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Because of the high heritability of breast density, and the role of the insulin-like growth factor (IGF) pathway in cellular proliferation and breast development, we examined the association between common genetic variation in this pathway and mammographic density.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>We conducted a cross-sectional analysis among controls (<jats:italic>n<\/jats:italic> = 1,121) who were between the ages of 42 and 78 years at mammography, from a breast cancer case-control study nested within the Nurses' Health Study cohort. At the time of mammography, 204 women were premenopausal and 917 were postmenopausal. We genotyped 29 haplotype-tagging SNPs demonstrated to capture common genetic variation in IGF1, IGF binding protein (IGFBP)-1, and IGFBP-3.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>Common haplotype patterns in three of the four haplotype blocks spanning the gene encoding IGF1 were associated with mammographic density. Haplotype patterns in block 1 (<jats:italic>p<\/jats:italic> = 0.03), block 3 (<jats:italic>p<\/jats:italic> = 0.009), and block 4 (<jats:italic>p<\/jats:italic> = 0.007) were associated with mammographic density, whereas those in block 2 were not. None of the common haplotypes in the three haplotype blocks spanning the genes encoding IGFBP-1\/IGFBP-3 were significantly associated with mammographic density. Two haplotype-tagging SNPs in IGF1, rs1520220 and rs2946834, showed a strong association with mammographic density. Those with the homozygous variant genotype for rs1520220 had a mean percentage mammographic density of 19.6% compared with those with the homozygous wild-type genotype, who had a mean percentage mammographic density of 27.9% (<jats:italic>p<\/jats:italic> for trend &lt; 0.0001). Those that were homozygous variant for rs2946834 had a mean percentage mammographic density of 23.2% compared with those who were homozygous wild-type with a mean percentage mammographic density of 28.2% (<jats:italic>p<\/jats:italic> for trend = 0.0004). Permutation testing demonstrated that results as strong as these are unlikely to occur by chance (<jats:italic>p<\/jats:italic> = 0.0005).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusion<\/jats:title>\n                        <jats:p>Common genetic variation in IGF1 is strongly associated with percentage mammographic density.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/bcr1655","type":"journal-article","created":{"date-parts":[[2007,2,14]],"date-time":"2007-02-14T19:10:22Z","timestamp":1171480222000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Common genetic variation in IGF1, IGFBP-1, and IGFBP-3 in relation to mammographic density: a cross-sectional study"],"prefix":"10.1186","volume":"9","author":[{"given":"Rulla M","family":"Tamimi","sequence":"first","affiliation":[]},{"given":"David G","family":"Cox","sequence":"additional","affiliation":[]},{"given":"Peter","family":"Kraft","sequence":"additional","affiliation":[]},{"given":"Michael N","family":"Pollak","sequence":"additional","affiliation":[]},{"given":"Christopher A","family":"Haiman","sequence":"additional","affiliation":[]},{"given":"Iona","family":"Cheng","sequence":"additional","affiliation":[]},{"given":"Matthew L","family":"Freedman","sequence":"additional","affiliation":[]},{"given":"Susan E","family":"Hankinson","sequence":"additional","affiliation":[]},{"given":"David J","family":"Hunter","sequence":"additional","affiliation":[]},{"given":"Graham A","family":"Colditz","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2007,2,14]]},"reference":[{"key":"1620_CR1","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1093\/jnci\/87.21.1622","volume":"87","author":"C Byrne","year":"1995","unstructured":"Byrne C, Schairer C, Wolfe J, Parekh N, Salane M, Brinton LA, Hoover R, Haile R: Mammographic features and breast cancer risk: effects with time, age, and menopause status. 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