Belbin O, Dunn J L, Chappell S, Ritchie A E, Ling Y, Morgan L, Pritchard A, Warden D R, Lendon C L, Lehmann D J, Mann D M A, Smith A D, Kalsheker N, Morgan K
Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK.
Neurobiol Aging. 2008 Aug;29(8):1167-76. doi: 10.1016/j.neurobiolaging.2007.02.021. Epub 2007 Mar 26.
There is biochemical and animal model evidence supporting a pathological role of the ACT gene in AD. However, direct genetic evidence remains controversial and has been mostly limited to individual single nucleotide polymorphism (SNP) analysis. To resolve this apparent conflict we have used a high-density ACT SNP map, constructed haplotypes and explored correlations with phenotype. SNPs were identified by sequencing and used to construct haplotypes in 668 AD patients and 419 controls and a case-control association study was performed. Five SNPs, comprising five common haplotypes, represented 93% of ACT gene variation. Although no single SNP or haplotype was associated with AD status, a SNP in intron 2 was associated with later onset and more rapid cognitive decline (P=0.04). This SNP was both individually associated with severe astrocytosis (P=0.004) in AD patients and when combined with the signal sequence SNP (P=0.002). This suggests that astrocytosis may have a protective function for a limited period in some patients. These SNP associations either support a direct role for the ACT gene, in AD pathology or alternatively reflect linkage with polymorphisms in other genes nearby.
