Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1997-01-02
1999-08-24
Duffy, Patricia A.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435975, 536 243, 536 2431, 536 2433, 536 253, C12Q 168, C07H 2104
Patent
active
059423927
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to genetic markers used jointly for the diagnosis of Alzheimer's disease.
Alzheimer's disease is a brain pathology characterized by an early dementia with a loss of cortical neurons associated with plaques of .beta.-amyloid, neurofibrillary tangles and, in most cases, an amyloid angiopathy. It is strongly suspected that there is a genetic influence in the aetiology of Alzheimer's disease (WO 94/01772).
This genetic component has been brought to the fore over many years by indirect observations which suggest that the disease is inherited in autosomal dominant fashion with an age-dependant penetrance in order to explain the family links between individuals suffering from the disease. Recent molecular genetic studies have enabled putative genes for Alzheimer's disease to be isolated by looking for chromosome-specific polymorphic genetic markers (Bird et al., 1989, Neurobiology of Aging 10, 432-434).
Three chromosomal localizations have been described as being involved in the early onset familial forms (age at onset under 60 years): chromosome 21, chromosome 14 and chromosome 19. Two linkage studies have suggested that the chromosomal region 19q13.2 was associated with late onset familial forms of Alzheimer's disease (Pericak-Vance et al., Am. J. Hum. Genet. (1991), 48, 1034-1050; Schellenberg et al., Ann. Neurol. (1992), 31, 223-227). Within this chromosomal region, the group of genes for apolipoproteins (APO) E-CI-CI'-CII is a candidate zone. Among the products of these genes, apolipoprotein E (APOE) is involved especially in the nervous system: APOE is present in the senile plaques and possesses a binding affinity for the peptide .beta.-A4. Strittmatter et al. (Proc. Natl. Acad. Sci. (1993) 90, 177-181) have described an increased frequency of the .epsilon.4 allele of the APOE gene in the late onset familial forms of Alzheimer's disease. This observation has been confirmed for the familial forms (Corder et al., Science (1993), 261, 921-923) and the sporadic forms of Alzheimer's disease (Corder et al., Science (1993), 261, 921-923; Saunders et al., Neurology (1993), 13, 1467-1472).
Moreover, Schellenberg et al. (Ann. Neurol. 1992, 31: 223-227) have reported a genetic association between the F allele of the apolipoprotein CII gene (TaqI restriction fragment length polymorphism (RFLP) allele) and the familial form of Alzheimer's disease.
The authors of the present invention have carried out a study covering two populations of different origins, one suffering from a late onset form of Alzheimer's disease (after 65 years) and the other from an early onset form of Alzheimer's disease (before 65 years), which permitted a significant increase to be established in both groups of at least two of the following genetic markers: APOE .epsilon.4 allele, short D19S178 allele and long APO CII allele.
The localization of the APOE, APO CII (APO C2) and D19S178 markers on chromosome 19 is known and described, in particular, by Williamson et al. (Cyto Genetic and Cell Genetic 1991, vol. 58, p. 1678).
Thus the subject of the present invention is the joint use of at least two genetic markers selected from APOE, D19S178 and APO CII for the diagnosis of Alzheimer's disease, the genetic markers preferably consisting of APOE and D19S178 and/or APO CII, and as a further preference APOE, D19S178 and APO CII.
The genetic markers used are advantageously the APOE .epsilon.4 allele, the short D19S178 allele and the long APO CII allele.
The APOE gene possesses three alleles: .epsilon.2, .epsilon.3 and .epsilon.4.
Long APO CII allele is understood to mean an allele comprising more than 30.+-.3, and preferably more than 30, consecutive repeats of the bases cytosine-adenine.
Short D19S178 allele is understood to mean an allele comprising fewer than 167.+-.4, and preferably fewer than 167, nucleotides.
The subject of the invention is also a method of diagnosis of Alzheimer's disease, characterized in that the presence of at least two of the following markers is tested for in a biological sample from a patient: APO
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Amouyel Philippe
Chartier-Harlin Marie-Christine
Duffy Patricia A.
Institut National de la Sante et de la Recherche Medicale
Institut Pasteur de Lille
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