4505

Insulin-like growth factor I is a key gene in regulating cell proliferation and inhibiting apoptosis, and is believed to play an important role in cancer development. Several prospective studies have demonstrated that men in the highest quartile of circulating IGF-I have an approximately 3-fold increase risk of prostate cancer compared to men in the lowest quartile. It is hypothesized that higher circulating levels of IGF-I may relate to elevated tissue bioactivity leading to an increase in epithelial turnover and thus more opportunities for genetic alterations resulting eventually in transformation. To investigate IGF-I as a candidate gene in prostate cancer pathogenesis, we utilized a haplotype-based approach to identify common disease-associated variants among African-American, Hawaiian, Japanese-American, Latino, and White men in the Multiethnic Cohort (MEC). The IGF-I gene is located on chromosome 12 and is comprised of four exons with numerous regions of conserved mouse homology. 102 SNPs were genotyped to densely survey the genetic variation across 114.2 kb of the IGF-I locus. Of the 102 SNPs genotyped, 47 SNPs were polymorphic, 38 SNPs were monomorphic (displaying only a single allele), and 17 SNPs did not meet genotyping standards. Using 47 polymorphic SNPs (1 every ∼ 2.4 kb), we characterized the linkage disequilibrium and haplotype patterns of IGF-I among 70 individuals from each ethnic group. Three regions of strong linkage disequilibrium (blocks 1-3) were identified. Within each block, common haplotypes (>5%) account for more than 80% of the diversity across the locus. We employed a correlation-based approach to capture the haplotype diversity within each block using a reduced set of haplotype-tagging SNPs (htSNPs). Sixteen htSNPs were selected that demonstrate a strong correlation with the haplotypes observed in the full dataset. Currently, we are genotyping these selected htSNPs in a prostate cancer case-control study in the MEC (cases, n=2,188; controls, n=2,319). In addition, we have measured plasma levels of IGF-I in 500 control males (100 subjects from each ethnic group), which will provide the opportunity to examine the relationship between haplotypic variation and IGF-I levels.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]