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Characterization of the poly-T variant in the TOMM40 gene in diverse populations.

Publication ,  Journal Article
Linnertz, C; Saunders, AM; Lutz, MW; Crenshaw, DM; Grossman, I; Burns, DK; Whitfield, KE; Hauser, MA; McCarthy, JJ; Ulmer, M; Allingham, R ...
Published in: PLoS One
2012

We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined for rs10524523, hereafter '523', based on the number of 'T'-residues: 'Short' (S, T≤19), 'Long' (L, 20≤T≤29) and 'Very Long' (VL, T≥30). Homopolymers, particularly long homopolymers like '523', are difficult to genotype because 'slippage' occurs during PCR-amplification. We initially genotyped this locus by PCR-amplification followed by Sanger-sequencing. However, we recognized the need to develop a higher-throughput genotyping method that is also accurate and reliable. Here we describe a new '523' genotyping assay that is simple and inexpensive to perform in a standard molecular genetics laboratory. The assay is based on the detection of differences in PCR-fragment length using capillary electrophoresis. We discuss technical problems, solutions, and the steps taken for validation. We employed the novel assay to investigate the '523' allele frequencies in different ethnicities. Whites and Hispanics have similar frequencies of S/L/VL alleles (0.45/0.11/0.44 and 0.43/0.09/0.48, respectively). In African-Americans, the frequency of the L-allele (0.10) is similar to Whites and Hispanics; however, the S-allele is more prevalent (0.65) and the VL-allele is concomitantly less frequent (0.25). The allele frequencies determined using the new methodology are compared to previous reports for Ghanaian, Japanese, Korean and Han Chinese cohorts. Finally, we studied the linkage pattern between TOMM40-'523' and APOE alleles. In Whites and Hispanics, consistent with previous reports, the L is primarily linked to ε4, while the majority of the VL and S are linked to ε3. Interestingly, in African-Americans, Ghanaians and Japanese, there is an increased frequency of the '523'S-APOEε4 haplotype. These data may be used as references for '523' allele and '523'-APOE haplotype frequencies in diverse populations for the design of research studies and clinical trials.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2012

Volume

7

Issue

2

Start / End Page

e30994

Location

United States

Related Subject Headings

  • Population Groups
  • Poly T
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Methods
  • Membrane Transport Proteins
  • Introns
  • Humans
  • Haplotypes
  • Genotype
  • General Science & Technology
 

Citation

APA
Chicago
ICMJE
MLA
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Linnertz, C., Saunders, A. M., Lutz, M. W., Crenshaw, D. M., Grossman, I., Burns, D. K., … Chiba-Falek, O. (2012). Characterization of the poly-T variant in the TOMM40 gene in diverse populations. PLoS One, 7(2), e30994. https://doi.org/10.1371/journal.pone.0030994
Linnertz, Colton, Ann M. Saunders, Michael W. Lutz, Donna M. Crenshaw, Iris Grossman, Daniel K. Burns, Keith E. Whitfield, et al. “Characterization of the poly-T variant in the TOMM40 gene in diverse populations.PLoS One 7, no. 2 (2012): e30994. https://doi.org/10.1371/journal.pone.0030994.
Linnertz C, Saunders AM, Lutz MW, Crenshaw DM, Grossman I, Burns DK, et al. Characterization of the poly-T variant in the TOMM40 gene in diverse populations. PLoS One. 2012;7(2):e30994.
Linnertz, Colton, et al. “Characterization of the poly-T variant in the TOMM40 gene in diverse populations.PLoS One, vol. 7, no. 2, 2012, p. e30994. Pubmed, doi:10.1371/journal.pone.0030994.
Linnertz C, Saunders AM, Lutz MW, Crenshaw DM, Grossman I, Burns DK, Whitfield KE, Hauser MA, McCarthy JJ, Ulmer M, Allingham R, Welsh-Bohmer KA, Roses AD, Chiba-Falek O. Characterization of the poly-T variant in the TOMM40 gene in diverse populations. PLoS One. 2012;7(2):e30994.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2012

Volume

7

Issue

2

Start / End Page

e30994

Location

United States

Related Subject Headings

  • Population Groups
  • Poly T
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Methods
  • Membrane Transport Proteins
  • Introns
  • Humans
  • Haplotypes
  • Genotype
  • General Science & Technology