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

Yan Ding, Garrett Larson, Guillermo Rivas, Cathryn Lundberg, Louis Geller, Ching Ouyang, Jeffrey Weitzel, John Archambeau, Jerry Slater, Mary B. Daly, Al B. Benson, John M. Kirkwood, Peter J. O'Dwyer, Rebecca Sutphen, James A. Stewart, David Johnson, Magnus Nordborg, Theodore G. Krontiris

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Abstract

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.

Original languageEnglish (US)
Article numbere3533
JournalPLoS One
Volume3
Issue number10
DOIs
StatePublished - Oct 27 2008

Fingerprint

Genetic Selection
prostatic neoplasms
histidine
Histidine
Introns
natural selection
Single Nucleotide Polymorphism
introns
Prostatic Neoplasms
Genes
haplotypes
genes
Haplotypes
tumor suppressor genes
conserved sequences
Pan troglodytes
human population
genotyping
linkage (genetics)
Tumors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Ding, Y., Larson, G., Rivas, G., Lundberg, C., Geller, L., Ouyang, C., ... Krontiris, T. G. (2008). Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk. PLoS One, 3(10), [e3533]. https://doi.org/10.1371/journal.pone.0003533

Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk. / Ding, Yan; Larson, Garrett; Rivas, Guillermo; Lundberg, Cathryn; Geller, Louis; Ouyang, Ching; Weitzel, Jeffrey; Archambeau, John; Slater, Jerry; Daly, Mary B.; Benson, Al B.; Kirkwood, John M.; O'Dwyer, Peter J.; Sutphen, Rebecca; Stewart, James A.; Johnson, David; Nordborg, Magnus; Krontiris, Theodore G.

In: PLoS One, Vol. 3, No. 10, e3533, 27.10.2008.

Research output: Contribution to journalArticle

Ding, Y, Larson, G, Rivas, G, Lundberg, C, Geller, L, Ouyang, C, Weitzel, J, Archambeau, J, Slater, J, Daly, MB, Benson, AB, Kirkwood, JM, O'Dwyer, PJ, Sutphen, R, Stewart, JA, Johnson, D, Nordborg, M & Krontiris, TG 2008, 'Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk', PLoS One, vol. 3, no. 10, e3533. https://doi.org/10.1371/journal.pone.0003533
Ding, Yan ; Larson, Garrett ; Rivas, Guillermo ; Lundberg, Cathryn ; Geller, Louis ; Ouyang, Ching ; Weitzel, Jeffrey ; Archambeau, John ; Slater, Jerry ; Daly, Mary B. ; Benson, Al B. ; Kirkwood, John M. ; O'Dwyer, Peter J. ; Sutphen, Rebecca ; Stewart, James A. ; Johnson, David ; Nordborg, Magnus ; Krontiris, Theodore G. / Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk. In: PLoS One. 2008 ; Vol. 3, No. 10.
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abstract = "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.",
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AU - Ouyang, Ching

AU - Weitzel, Jeffrey

AU - Archambeau, John

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AU - Daly, Mary B.

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AU - Kirkwood, John M.

AU - O'Dwyer, Peter J.

AU - Sutphen, Rebecca

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