PLoS ONE (Jan 2008)

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

DOI
https://doi.org/10.1371/journal.pone.0003533
Journal volume & issue
Vol. 3, no. 10
p. e3533

Abstract

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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, re-sequencing 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 chi(2) = 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 chi(2) = 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 (pi = 0.0072, Tajima's D = 3.31, 14 SNPs) and the Japanese (pi = 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.