Human Molecular Genetics, 2000, Vol. 9, No. 15 2275-2280
© 2000 Oxford University Press
The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer’s disease
1INSERM U508, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019 Lille Cédex, France, 2Molecular Psychiatry Department, Division of Neuroscience, Queen Elisabeth Psychiatry Hospital, University of Birmingham, Birmingham B15 2QZ, UK, 3Birdsall Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA, 4Centre de Gériatrie de Wasquehal-Moulinel, rue Salvador Allende, BP 165, 59444 Wasquehal, France, 5Department of Mental Health, University of Aberdeen, Aberdeen,UK, 6CHRU de Lille, Clinique Neurologique, Centre de la Mémoire, Hôpital Salengro, 59037 Lille Cédex, France and 7Laboratory Medicine Academic Group, Department of Medicine, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK
Received 26 May 2000; Revised and Accepted 31 July 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTION RESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Although the
4 allele of the apolipoprotein E gene appears as an important biological marker for Alzheimer’s disease (AD) susceptibility, other genetic determinants are clearly implicated in the AD process. Here, we propose that a genetic variation in the transcriptional factor LBP-1c/CP2/LSF gene, located close to the LRP locus, is a genetic susceptibility factor for AD. We report an association between a non-coding polymorphism (G
A) in the 3'-untranslated region of this gene and sporadic AD in French and British populations and a similar trend in a North American population. The combined analysis of these three independent populations provides evidence of a protective effect of the A allele (OR = 0.58, 95% CI 0.44–0.75). We describe a potential biologically relevant role for the A allele whereby it reduces binding to nuclear protein(s). The absence of the A allele was associated with a lower LBP-1c/CP2/LSF gene expression in lymphocytes from AD cases compared with controls. Our data suggest that polymorphic variation in the implication of the LBP-1c/CP2/LSF gene may be important for the pathogenesis of AD, particularly since LBP-1c/CP2/LSF interacts with proteins such as GSKß, Fe65 and certain factors involved in the inflammatory response. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTION RESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The majority of Alzheimer’s disease (AD) is of late onset and is inherited in a complex pattern involving environmental factors and multiple genes that modify risk. Many candidate genes have been examined but only variations in the apolipoprotein E gene on chromosome 19 are consistently associated with sporadic AD, with the
4 allele occurring two to three times more frequently compared with non-demented controls (1). However, family, twin and population data all suggest that other genetic loci remain to be identified (2).
It has been established that an unknown gene on chromosome 12 is implicated in the causation of AD (3–6). Two very plausible genes are located in the large region of interest of this chromosome, the 
2-macroglobulin (2M) and the lipoprotein receptor related protein (LRP) genes, and both have been proposed to be associated with AD (7–9). However, no consensus has been reached on the effect of the studied polymorphisms on the risk for AD (10–13) and their functional relevance remains to be established. These uncertainties leave open the possibility that other gene(s) may be responsible for the observed risk associated with AD at this locus. We employed a candidate gene strategy to look at genes likely to interact with proteins implicated in the AD process, which are located within the AD locus on chromosome 12. The transcriptional factor LBP-1c/CP2/LSF appears to be a good candidate gene for the following reasons: (i) it is located close to the LRP gene (
6 cM); (ii) it has been implicated in the control of expression of 2M and glycogen synthase kinase-3ß (GSK3ß) expression (14,15); (iii) it may modulate the activation of the human immunodeficiency virus or the herpes simplex virus type 1 (16,17), infectious agents claimed to increase the risk of dementia in individuals bearing at least one apolipoprotein E 4 allele (18,19); and (iv) it interacts with the Fe65 protein, thought to control the internalization and processing of amyloid protein precursor (APP) (20) and which has recently been associated with AD (21). Collectively, these data lead us to sequence the LBP-1c/CP2/LSF gene in cases of sporadic AD in order to find genetic variations that might modify the risk of developing AD.
