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Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Ding, Y and Larson, G and Rivas, G and Lundberg, C and Geller, L and Ouyang, C and Weitzel, J and Archambeau, J and Slater, J and Daly, MB and Benson, AB and Kirkwood, JM and O'Dwyer, PJ and Sutphen, R and Stewart, JA and Johnson, D and Nordborg, M and Krontiris, TG (2008) Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk. PLoS ONE, 3 (10).

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Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Ding, Y
Larson, G
Rivas, G
Lundberg, C
Geller, L
Ouyang, C
Weitzel, J
Archambeau, J
Slater, J
Daly, MB
Benson, AB
Kirkwood, JMkirkwood@pitt.eduKIRKWOOD
O'Dwyer, PJ
Sutphen, R
Stewart, JA
Johnson, D
Nordborg, M
Krontiris, TG
ContributionContributors NameEmailPitt UsernameORCID
Date: 27 October 2008
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 3
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0003533
Refereed: Yes
PubMed Central ID: PMC2568805
PubMed ID: 18953408
Date Deposited: 24 Jul 2012 18:49
Last Modified: 22 Jun 2021 14:55


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