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Genetic Association of Complement Receptor 1 Polymorphism

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Genetic Association of Complement Receptor 1 Polymorphism Alzheimer’s & Dementia 7 (2011) e124–e129 Genetic association of complement receptor 1 polymorphism rs3818361 in Alzheimer’s disease Carmen Antunez a,b, Merce Boadac,d, Jesus Lopez-Arrieta e, Concha Moreno-Reyf, Isabel Hernandezc, Juan Marına, Javier Gayanf, Alzheimer’s Disease Neuroimaging Initiative, Antonio Gonzalez-Perezf, Luis M. Realf, Montserrat Alegretc, Lluis Tarragac, Reposo Ramırez-Lorcaf, Agustın Ruizf,* aDementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain bAlzheimUr Foundation, Murcia, Spain cMemory Clinic of Fundacio ACE, Institut Catala de Neurciencies Aplicades, Barcelona, Spain dInstitut de Recerca, Universitat Autonoma de Barcelona (VHIR-UAB), Hospital Universitari Vall d’Hebron, Barcelona, Spain eMemory Unit, University Hospital La Paz-Cantoblanco, Madrid, Spain fDepartment of Structural Genomics, Neocodex, Sevilla, Spain Abstract Complement receptor 1 gene polymorphism rs3818361 was recently shown to increase the risk of Alzheimer’s disease (AD). We performed an independent replication study of this genetic variant in 2470 individuals from Spain. By applying an allelic model, we observed a trend toward an association between this marker and late-onset AD susceptibility in our case–control study (odds ratio 5 1.114, 95% confidence interval: 0.958–1.296, P 5.16). Meta-analysis of available studies (n 5 31,771 individuals), including previous studies and public genome-wide association study resources (Alzheimer’s Disease Neuroimaging Initiative, Translational Genomics Research Institute, and Multi-site Collaborative Study for Genotype-Phenotype Associations in Alzheimer’s Disease), strongly supports the effect of rs3818361 (odds ratio 5 1.180, 95% confidence interval: 1.113–1.252, P , 2.99E-8) and suggests the existence of between-study heterogeneity (P , .05). We concluded that the complement receptor 1 gene may contribute to AD risk, although its effect size could be smaller than previously estimated. Ó 2011 The Alzheimer’s Association. All rights reserved. Keywords: Alzheimer’s disease; Association; CR1; Genotype; Meta-analysis; Molecular genetics; Polymorphism The genetic basis of Alzheimer’s disease (AD) has been the sample identified a genome-wide significant signal for a single focus of several genome-wide association studies (GWAS). nucleotide polymorphism (SNP) within the complement com- Recently, a large case–control study performed in a French ponent receptor 1 locus (complement receptor 1 [CR1], com- plement component 3b/4b receptor, C3-binding protein, C3BR, C4BR, or CD35, Mendelian Inheritance in Man code Some of the data used in this article were obtained from the Alz- 120620). Importantly, this finding was replicated in multiple heimer’s Disease Neuroimaging Initiative (ADNI) database (www.loni.u- AD case–control series from Belgium, Finland, Italy, and cla.edu/ADNI). As such, the investigators within ADNI contributed to Spain [1]. Consequently, the authors proposed that CR1 the design and implementation of ADNI and/or provided data but did not markers may act as a modifying genetic factor for AD risk. participate in the analysis or writing of this report. A complete listing of Furthermore, a consistent signal within CR1 gene was ob- ADNI investigators is available at www.loni.ucla.edu/ADNI/Collabora- tion/ADNI_Authorship_list.pdf. served in a concurrent independent GWA study published by C.A., M.B., J.L., A.I.H., J.M., L.T., and M.A. declare no conflicts of in- other European researchers, although no GWAS significance terests. C.M.-R., R.R.-L., J.G., and A.G.-P. are employees in Neocodex SL. was achieved in that particular study [2]. L.M.R. and A.R. are shareholders in Neocodex SL. The CR1 gene is located on chromosome 1q32, and it is *Corresponding author. Tel.: 134 955 047 618; Fax: 134 955 047 325. strongly expressed in myeloid cell lines, whole blood, breast, E-mail address: [email protected] 1552-5260/$ - see front matter Ó 2011 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2011.05.2412 C. Antunez et al. / Alzheimer’s& Dementia 7 (2011) e124–e129 e125 ovary, or spleen and weakly expressed in other tissues, in- subjects have been recruited from over 50 sites across the cluding pancreatic islets, brain cortex, hypothalamus, or sal- U.S. and Canada. The initial goal of ADNI was to recruit ivary glands [3]. This gene is a member of the receptors of 800 adults, ages 55 to 90, to participate in the research—ap- complement activation (RCA) family. It is located within proximately 200 cognitively normal older individuals to be the “cluster RCA” region of chromosome 1 [3], and its func- followed for 3 years, 400 people with MCI to be followed tion with regard to AD is still poorly understood, although for 3 years and 200 people with early AD to be followed this protein could be involved in erythrocyte amyloid beta for 2 years.” For up-to-date information, please refer to the 42 sequestration and clearance from whole blood [1]. Web site www.adni-info.org. Because the follow-up