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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
Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk
PLoS ONE. 2008 ;3(10) :e3533
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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.
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 AG15720/AG/NIA NIH HHS/United States HG-002790/HG/NHGRI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. United States PloS one PLoS ONE. 2008;3(10):e3533. Epub 2008 Oct 27.