Abstract.
Apolipoprotein D (apoD) is a lipoprotein–associated glycoprotein, structurally unrelated to apoE, that transports small hydrophobic ligands including cholesterol and sterols. Levels are increased in the hippocampus and CSF of Alzheimer’s disease (AD) patients. We tested whether variation in the APOD gene affects AD risk. Four single nucleotide polymorphisms (SNPs) were investigated (in map order): exon 2, 15T→C encodes an amino acid substitution Phe→Ser at codon 15; intron 2, –352G→A; intron 3, +45C→T; intron 4, +718C→T, determined by SNaPshot assay. SNP frequencies for 394 eastern Finnish AD patients were compared with those found for 470 control subjects, dividing subjects also into early–onset AD (EOAD; ≤ 65 years) and late–onset AD (LOAD; >65 years) groups. The –352G allele was associated with a significant 3–fold increase in the risk of EOAD (OR: 2.7; 95% CI: 1.1–6.5). The –352G containing haplotypes were more common for EOAD cases (TGCC: 0.48 vs 0.41; TGCT: 0.08 vs 0.01 (p = 0.002). In the Grade–of–membership analysis, APOD genotype frequencies at each SNP site and disease status were used to construct two latent groups: the affected group carried –352 as GG or GA and +45 CC, was often women and enriched in APOE ε4. Each method suggested that the –352G allele frequency is higher for EOAD in the eastern Finnish population.
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Belloir B, Kövari E, Surini-Demiri M, Savioz A (2001) Altered apolipoprotein D expression in the brain of patients with Alzheimer disease. J Neurosci Res 64:61–69
Boldt A, Petzl-Erler M (2002) A new strategy for mannose-binding lectin gene haplotyping. Hum Mutat 19:296–306
Connor JR, Milward EA, Moalem S, Sampietro M, Boyer P, Percy ME, Vergani C, Scott RJ, Chorney M (2001) Is hemochromatosis a risk factor for Alzheimer’s disease? J Alzheimer’s Dis 3:471–477
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
Desai PP, Bunker CH, Ukoli FAM, Kamboh MI (2002) Genetic variation in the apolipoprotein D gene among African blacks and its significance in lipid metabolism. Atherosclerosis 163:329–338
Desai PP, Hendrie HC, Evans RM, Murrell JR, DeKosky ST, Kamboh MI (2003) Genetic variation in apolipoprotein D affects the risk of Alzheimer disease in African-Americans. Am J Med Genet 116:98–101
Drayna DT, McLean JW, Wion KL, Trent JM, Drabkin HA, Lawn RM (1987) Human apolipoprotein D gene: gene sequence, chromosomal localization, and homology to the α2μ-globulin superfamily. DNA 6:199–204
Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927
Flower DR (1994) The lipocalin protein family: a role in cell regulation. FEBS Lett 354:7–11
Hiltunen M, Mannermaa A, Thompson D, Easton D, Pirskanen M, Helisalmi S, Koivisto AM, Lehtovirta M, Ryynänen M, Soininen H (2001) Genome-wide linkage disequilibrium mapping of late-onset Alzheimer’s disease in Finland. Neurology 57:1663–1668
Kuusisto J, Koivisto K, Kervinen K, Mykkänen L, Helkala E-L,Vanhanen M, Hänninen T, Pyörälä K, Kesäniemi A, Riekkinen P, Laakso M (1994) Association of apolipoprotein E phenotype with late-onset Alzheimer’s disease: a population-based study. BMJ 309:636–638
Lehtovirta M, Soininen H, Helisalmi S, Mannermaa A, Helkala E-L, Hartikainen P, Hänninen T, Ryynänen M, Riekkinen P Sr (1996) Clinical and neuropsychological characteristics in familial and sporadic Alzheimer’s disease: relation to apolipoprotein E polymorphism. Neurology 46:413–419
Manton KG, Woodbury MA, Tolley HD (1994) Statistical Applications Using Fuzzy Sets. John Wiley & Sons, New York
McKhann G, Drachman D, Folstein M, Katzman R, Prica D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944
Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L, CERAD neuropathologists (1991) The Consortium to Establish a Registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486
Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM (1999) Diabetes mellitus and the risk of dementia: the Rotterdam study. Neurology 53:1937–1942
Rassart E, Bedirian A, Do Carmo S, Guinard O, Sirois J, Terrisse L, Milne R (2000) Apolipoprotein D Biochim Biophys Acta 1482:185–198
Raymond ML, Rousset F (1995) An exact test for population differentiation. Evolution 49:1280–1283
Richardson DR, Ponka P (1997) The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim Biophys Acta 1331:1–40
Suresh S, Yan Z, Patel RC, Patel YC, Patel SC (1998) Cellular cholesterol storage in the Niemann-Pick disease type C mouse is associated with increased expression and defective processing of apolipoprotein DJ Neurochem 70:242–251
Terrisse L, Poirier J, Bertrand P, Merched A, Visvikis S, Siest G, Milne R, Rassart E (1998) Increased levels of apolipoprotein D in cerebrospinal fluid and hippocampus of Alzheimer’s patients. J Neurochem 71:1643–1650
Thomas EA, Dean B, Pavey G, Sutcliffe JG (2001) Increased CNS levels of apolipoprotein D in schizophrenic and bipolar subjects: implications for the pathophysiology of psychiatric disorders. Proc Natl Acad Sci USA 98:4066–4071
Tsukamoto K, Watanabe T, Matsushima T, Kinoshita M, Kato H, Hashimoto Y, Kurokawa K, Teramoto T (1993) Determination by PCR-RFLP of apoE genotype in a Japanese population. J Lab Clin Med 121:598–602
Vandenplas S, Grobler-Rabie A, Brebner K, Rickets M, Wallis G, Bester A, Boyd C, Mathew C (1984) Blot hybridisation of genomic DNA. J Med Genet 21:164–172
Vijayaraghavan S, Hitman GA, Kopelman PG (1994) Apolipoprotein-D polymorphism – a genetic marker for obesity and hyperinsulinemia. J Clin Endocrinol Metab 79:568–570
Ward RJ, Zhang Y, Crichton RR (2001) Aluminium toxicity and iron homeostasis. J Inorg Biochem 87:9–14
Woodbury MA, Clive J, Garson A Jr (1978) Mathematical typology: a grade of membership technique for obtaining disease definition. Comput Biomed Res 11:277–298
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Helisalmi, S., Hiltunen, M., Vepsäläinen, S. et al. Genetic variation in apolipoprotein D and Alzheimer’s disease. J Neurol 251, 951– 957 (2004). https://doi.org/10.1007/s00415-004-0470-8
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DOI: https://doi.org/10.1007/s00415-004-0470-8