Abstract
Several recent case-control studies have examined the association between single nucleotide polymorphisms (SNPs) in the promoter region of the apolipoprotein E gene (APOE) and risk of Alzheimer disease (AD), with conflicting results. We assessed the relation between five APOE region SNPs and risk of AD in both case-control and family-based analyses. We observed a statistically significant association with the +5361T allele in the overall case-control analysis (P value=0.04) after adjusting for the known effect of the APOE-4 allele. Further analysis revealed this association to be limited to carriers of the APOE-4 allele. Age-stratified analyses in the patients with age at onset of 80 years or greater and age-matched controls showed that the −219T allele (P value=0.009) and the +113C allele (P value=0.03) are associated with increased risk of AD. Despite these findings, haplotype and family-based association analyses were unable to provide evidence that the APOE region SNPs influenced risk of AD independent of the APOE-4 allele. In addition to risk, we tested for association between the SNPs and age at onset of AD, but found no association in the case-control or family based analyses. In conclusion, SNPs +5361, or a SNP in strong linkage disequilibrium, may confer some additional risk for developing AD beyond the risk due to APOE-4; however, the effect independent of APOE-4 is likely to be small.
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Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923
Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472
Nickerson DA, Taylor SL, Fullerton SM, Weiss KM, Clark AG, Stengard JH, Salomaa V, Boerwinkle E, Sing CF (2000) Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene. Genome Res 10:1532–1545
Artiga MJ, Bullido MJ, Sastre I, Recuero M, García MA, Aldudo J, Vázquez J, Valdivieso F (1998) Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett 421:105–108
Artiga MJ, Bullido MJ, Frank A, Sastre I, Recuero M, García MA, Lendon CL, Han SW, Morris JC, Vázquez J, Goate A, Valdivieso F (1998) Risk for Alzheimer’s disease correlates with transcriptional activity of the APOE gene. Hum Mol Genet 7:1887–1892
Lambert JC, Araria-Goumidi L, Myllykangas L, Ellis C, Wang JC, Bullido MJ, Harris JM, Artiga MJ, Hernandez D, Kwon JM, Frigard B, Petersen RC, Cumming AM, Pasquier F, Sastre I, Tienari PJ, Frank A, Sulkava R, Morris JC, St Clair D, Mann DM, Wavrant-DeVrieze F, Ezquerra-Trabalon M, Amouyel P, Hardy J, Haltia M, Valdivieso F, Goate AM, Perez-Tur J, Lendon CL, Chartier-Harlin MC (2002) Contribution of APOE promoter polymorphisms to Alzheimer’s disease risk. Neurology 59:59–66
Bullido MJ, Artiga MJ, Recuero M, Sastre I, Garcia MA, Aldudo J, Lendon C, Han SW, Morris JC, Frank A, Vazquez J, Goate A, Valdivieso F (1998) A polymorphism in the regulatory region of APOE associated with risk for Alzheimer’s dementia. Nat Genet 18:69–71
Casadei VM, Ferri C, Veglia F, Gavazzi A, Salani G, Cattaneo M, Sorbi S, Annoni G, Licastro F, Mariani C, Franceschi M, Grimaldi LM (1999) APOE-491 promoter polymorphism is a risk factor for late-onset Alzheimer’s disease. Neurology 53:1888–1889
Bullido MJ, Valdivieso F (2000) Apolipoprotein E gene promoter polymorphisms in Alzheimer’s disease. Microsc Res Tech 50:261–267
Wang JC, Kwon JM, Shah P, Morris JC, Goate A (2000) Effect of APOE genotype and promoter polymorphism on risk of Alzheimer’s disease. Neurology 55:1644–1649
Zurutuza L, Verpillat P, Raux G, Hannequin D, Puel M, Belliard S, Michon A, Pothin Y, Camuzat A, Penet C, Martin C, Brice A, Campion D, Clerget-Darpoux F, Frebourg T (2000) APOE promoter polymorphisms do not confer independent risk for Alzheimer’s disease in a French population. Eur J Hum Genet 8:713–716
Heijmans BT, Slagboom PE, Gussekloo J, Droog S, Lagaay AM, Kluft C, Knook DL, Westendorp RG (2002) Association of APOE epsilon2/epsilon3/epsilon4 and promoter gene variants with dementia but not cardiovascular mortality in old age. Am J Med Genet 107:201–208
Halimi G, Duplan L, Bideau C, Iniesta D, Berthezene P, Oddoze C, Verdier JM, Michel B, Berge-Lefranc JL (2000) Association of APOE promoter but not A2 M polymorphisms with risk of developing Alzheimer’s disease. Neuroreport 11:3599–3601
