Haplotypic variation in MRE11, RAD50 and NBS1 and risk of non-Hodgkin's lymphoma.

The MRE11-RAD50-NBS1 tri-complex is involved in the cellular response to DNA double strand breaks, detecting DNA damage, activating cell cycle checkpoints and apoptosis. Defects in members of the tri-complex are linked to increased chromosomal instability and in lymphoma predisposition. Using genotyping data from six intronic or gene flanking variants in MRE11, five in NBS1 and six in RAD50 in 461 non-Hodgkin's lymphoma cases and 461 age, sex matched controls, Phase 2.1 was used to impute haplotypes for each of these genes. It was observed that the average variant density (12 kb) was dense enough to capture the majority of genetic variation for each locus examined, encoded by four or five common haplotypes. There were no significant differences in allele or genotype frequency, global haplotype distribution between the cases and control, nor effect for individual haplotypes when analysed by unconditional logistic regression for either RAD50 or NBS1. A protective effect against follicular lymphoma was seen for the MRE11 rs601341 variant, the homozygous T allele being associated with an odds ratio (OR) of 0.50, 95% confidence interval (95% CI) 0.26 - 0.97, while a protective effect was seen for the MRE11 haplotype GCTCA (OR 0.72, 95% CI 0.53 - 0.97) for diffuse large B-cell lymphoma. While reproduction of this data in other datasets is indicated, the results are indicative for a role for MRE11 in non-Hodgkin's lymphoma.