Universitario La Paz-Cantoblanco (Madrid, Spain); and Unidad de Demencias, Hospital Virgen de la Arrixaca and Fundación Alzheimur (Murcia, Spain). Mean age at diagnosis in this AD sample was 77.55 ± 7.73 years. All patients fulfilled the Diagnostic and Statistical
Univariate case-control analyses
Three polymorphic markers within ESR1 gene were selected for association analysis. Two markers rs3844508 and rs2234693 are located within ESR1 intron 1. The ESR1-NCD1 deletion is located within the ESR1 intron 6 (Galan et al., 2008). The markers within ESR1 intron 1 are in partial linkage disequilibrium (D' = 0.81; p < 0.001), and intron 1 markers and ESR1-NCD1 deletion are in linkage equilibrium in our series (0<D'<0.20; p > 0.70).
Genotyping call rates for rs3844508, rs2234693, and ESR1-NCD1
Discussion
The role of ESR1 receptor in LOAD has been extensively studied. We have reviewed 19 independent studies registered in the Alzgene web site (www.alzforum.org). Most of them (16 studies) analyzed intron 1 markers, including classic PvuII (rs2234693), but their conclusions were discordant. Six studies (156<n<230 ad cases) found no association of PvuII with AD (den Heijer et al., 2004, Lambert et al., 2001, Maruyama et al., 2000, Rodríguez et al., 2006, Usui et al., 2006), whereas 10 independent
Disclosure statement
M. Boada, J. López-Arrieta, A. Caruz, I. Hernández, A. Mauleón, M. Rosende-Roca, P. Martínez-Lage, J. Marín, L. Tárraga, M. Alegret, J.R. Pedrajas, and N. Urda declare no conflicts of interests. C. Antunez is the Director of Alzheimur Foundation. C. Moreno-Rey, R. Ramírez-Lorca, F.J. Morón, J.L. Royo, M.E. Saez, J. Gayán, A. González-Pérez, and J.J. Galán are employees in Neocodex SL. L.M. Real and A. Ruiz are shareholders in Neocodex SL. F.J. Morón, M.E. Saez, J.L. Royo, L.M. Real, A. Ruiz,
Acknowledgements
This work was partially supported by European Commission 5th Framewok Programme (QLTR-2001-02403), Agencia IDEA, Consejería de Innovación, Ciencia y Empresa (830882); Corporación Tecnológica de Andalucía (07/126); Ministerio de Innovación (PCT-010000-2006-1; PCT-A41502790-2007 - PCT-010000-2007-18) and Fundación Alzheimur (Comunidad Autónoma de la Region de Murcia (CARM), Murcia, Spain).
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Interlinking polymorphisms, estrogens, and Alzheimer disease
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2018, PsychoneuroendocrinologyPolymorphisms in sex steroid receptors: From gene sequence to behavior
2017, Frontiers in NeuroendocrinologyGrade of inflammation in boys with type 1 diabetes depends on the IVS1 -397T>C estrogen receptor α polymorphism
2015, Journal of Diabetes and its ComplicationsCitation Excerpt :Associations between PvuII or XbaI polymorphisms and certain clinical conditions have been verified. These studies concern: risk of cardiovascular disease development (Herrington et al., 2002b; Myśliwska et al., 2009), osteoporosis (Albagha, McGuigan, Reid, & Ralstom, 2001; Becherini et al., 2009), cancer (Haiman et al., 1999; Weiderpass et al., 2000), increased blood pressure (Ellis, Infantino, & Harrap, 2004), spontaneous abortion (Anousha et al., 2013), multiple sclerosis (Niino, Kikuchi, Fukazawa, Yabe, & Tashiro, 2000), depression (Ryan & Ancelin, 2012), Alzheimer's disease (Boada et al., 2012), diabetes type 2 and obesity (Albagha et al., 2001), as well as type 1 diabetes (Ryba et al., 2011; Ryba-Stanisławowska, Rybarczyk-Kapturska, Brandt, Myśliwiec, & Myśliwska, 2014). Our previous studies unveiled connections between inflammatory response and the polymorphic variants of the ER-α gene.
Meta-analysis of PvuII, XbaI variants in ESR1 gene and the risk of Alzheimer's disease: The regional European difference
2014, Neuroscience LettersCitation Excerpt :The selections in each step are shown in the Fig. 1. When extracting data, a total of 11 and 10 case-control studies were selected for the relationship between ESR1 PvuII [9–11,19–24], XbaI [9–11,20–23,25] genotype and risk of AD in Caucasians, respectively. 2581 cases and 2884 controls were included within the studies about PvuII polymorphism in European population.
Estrogen receptor polymorphisms and incident dementia: The prospective 3C study
2014, Alzheimer's and DementiaCitation Excerpt :Indeed, several case-control studies have examined differences in the frequency of ESR1 polymorphisms between patients with late-onset AD and controls, but the exact association remains unclear. Some of these studies have reported that AD patients had a significantly higher frequency of the minor C and G alleles of rs2234693 and rs9340799, respectively [8–11]; however, other studies have found no significant associations [12–14] or even reverse associations [15,16]. Meta-analyses conducted a few years ago found a small but significant association between the minor alleles of these polymorphisms and an increased risk of AD (odds ratio [OR] ∼1.2) [17,18]; however, this is not supported by the most recent meta-analysis on the Alzheimer's Research Forum (http://www.alzgene.org).