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RESULTS |
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TOPABSTRACTINTRODUCTION RESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Sequencing the cDNA produced by RT–PCR from total mRNA of lymphocytes (Table 1) [GenBank accession no. U03494 (22)], we found two single nucleotide polymorphisms in the 5'-untranslated region (UTR) and the 3'-UTR but not in coding sequences. Furthermore, another polymorphism was detected in the promoter sequence [GenBank accession no. U01965 (23)]. We analysed these three polymorphisms according to their potential action on LBP-1c/CP2/LSF expression and tested their impact on the risk of developing AD in a French population. The genotypic distribution for all three polymorphisms was in Hardy–Weinberg equilibrium (Tables 2 and 3). An association with modified risk for AD was detected only with the 3'-UTR polymorphism, which is located 15 bases downstream of the stop codon (Table 3). Individuals bearing at least one A allele had reduced risk for AD (OR = 0.48, 95% CI 0.33–0.70, P < 0.0002).
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Two independent Caucasian populations from the USA and UK were used to test further this association. We detected a similar effect in the UK population (OR = 0.46, 95% CI 0.23–0.93, P < 0.03, adjusted for gender and age), but we did not observe a significant protective effect of the 3'-UTR A allele in the US population (OR = 0.87, 95% CI 0.56–1.38, P < 0.5, adjusted for age and gender) (Table 3).
We then combined data from the three populations since the 3'-UTR genotype distributions were not significantly different and the impact of the 4 allele was similar between populations (data not shown). We found in these 1139 AD cases and 1317 controls that individuals bearing at least one 3'-UTR A allele had a lower risk of developing AD (OR = 0.58, 95% CI 0.44–0.75, P < 0.0001). We also found evidence for a decrease in the protective effect with age (OR = 0.43 before 70 years, CI 95% 0.27–0.68, P < 0.0004; OR = 0.52 between 70–80 years, 95% CI 0.33–0.83, P < 0.006; OR = 0.83 after 80 years, 95% CI 95% 0.51–1.37, P < 0.46). This age-related observation may explain why the effect of the 3'-UTR A allele was not significant in the older US population, whereas a similar trend was observed before 70 years in the US population (OR = 0.43, 95% CI 0.09–1.96, P < 0.29). We could not detect any statistical interaction among the 3'-UTR polymorphism, gender and apolipoprotein E genotype.
We next considered whether the 3'-UTR polymorphism had a biologically relevant role consistent with a modification of risk for AD. We used electrophoretic mobility shift assays to determine an allele-dependent protein binding to the sequence containing the 3'-UTR polymorphism. We compared the affinity for neuroblastoma nuclear proteins for oligomers containing the 3'-UTR G and A alleles. The A allele displayed an average 3.75-fold lower affinity than the G allele under equilibrium conditions (Fig. 1).
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We finally investigated whether this difference was reflected by altered expression of the LBP-1c/CP2/LSF gene. Using a semi-quantitative RT–PCR assay, we estimated the ratio between the amount of the LBP-1c/CP2/LSF and ß-actin mRNA from lymphocytes of control and AD individuals (Fig. 2). The level of expression of the LBP-1c/CP2/LSF gene in relation to the ß-actin gene was decreased in AD cases compared with controls irrespective of genotype (35.9 ± 10.8 and 50.6 ± 6.1, respectively; P < 0.005). Dividing cases and controls into those bearing the common genotypes revealed that this difference was due mainly to a lower expression in GG bearers (33.8 ± 10.2; P < 0.002). No difference was found between cases and controls bearing the GA genotype (47.7 ± 6.1; P < 0.9). Consequently, LBP-1c/CP2/LSF expression was lower in AD cases bearing GG compared with GA genotypes, although this difference did not reach statistical significance (GG = 33.8 ± 10.2 versus GA = 47.7 ± 6.1; P < 0.06).
