Genetic variation and circulating levels of IGF-I and IGFBP-3 in relation to risk of proliferative benign breast disease.
Insulin-like growth factor-I (IGF-I) and its major binding protein IGFBP-3 have been implicated in breast carcinogenesis. We examined the associations between genetic variants and circulating levels of IGF-I and IGFBP-3 with proliferative benign breast disease (BBD), a marker of increased breast cancer risk, in the Nurses' Health Study II (NHSII). Participants were 359 pathology-confirmed proliferative BBD cases and 359 matched controls. Circulating IGF-I and IGFBP-3 levels were measured in blood samples collected between 1996 and 1999. Thirty single nucleotide polymorphisms (SNPs) in IGF-I, IGFBP-1, and IGFBP-3 genes were selected using a haplotype tagging approach and genotyped in cases and controls. Circulating IGF-I levels were not associated with proliferative BBD risk. Higher circulating IGFBP-3 levels were significantly associated with increased risk of proliferative BBD (highest vs. lowest quartile odds ratio (OR) [95% confidence interval (CI)], 1.70 (1.06-2.72); p-trend = 0.03). The minor alleles of 2 IGFBP-3 SNPs were associated with lower proliferative BBD risk (homozygous variant vs. homozygous wild-type OR (95% CI): rs3110697: 0.6 (0.4-0.9), p-trend = 0.02; rs2132570: 0.2 (0.1-0.6), p-trend = 0.02). Three other IGFBP-3 SNPs (rs2854744, rs2960436 and rs2854746) were significantly associated with circulating IGFBP-3 levels (p < 0.01). Although these SNPs were not significantly associated with proliferative BBD risk, there was suggestive evidence that the alleles associated with higher circulating IGFBP-3 levels were also associated with higher risk of proliferative BBD. These results suggest that genetic variants and circulating levels of IGFBP-3 may play a role in the early stage of breast carcinogenesis.
Su
Xuefen
X
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Colditz
Graham A
GA
Willett
Walter C
WC
Collins
Laura C
LC
Schnitt
Stuart J
SJ
Connolly
James L
JL
Pollak
Michael N
MN
Rosner
Bernard
B
Tamimi
Rulla M
RM
D000328:Adult; D001941:Breast Diseases / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood* / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I