A comprehensive haplotype analysis of IGF-1 and breast cancer risk: the multiethnic cohort

Proc Amer Assoc Cancer Res, Volume 46, 2005 2555 A number of experimental and epidemiologic studies support the role of Insulin-Like Growth Factor-1 (IGF-1) in the etiology of breast cancer. We employed a haplotype-based association approach to examine the contribution of common genetic variation at the IGF-1 locus to breast cancer risk among African-American, Hawaiian, Japanese, Latina and White women in the Multiethnic Cohort Study (MEC). We characterized linkage disequilibrium and haplotype patterns at the IGF -1 locus by genotyping 64 densely spaced single-nucleotide polymorphisms (SNPs) (1 SNP per 2.4 kb) spanning 156 kb in a multiethnic panel (N=69-70 for each ethnic group) (Cheng et al ). Four distinct haplotype blocks, ranging from 11 to 60 kb, were identified and within each block, six to ten common haplotypes (i.e. frequency ≥ 5%) were observed. Twenty-nine haplotype-tagging SNPs (htSNPs) were selected to predict the common haplotypes with high probability (average Rh2=0.86) and genotyped in a large breast cancer case-control study of 1,716 cases and 2,505 controls. The frequency of the common haplotypes predicted by the htSNPs in the multiethnic panel were similar to those observed in the larger sample of cases and controls. Odds Ratios (OR) and 95% confidence intervals for each haplotype were estimated using all other haplotypes as the reference group. All analyses were adjusted for age and also for ethnicity in any analysis that combined all five ethnic groups. Global likelihood ratio tests of common haplotype effects in each block were not significant ( P > 0.4). Assessment of individual haplotype effect within each block and single SNP analysis also yielded no significant association with breast cancer risk. Analysis of cases with advanced disease only (N=447) did not alter the results. Our findings suggest that common genetic variation in IGF-1 is not a major contributor to breast cancer susceptibility in this multiethnic cohort. We are currently examining the relationship between IGF-1 haplotypes and circulating IGF-1 levels and also between two genes that produce IGF binding proteins, IGFBP-1 and IGFBP-3 , with breast cancer risk.