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DISCUSSION |
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TOPABSTRACTINTRODUCTION RESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Present epidemiological data, combining three independent European and American populations, suggest that a biallelic polymorphism in the 3'-UTR region of the LBP-1c/CP2/LSF gene influences the risk of AD, with the 3'-UTR A allele being associated with a reduction in this risk. This protective effect seems to be greater in people under 70 years of age, as shown in the UK and French populations and as suggested in the US population. This protective effect was not observed with the promoter and 5'-UTR polymorphisms. No other coding polymorphisms were detected in this gene, but sequencing of the introns needs to be performed in order to exclude the potential implication of another polymorphism in linkage disequilibrium with the 3'-UTR polymorphism. However, the relevance of this polymorphism is underlined by the functional experiments. Indeed, we show that the 3'-UTR sequence binds protein(s) and that the 3'-UTR A allele binds with weaker affinity compared with the G allele. The LBP-1c/CP2/LSF expression in lymphocytes is lower in AD compared with controls. The absence of an A allele is associated with reduced expression of the LBP-1c/CP2/LSF gene. Our results are therefore consistent with a modulation of the LBP-1c/CP2/LSF gene expression by the 3'-UTR sequence containing this G
A polymorphism and this may operate through differential binding to a nuclear protein. However, since the decrease in expression of the LBP-1c/CP2/LSF gene only appears in AD carriers of the GG genotype, it is possible that this decrease in expression is due to interaction of homozygosity with another risk factor.
The implication of these findings for AD is not yet clear. However, several observations suggest a plausible role for this gene in causing this disorder. The LBP-1c/CP2/LSF protein may control the expression of certain proteins of interest in AD, including GSK3ß and serum amyloid A3 (SAA3) (14,15) or it may interact with the Fe65 protein (an APP binding protein) (20). This transcriptional factor may be a missing link between the APP processing and the hyperphosphorylation of the tau protein, possibly via control of GSK3ß gene expression. Moreover, this gene is directly implicated in the regulation of inflammatory processes, controlling not only growth-responsive promoters during mitogenic stimulation of resting T cells (24) but also the expression of the SAA3 protein, a major acute-phase protein (14) recently detected in tissues from patients with AD (25). It has also been proposed that LBP-1c/CP2/LSF may establish co-operative interactions with NF
B p65, interleukin-1 or tumour necrosis factor (14,26). If the impact of the variation in the LBP-1c/CP2/LSF gene in AD is confirmed, present findings may provide new evidence supporting a role for the inflammatory response in the development of AD (27).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTION RESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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DNA sequencing
Genomic DNA (Stratagene, La Jolla, CA) or mRNA (Qiagen, Hilden, Germany) was extracted from peripheral blood leukocytes using standard procedures. The primers used to sequence the mRNA and the promoter region are described in Table 1. Purified RT–PCR or PCR products were sequenced directly using the Taq Big Dye Terminator sequencing kit (Perkin-Elmer Applied Biosystems, Foster City, CA).
Study subjects
All probable AD cases fulfilled International Criteria for dementia (DSM-III-R and NINCDS-ADRDA) (France: n = 684, age = 72.8 ± 8.5, age at onset = 69.4 ± 8.4, 37% of men; USA: n = 296, age = 78.2 ± 9.4, age at onset = 75.7 ± 0.2, 33% of men; UK: n = 159, age = 65.7 ± 11.1 and age at onset = 65.7 ± 11.0, 33% of men). In the Scottish population, only 14 cases presented family history, whereas all cases were sporadic in the two other populations. In the Manchester series of definite AD cases, diagnoses were confirmed by neuropathological examination according to ADRDA criteria (n = 73, age = 74.0 ± 8.4, age at onset = 65.7 ± 8.3, 47% of men). Controls were defined as subjects without DMS-III-R dementia criteria and with integrity of cognitive functions (France: n = 650, age = 73.2 ± 8.6, 37% of men; USA: n = 462, age = 79.2 ± 9.3, 33% of men; UK: n = 159, age = 60.8 ± 11.3, 49% of men).
