BACKGROUND: The NOTCH4 gene is located at 6p21.3, a site shown in several studies to have significant linkage with Alzheimer's disease. OBJECTIVE: To investigate the potential impact of two polymorphisms within this gene on the risk of developing Alzheimer's disease. METHODS: Genotyping of promoter and 5'-UTR polymorphisms was done in Scottish, English, and French populations. The potential functionality of the 5'-UTR polymorphism was assessed by testing its impact on A beta load in Alzheimer brains and also by undertaking electrophoretic mobility shift assays and transfection experiments. RESULTS: No association of the Notch4 polymorphisms alone with the disease was observed in any of the populations. However, an interaction of the 5'-UTR C/T polymorphism with the epsilon 4 allele of the APOE gene was detected in United Kingdom populations but not in the French. No relation between the 5'-UTR polymorphism and A beta loads was detected overall or in the presence or absence of the epsilon 4 allele. No DNA protein specific binding was found with proteins from neuroblastoma, glioma, or astrocytoma cells, and no allele dependent transcriptional activity was detected. CONCLUSIONS: No association between two NOTCH4 polymorphisms alone and Alzheimer's disease was observed in the three populations, but there was evidence of an increased risk associated with the 5'-UTR CC genotype in epsilon 4 bearers in the United Kingdom. As no functionality for this polymorphism could be determined, it is likely that the interaction is spurious or results from a linkage disequilibrium of this 5'-UTR polymorphism with another marker elsewhere in the 6p21.3 locus.
BACKGROUND: The NOTCH4 gene is located at 6p21.3, a site shown in several studies to have significant linkage with Alzheimer's disease. OBJECTIVE: To investigate the potential impact of two polymorphisms within this gene on the risk of developing Alzheimer's disease. METHODS: Genotyping of promoter and 5'-UTR polymorphisms was done in Scottish, English, and French populations. The potential functionality of the 5'-UTR polymorphism was assessed by testing its impact on A beta load in Alzheimer brains and also by undertaking electrophoretic mobility shift assays and transfection experiments. RESULTS: No association of the Notch4 polymorphisms alone with the disease was observed in any of the populations. However, an interaction of the 5'-UTR C/T polymorphism with the epsilon 4 allele of the APOE gene was detected in United Kingdom populations but not in the French. No relation between the 5'-UTR polymorphism and A beta loads was detected overall or in the presence or absence of the epsilon 4 allele. No DNA protein specific binding was found with proteins from neuroblastoma, glioma, or astrocytoma cells, and no allele dependent transcriptional activity was detected. CONCLUSIONS: No association between two NOTCH4 polymorphisms alone and Alzheimer's disease was observed in the three populations, but there was evidence of an increased risk associated with the 5'-UTR CC genotype in epsilon 4 bearers in the United Kingdom. As no functionality for this polymorphism could be determined, it is likely that the interaction is spurious or results from a linkage disequilibrium of this 5'-UTR polymorphism with another marker elsewhere in the 6p21.3 locus.
Authors: H Payami; G D Schellenberg; S Zareparsi; J Kaye; G J Sexton; M A Head; S S Matsuyama; L F Jarvik; B Miller; D Q McManus; T D Bird; R Katzman; L Heston; D Norman; G W Small Journal: Neurology Date: 1997-08 Impact factor: 9.910
Authors: Deborah Blacker; Lars Bertram; Aleister J Saunders; Thomas J Moscarillo; Marilyn S Albert; Howard Wiener; Rodney T Perry; Julianne S Collins; Lindy E Harrell; Rodney C P Go; Amy Mahoney; Terri Beaty; M Danielle Fallin; Dimitrios Avramopoulos; Gary A Chase; Marshal F Folstein; Melvin G McInnis; Susan S Bassett; Kimberly J Doheny; Elizabeth W Pugh; Rudolph E Tanzi Journal: Hum Mol Genet Date: 2003-01-01 Impact factor: 6.150
Authors: A Joutel; C Corpechot; A Ducros; K Vahedi; H Chabriat; P Mouton; S Alamowitch; V Domenga; M Cécillion; E Marechal; J Maciazek; C Vayssiere; C Cruaud; E A Cabanis; M M Ruchoux; J Weissenbach; J F Bach; M G Bousser; E Tournier-Lasserve Journal: Nature Date: 1996-10-24 Impact factor: 49.962
Authors: J S Collins; R T Perry; B Watson; L E Harrell; R T Acton; D Blacker; M S Albert; R E Tanzi; S S Bassett; M G McInnis; R D Campbell; R C Go Journal: Am J Med Genet Date: 2000-12-04
Authors: L A Farrer; L A Cupples; J L Haines; B Hyman; W A Kukull; R Mayeux; R H Myers; M A Pericak-Vance; N Risch; C M van Duijn Journal: JAMA Date: 1997 Oct 22-29 Impact factor: 56.272
Authors: Richard Sherva; Clinton T Baldwin; Rivka Inzelberg; Badri Vardarajan; L Adrienne Cupples; Kathryn Lunetta; Abdalla Bowirrat; Adam Naj; Margaret Pericak-Vance; Robert P Friedland; Lindsay A Farrer Journal: J Alzheimers Dis Date: 2011 Impact factor: 4.472