NDLI: Genetic variation in α1-antichymotrypsin and its association with Alzheimer’s disease

Content Provider	Springer Nature Link
Author	Wang, Xiaoyan DeKosky, Steven T. Luedecking Zimmer, Erin Ganguli, Mary Kamboh, Ilyas M.
Copyright Year	2002
Abstract	Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by extracellular neuritic plaques and intracellular neurofibrillary tangles in brain parenchyma. Alpha-1-antichymotrypsin (ACT) is a component of plaque cores, can bind to Aβ, and has been proposed as a possible candidate gene for AD susceptibility. The genetic association between the ACT codon –17A allele of the signal peptide polymorphism and AD has been shown in some, but not in all studies. One hypothesis is that the ACT codon –17A allele is in linkage disequilibrium with unknown functional mutation(s) in the ACT gene. This study was undertaken to identify new mutation(s) in the ACT gene by PCR-SSCP-sequencing and, in conjunction with known mutations, to assess their role in affecting the risk of AD. A total of seven new point mutations were observed: 5′UTR(A→G), Asp128Asn(G→A), Ser250Ser(C→T), Leu301Pro(T→C), Thr324Thr(A→G), G→A in intron 4, and 3′UTR C→A. Of these, mutations at codon 250, codon 324, intron 4 and 3′UTR showed a frequency of 1% or more. Of the known mutations, Thr–17Ala(A→G), Lys76Lys(A→G) and Leu241Leu(G→A) occur at a polymorphic level. The ACT codon –17A allele was associated with increased risk of AD (OR for AA vs TT: 1.71; 95% CI: 1.16–2.53; P=0.007), especially in the presence of the APOE4 allele (OR for AA vs TT: 2.35; 95% CI: 1.13–4.85; P=0.02). The codon 241A allele and the codon 250T allele were associated with protective effects against AD (OR: 0.36; 95% CI: 0.13–0.86; P=0.02) (OR:0.39; 95% CI: 0.18–0.85; P=0.02). irrespective of the APOE4 status. The codon 324G allele was associated with a marginal protective effect (OR:0.57; 95% CI: 0.26–1.26; P=0.17). While the codon 241A allele was in linkage disequilibrium with the codon –17A allele, the codon 250T and codon 324G alleles were non-randomly associated with the codon –17T allele. In contrast, the codon 76G (OR:1.34; 95% CI: 0.92–1.95; P=0.13), codon 227G (OR:3.96; 95% CI: 0.83–18.8; P=0.08) and intron 4G (OR:1.47; 95% CI: 0.88–2.29; P=0.15) alleles were associated with a modest risk of AD, and all were in linkage disequilibrium with the codon –17A allele. EH-based haplotype analysis showed that certain haplotypes are associated with either higher or lower risk of AD. Our data indicate that the ACT gene harbors several potentially important variable sites, which are associated with either an increased or decreased risk of AD. The non-random combination of risk and protective alleles may explain, in part, why the association studies regarding the ACT codon –17A have been inconsistent, especially if the frequency of other ACT mutations varies between populations.
Starting Page	356
Ending Page	365
Page Count	10
File Format	PDF
ISSN	03406717
Journal	Human Genetics
Volume Number	110
Issue Number	4
e-ISSN	14321203
Language	English
Publisher	Springer-Verlag
Publisher Date	2002-03-19
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Human Genetics Molecular Medicine Gene Function Metabolic Diseases
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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