Abstract A7: Using haplotype analysis to find significant associations between genes and Hodgkin's disease

Abstract

Abstract Background: With increasing amounts of genes available for study, more opportunities are available to discover key associations between genetic factors and disease. In a previous study on Hodgkin disease, we observed powerful positive associations between genes on chromosomes 3 and 19. In this study, we expanded the previous analyses to include 62 single nucleotide polymorphisms (SNPs) in DNA repair and inflammation pathway genes located throughout the genome and evaluated possible associations for Hodgkin disease by inferring haplotypes at the individual gene level. Methods: Genetic and epidemiological data were obtained from a case-control study conducted at M.D. Anderson Cancer Center between 1987 and 1992 including 200 cases and 220 controls. Haplotypes were initially inferred with Haploview using linkage disequilibrium plots, and differences in haplotypes between cases and controls were determined with PHASE. Linear modeling with haplotypes, through both joint and separate effects haplotype modeling, with sex, race, smoking status, and age as confounders, were conducted with Haplo.stats. A joint-effects linear model allows each haplotype to be compared to the most frequent haplotype. A separate-effects linear model compares a haplotype to all of the other haplotypes possible for study. Results: With the joint effects haplotype model, some significant haplotype associations with Hodgkin disease were observed with DNA repair gene XPC on chromosome 3 and inflammation pathway gene ILR4 on Chromosome 16. For DNA repair gene XPC, susceptible associations with Hodgkin disease were discovered with the use of an additive genetic model with haplotype CT from SNPs rs2228001 (XPC 499 A>C) and rs2228000 (XPC 939 C>T) (OR = 1.49, 95% CI = 1.03–2.16) and a dominant genetic model with the same haplotype (OR = 1.75, 95% CI = 1.15–2.13). For inflammation pathway gene ILR4, protective associations with Hodgkin disease were discovered with the use of an additive genetic model with haplotype TC from SNPs rs1805012 (XPC 499 T>C) and rs1805015 (XPC 939 T>C) (OR = 0.63, 95% CI = 0.33–0.99) and a dominant genetic model with the same haplotype (OR = 0.48, 95% CI = 0.26–0.88). The separate effects haplotype model also highlighted associations between haplotypes and Hodgkin disease on these same genes. Other significant associations between haplotypes and Hodgkin disease were observed on chromosomes 5 with inflammation pathway gene IL4 and chromosome 19 with DNA repair gene. Conclusions: The basis for haplotype analysis to analyze the effects of linked SNPs associated with Hodgkin disease has been demonstrated. Furthermore, the interactions between specific SNPs in both the inflammation and the DNA repair pathway have been shown to play an important role in possible Hodgkin disease development. By targeting specific aspects of the genome that show either an increase or decrease in Hodgkin risk, identification of high risk individuals could be achieved. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A7.