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APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism.
Nat Genet. 1995 Aug; 10(4):486-8.NGen

Abstract

Genetic studies on Alzheimer's disease (AD), a devastating neurodegenerative disorder, have identified the apolipoprotein E (APOE) gene as a strong susceptibility marker for AD. The E*4 allele of APOE is a major risk factor for AD regardless of age of onset or family history. However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD emphasizes the involvement of other environmental or genetic elements that, either in conjunction with APOE*4 or alone, increase an individual's risk of developing AD. Among the candidate genes that may affect the risk of this multifactorial disease is the gene coding for alpha 1-antichymotrypsin (ACT). Like APOE protein, ACT binds to beta-amyloid peptide (A beta P) with high affinity in the filamentous deposits found in the AD brain and serves as a strong stimulatory factor in the polymerization of A beta P into amyloid filaments. In AD brains, ACT expression is enhanced, particularly in areas that develop amyloid plaques, suggesting that ACT may play an important role in the pathogenesis of AD. Here we show that a common polymorphism in the signal peptide of ACT confers a significant risk for AD. Furthermore, the APOE*4 gene dosage effect associated with AD risk is significantly modified by the ACT polymorphism. We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control. Our data show that ACT behaves as a modifier gene that alters the AD risk conventionally associated with the APOE*4 allele.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

7670501

Citation

Kamboh, M I., et al. "APOE*4-associated Alzheimer's Disease Risk Is Modified By Alpha 1-antichymotrypsin Polymorphism." Nature Genetics, vol. 10, no. 4, 1995, pp. 486-8.
Kamboh MI, Sanghera DK, Ferrell RE, et al. APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism. Nat Genet. 1995;10(4):486-8.
Kamboh, M. I., Sanghera, D. K., Ferrell, R. E., & DeKosky, S. T. (1995). APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism. Nature Genetics, 10(4), 486-8.
Kamboh MI, et al. APOE*4-associated Alzheimer's Disease Risk Is Modified By Alpha 1-antichymotrypsin Polymorphism. Nat Genet. 1995;10(4):486-8. PubMed PMID: 7670501.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism. AU - Kamboh,M I, AU - Sanghera,D K, AU - Ferrell,R E, AU - DeKosky,S T, PY - 1995/8/1/pubmed PY - 1995/8/1/medline PY - 1995/8/1/entrez SP - 486 EP - 8 JF - Nature genetics JO - Nat. Genet. VL - 10 IS - 4 N2 - Genetic studies on Alzheimer's disease (AD), a devastating neurodegenerative disorder, have identified the apolipoprotein E (APOE) gene as a strong susceptibility marker for AD. The E*4 allele of APOE is a major risk factor for AD regardless of age of onset or family history. However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD emphasizes the involvement of other environmental or genetic elements that, either in conjunction with APOE*4 or alone, increase an individual's risk of developing AD. Among the candidate genes that may affect the risk of this multifactorial disease is the gene coding for alpha 1-antichymotrypsin (ACT). Like APOE protein, ACT binds to beta-amyloid peptide (A beta P) with high affinity in the filamentous deposits found in the AD brain and serves as a strong stimulatory factor in the polymerization of A beta P into amyloid filaments. In AD brains, ACT expression is enhanced, particularly in areas that develop amyloid plaques, suggesting that ACT may play an important role in the pathogenesis of AD. Here we show that a common polymorphism in the signal peptide of ACT confers a significant risk for AD. Furthermore, the APOE*4 gene dosage effect associated with AD risk is significantly modified by the ACT polymorphism. We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control. Our data show that ACT behaves as a modifier gene that alters the AD risk conventionally associated with the APOE*4 allele. SN - 1061-4036 UR - https://www.unboundmedicine.com/medline/citation/7670501/APOE_4_associated_Alzheimer's_disease_risk_is_modified_by_alpha_1_antichymotrypsin_polymorphism_ L2 - http://dx.doi.org/10.1038/ng0895-486 DB - PRIME DP - Unbound Medicine ER -