and replication of GWAS findings The CR1 gene polymorphism rs3818361 was genotyped provide further validation of proposed signals, we decided to in a LightCycler 480 instrument (Roche Diagnostics, Basel, evaluate a CR1 marker with the most consistent association Switzerland) by using the LightCycler 480 Probes Master kit to AD (rs3818361) as a genetic modifying factor for AD risk according to the manufacturer’s instructions (Supplementary in a sample of the Spanish population. Methods and Supplementary Table 1). To conduct statistical To conduct this research, we studied 2470 Spanish individ- analysis and phenotype–genotype correlations, we used tests uals previously selected to evaluate other SNPs associated with adapted from the study conducted by Sasieni (available AD [4]. Specifically, the sample included 1140 patients with online at http://ihg2.helmholtz-muenchen.de/) [6]. Age-, sporadic AD diagnosed as possible or probable AD in accor- sex-, and APOE genotype-adjusted binary logistic regression dance with National Institute of Neurological and Communica- analyses were performed using SPSS 15.0 software (SPSS, tive Diseases and Stroke/Alzheimer’s Disease and Related Chicago, IL). Meta-analyses were conducted using Episheet Disorders Association criteria [5], 1209 control subjects with (http://krothman.byethost2.com/Episheet.xls). Specifically, unknown cognitive status from the general population, and the pooled estimate and 95% confidence intervals (CIs) 121 neuropsychologically healthy elderly control (NHEC) were estimated by assuming a random effects model. A forest subjects screened for the absence of cognitive impairment by plot with allelic ORs from published studies and the pooled a structured interview including neurological mental status OR was constructed using Episheet. examination, category fluency test, and Folstein Mini-Mental The referral centers’ ethics committees and Neocodex State Examination. Mean (SD) age at recruitment was 78.8 have approved this research protocol, which is in compliance (7.9), 49.9 (9.2), and 77.5 (9.4) years in patients, control with Spanish national legislation and the Code for Ethical subjects, and NHECs, respectively. The total number (%) of Principles for Medical Research Involving Human Subjects females in these groups was 797 (69.9%), 638 (52.8%), and of the World Medical Association Declaration of Helsinki. 63 (52.1%), respectively. Mean (SD) age at AD diagnosis Minor allele frequency, genotype distribution, and was 77.6 (7.7) years. DNA extraction procedures and apolipo- observed heterozygosity for rs3818361 marker in this sam- protein E (APOE) genotyping have been previously described ple of the Spanish population are in accordance with the [4]. As reported for other European populations, the presence National Center for Biotechnological Information database of APOE 34 allele was strongly associated with AD in our series and previous investigations [1]. The average genotyping (cases vs all controls; odds ratio [OR] 5 3.18, P 5 2.48E-37). call rate in our study was .97.9%. Hardy–Weinberg equilib- In addition, parts of data used in the preparation of this rium analyses in our population indicated no deviation for article were obtained from the Alzheimer’s Disease Neuro- the SNP marker studied (P . .31; Supplementary Table 2). imaging Initiative (ADNI) database (www.loni.ucla.edu/ We explored the association of CR1 rs3818361 marker ADNI). “The ADNI was launched in 2003 by the National with AD phenotype using different tests adapted from the Institute on Aging (NIA), the National Institute of Biomed- study conducted by Sasieni and compared AD versus control ical Imaging and Bioengineering (NIBIB), the Food and subjects, AD versus NHECs, or AD versus all control sub- Drug Administration (FDA), private pharmaceutical compa- jects (Table 1). We found no evidence of significant associ- nies and non-profit organizations, as a $60 million, 5-year ation to AD in any comparison (P . .16). We also obtained public-private partnership. The primary goal of ADNI has adjusted estimates using binary logistic regression models been to test whether serial magnetic resonance imaging adjusting for age, sex, and APOE (dominant model). Again, (MRI), positron emission tomography (PET), and other bio- we did not detect any statistically significant effect on AD logical markers are related to the progression of mild cogni- susceptibility in our series (P . .60; Table 1). To assess tive impairment (MCI) and early AD. Determination of CR1–APOE (gene-gene) and CR1–sex interactions, we strat- sensitive and specific markers of very early AD progression ified our series according to APOE genotype and sex and ap- is intended to aid researchers and clinicians to develop new plied Mantel–Haenszel stratified analysis. No evidence of treatments and monitor their effectiveness, as well as lessen interaction was observed (data not shown). the time and cost of clinical trials. The Principal Investigator Overall, the CR1 rs3818361 marker was not significantly of this initiative is Michael W. Weiner, MD, VA Medical associated to AD in this sample of the Spanish population.
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