An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease

Arch Neurol. 2010 May;67(5):536-41. doi: 10.1001/archneurol.2010.88.

Abstract

I coauthored a recently published research article describing a variable length, poly-T polymorphism in the TOMM40 gene, adjacent to apolipoprotein E (APOE) on chromosome 19, that accounts for the age at onset distribution for a complex disease, late-onset Alzheimer disease. These new data explain the mean age at disease onset for patients with the APOE4/4 genotype and differentiate 2 forms of TOMM40 poly-T polymorphisms linked to APOE, with each form associated with a different age at disease onset distribution. When linked to APOE3 (encoding the epsilon3 isoform of APOE), the longer TOMM40 poly-T repeats (19-39 nucleotides) at the rs10524523 (hereafter, 523) locus are associated with earlier age at onset and the shorter TOMM40 523 alleles (11-16 nucleotides) are associated with later age at onset. The data suggest that the poly-T alleles are codominant, with the age at onset phenotype determined by the 2 inherited 523 alleles, but with variable expressivity. Additional data will further refine the relationship between the length of the poly-T alleles and age at disease onset and determine if the relationship is linear.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Age of Onset
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Apolipoproteins E / genetics
  • Chromosomes, Human, Pair 19 / genetics
  • DNA Repeat Expansion / genetics*
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Membrane Transport Proteins / genetics*
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Polymorphism, Genetic / genetics*

Substances

  • Apolipoproteins E
  • Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • TOMM40 protein, human