apolipoprotein-E dependent role for the FAS receptor in early onset Alzheimer's disease: finding of a positive association for a polymorphism in the TNFRSF6 gene.
The TNFRSF6 gene encodes FAS, a cell-surface receptor involved in apoptosis initiation. Elevated levels of FAS have been reported in the brains of Alzheimer's disease (AD) patients. We have tested a G/A polymorphism at position -670 in the TNFRSF6 gene for association with non-familial, early onset Alzheimer's disease (EOAD) by using dynamic allele-specific hybridization. In an initial set of Scottish EOAD cases (n=78) and controls (n=152), we found that, for individuals carrying one or two APOE4 alleles, the homozygous GG-genotype was enriched in the patients (26.7% versus 10.9% in controls). A second study was conducted on an independent set of Scottish individuals (87 EOAD, 358 controls). In this material, the TNFRSF6 GG-genotype frequency was elevated in patients regardless of APOE4 status (28.7% versus 15.1%) and was even more enriched in APOE4 carriers (35.9% versus 15.3%). A combination of the two sample sets (165 cases, 510 controls) gave a significant disease association for the TNFRSF6 GG-genotype that was irrespective of APOE4 (P=0.0020) and that was almost completely attributable to the enrichment present within the set of APOE4 carriers (P=0.0016). This represents an odds ratio of 8.71 for GG-homozygotes carrying at least one APOE4 allele compared with other TNFRSF6 genotypes in APOE4 non-carriers. The TNFRSF6 variation was further explored in Scottish late-onset Alzheimer's disease (n=159) but no associations were found. These results imply that TNFRSF6, in interaction with APOE4, is a genetic risk factor for sporadic EOAD. Hence, the AD risk contributed by APOE4 could be mechanistically related to a pathway in common with FAS-mediated apoptosis.
Feuk
L
L
Center for Genomics Research, Karolinska Institute, Stockholm, Sweden.
Prince
J A
JA
Breen
G
G
Emahazion
T
T
Carothers
A
A
St Clair
D
D
Brookes
A J
AJ
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism*; D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D011110:Polymorphism, Genetic; D012307:Risk Factors; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism*
D001057:Apolipoproteins E; D017931:DNA Primers; D019014:fas Receptor