Association Between Total Number of Deaths, Diabetes Mellitus, Incident Cancers, and Haplotypes in Chromosomal Region 8q24 in a Prospective Study

The 8q24 region is a gene desert but chromosomal aberrations and somatic amplification involving this region have been frequently reported in cancer, including translocations involving the proto-oncogene c-MYC. To investigate the role of variants in the 8q24 region, we have analysed a prospective study (N=10372) followed for 10 years, in which a large number of health events (N>1,500) occurred. We genotyped all subjects for 5 candidate SNPs (rs672888, rs1447295, rs9642880, rs16901979, rs6983267) identified in previous genome-wide scans. . While significant associations with single SNPs had smaller effects, we observed higher increases in risk for specific haplotypes and cancer types, in particular when subjects were homozygous for the haplotype: breast, haplotype 5/5 (CAGCT), HR=3.40 (1.24-9.21); prostate, grouped rare haplotypes, HR= 7.43 (3.00-18.37); brain, haplotype 7/7 (CGGCT), HR=13.48 (3.00-59.53). Significant associations were also observed between haplotypes and deaths from cardiovascular diseases and cerebrovascular diseases andthe most stable association was between haplotypes 4/4 and 5/5 and total deaths in men (217 observations; HR=3.5, 95% CI 1.8- 6.9; and 2.8, 1.3-6.4 respectively). In conclusion, we have observed a strong pleiotropic effect of the region in a large prospective study. This observation can shed light on the underlying mechanisms that link 8q24 variants with disparate diseases.