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A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease.

Publication ,  Journal Article
Roses, AD; Lutz, MW; Amrine-Madsen, H; Saunders, AM; Crenshaw, DG; Sundseth, SS; Huentelman, MJ; Welsh-Bohmer, KA; Reiman, EM
Published in: Pharmacogenomics J
October 2010

The ɛ4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE ɛ3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE ɛ3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE ɛ3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ɛ3 (70.5 ± 1.2 years versus 77.6 ± 2.1 years, P=0.02, n=34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases.

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Published In

Pharmacogenomics J

DOI

EISSN

1473-1150

Publication Date

October 2010

Volume

10

Issue

5

Start / End Page

375 / 384

Location

United States

Related Subject Headings

  • Risk
  • Predictive Value of Tests
  • Polymorphism, Single Nucleotide
  • Phylogeny
  • Pharmacology & Pharmacy
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Membrane Transport Proteins
  • Male
  • Linkage Disequilibrium
  • Humans
 

Citation

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Roses, A. D., Lutz, M. W., Amrine-Madsen, H., Saunders, A. M., Crenshaw, D. G., Sundseth, S. S., … Reiman, E. M. (2010). A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J, 10(5), 375–384. https://doi.org/10.1038/tpj.2009.69
Roses, A. D., M. W. Lutz, H. Amrine-Madsen, A. M. Saunders, D. G. Crenshaw, S. S. Sundseth, M. J. Huentelman, K. A. Welsh-Bohmer, and E. M. Reiman. “A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease.Pharmacogenomics J 10, no. 5 (October 2010): 375–84. https://doi.org/10.1038/tpj.2009.69.
Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG, Sundseth SS, et al. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. 2010 Oct;10(5):375–84.
Roses, A. D., et al. “A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease.Pharmacogenomics J, vol. 10, no. 5, Oct. 2010, pp. 375–84. Pubmed, doi:10.1038/tpj.2009.69.
Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG, Sundseth SS, Huentelman MJ, Welsh-Bohmer KA, Reiman EM. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. 2010 Oct;10(5):375–384.

Published In

Pharmacogenomics J

DOI

EISSN

1473-1150

Publication Date

October 2010

Volume

10

Issue

5

Start / End Page

375 / 384

Location

United States

Related Subject Headings

  • Risk
  • Predictive Value of Tests
  • Polymorphism, Single Nucleotide
  • Phylogeny
  • Pharmacology & Pharmacy
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Membrane Transport Proteins
  • Male
  • Linkage Disequilibrium
  • Humans