Genotyping
The primers used to amplify the three polymorphisms are described in Table 1. The different alleles were detected by a restriction fragment length polymorphism analysis of FokI, BstnI, BSP1286I sites, specific to the promoter G allele and the 5'-UTR G allele and 3'-UTR G allele. All genotypes containing the uncut allele were confirmed by a repeated assay.
Electrophoretic mobility shift assays
Nuclear extracts were prepared according to described methods (28). Single-stranded oligonucleotides (5'3') were end-labelled with digoxigenin, annealed to complementary oligomer and incubated for 20 min at room temperature with nuclear extract (5 µg for neuroblastoma Kelly). Proteins were added to a final volume of 20 µl of a mixture containing 20 mM Tris–HCl pH 9.0, 50 mM NaCl, 1 mM EDTA, 5% glycerol, 1 mM phenyl methylsulfonyl fluoride, 1 mM dithiothreitol, 5 µg/ml leupeptin, 5 µg/ml aprotinin, 0.5 mg/ml bovine serum albumin, 2 mg/ml poly(dIdC), 20 pmol/ml probe, and the mixture was incubated for 20 min at room temperature prior to gel analysis. The complexes were separated on a 5% non-denaturing polyacrylamide gel and semi-dry electrophoretic transfer was performed from gels to nitrocellulose membranes. Detection was as described by the supplier (Roche Diagnostics, Meylan, France).
Semi-quantitative RT–PCR assays
Total RNA extraction from the different cell lines was performed using RNeasy Mini kit (Qiagen). Co-amplification of the mRNA from the LBP-1c/CP2/LSF and ß-actin genes was performed using Titan one tube RT–PCR kit as described by the supplier (Roche Diagnostics). A 515 bp fragment of the LBP-1c/CP2/LSF mRNA was specifically amplified using forward primer 5'-CAAGCCACCACTACGAACTC-3' and reverse primer 5'-TTATCAGGAGGCAAACTCGA-3'. Another set of oligonucleotides giving a 482 bp fragment (forward: 5'-AGCATGAGTGATGTCCTTGC-3'; reverse: 5'-CCGCCATGTTTCCTCATAGT-3'), was used to amplify a different part of the LBP-1c/CP2/LSF mRNA in order to confirm the variation of expression.
Statistical analyses
The SAS software release 6.10 was used (SAS Institute, Cary, NC). Univariate analysis was performed using Pearson’s 
2 test. In the multivariate analysis, we coded the genotype of the 3'-UTR polymorphism by dichotomizing genotypes into the presence or absence of an A allele (AA+GA versus GG). The effects of this variable on the disease were assessed with a multiple logistic regression model adjusted for age and gender. Comparison of the LBP-1c/CP2/LSF gene expression according to status and 3'-UTR genotype was performed using non-parametric Wilcoxon test.
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ACKNOWLEDGEMENTS |
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We thank L. Buée, M.L. Caillet-Boudin, G. Chinetti, I. Torra and P. Delerive for their helpful discussion. J.-C.L. and L.G. are recipients of a Marie Curie Fellowship and a Conseil Régional du Nord-Pas de Calais, respectively. This work was supported by the Institut National pour la Santé et la Recherche Médicale (INSERM), the Institut Pasteur de Lille, the Conseil Régional du Nord-Pas de Calais ‘Axe Régional de Recherches sur les Maladies Neurodégénératives et le vieillissement cérébral’ (M.-C.C.-H., P.A. and F.P.) and the South Birmingham Mental Health Trust (C.L.L.).
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FOOTNOTES |
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+ To whom correspondence should be addresssed. Tel: +33 3 20 87 72 28; Fax: +33 3 20 87 78 94; Email: marie-christine.chartier@pasteur-lille.fr
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