Alvarez-Arcaya A, Combarros O, Llorca J, Sanchez-Guerra M, Berciano J, Fernandez-Luna JL (2001) The --491 TT apolipoprotein E promoter polymorphism is associated with reduced risk for sporadic Alzheimer’s disease. Neurosci Lett 304:204–208
Zill P, Engel R, Hampel H, Behrens S, Burger K, Padberg F, Stubner S, Moller HJ, Ackenheil M, Bondy B (2001) Polymorphisms in the apolipoprotein E (APOE) gene in gerontopsychiatric patients. Eur Arch Psychiatry Clin Neurosci 251:24–28
Beyer K, Lao JI, Gomez M, Riutort N, Latorre P, Mate JL, Ariza A (2002) Identification of a protective allele against Alzheimer disease in the APOE gene promoter. Neuroreport 13:1403–1405
Roks G, Cruts M, Houwing-Duistermaat JJ, Dermaut B, Serneels S, Havekes LM, Hofman A, Breteler MM, Van Broeckhoven C, Van Duijn CM (2002) Effect of the APOE-491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer disease: The Rotterdam Study. Am J Med Genet 114:570–573
McKhann G, Drachman D, Folstein M (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944
Kent WJ (2002) BLAT—the BLAST-like alignment tool. Genome Res 12:656–664
Elnitski L, Hardison RC, Li J, Yang S, Kolbe D, Eswara P, O’Connor MJ, Schwartz S, Miller W, Chiaromonte F (2003) Distinguishing regulatory DNA from neutral sites. Genome Res 13:64–72
Oliveira SA, Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons KE, Pahwa R, Stern MB, Hiner BC, Jankovic J, Ondo WG, Allen FH, Jr., Scott BL, Goetz CG, Small GW, Mastaglia FL, Stajich JM, Zhang F, Booze MW, Reaves JA, Middleton LT, Haines JL, Pericak-Vance MA, Vance JM, Martin ER (2003) Association study of Parkin gene polymorphisms with idiopathic Parkinson disease. Arch Neurol 60:975–980
Rozen S, Skaletsky HJ. Primer 3 (1998) Whitehead Institute
Zaykin D, Zhivotovsky L, Weir BS (1995) Exact tests for association between alleles at arbitrary numbers of loci. Genetica 96:169–178
Abecasis GR, Cookson WO (2000) GOLD—graphical overview of linkage disequilibrium. BioInformatics 16:182–183
Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434
Martin ER, Monks SA, Warren LL, Kaplan NL (2000) A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 67:146–154
Martin ER, Bass MP, Kaplan NL (2001) Correcting for a potential bias in the pedigree disequilibrium test. Am J Hum Genet 68:1065–1067
Martin ER, Bass MP, Gilbert JR, Pericak-Vance MA, Hauser ER (2003) Genotype-based association test for general pedigrees: the genotype-PDT. Genet Epidemiol 25:203–213
Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM (2004) Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 26:61–69
Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292
Fulker DW, Cherny SS, Sham PC, Hewitt JK (1999) Combined linkage and association sib-pair analysis for quantitative traits. Am J Hum Genet 64:259–267
Risch N, Teng J (1998) The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases: DNA pooling. Genome Res 8:1273–1288
Lambert JC, Pasquier F, Cottel D, Frigard B, Amouyel P, Chartier-Harlin MC (1998) A new polymorphism in the APOE promoter associated with risk of developing Alzheimer’s disease. Hum Mol Genet 7:533–540
Town T, Paris D, Fallin D, Duara R, Barker W, Gold M, Crawford F, Mullan M (1998) The −491A/T apolipoprotein E promoter polymorphism association with Alzheimer’s disease: independent risk and linkage disequilibrium with the known APOE polymorphism. Neurosci Lett 252:95–98
Acknowledgements
We thank all the families whose participation made this project possible. This research was supported by grants from the National Institutes of Health: R01 AG20135, R01 NS31153, R01 AG19757, R01 AG021547, and grants from the Alzheimer Association, including a Zenith award ZEN-01–2935. We also gratefully acknowledge the personnel at the Duke Center for Human Genetics who played an important part in this research.
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Nicodemus, K.K., Stenger, J.E., Schmechel, D.E. et al. Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease. Neurogenetics 5, 201–208 (2004). https://doi.org/10.1007/s10048-004-0189-9
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DOI: https://doi.org/10.1007/s10048-004-0189-9