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David C Johnson, Christine Ramos, Alex J. Szubert, Walter M Gregory, J. Anthony Child, Faith E Davies, MD, Brian GM Durie, MD, Brian G. Van Ness, PhD and Gareth J Morgan, MD, PhD
ABSTRACT: Peripheral neuropathy is a major adverse effect seen in multiple myeloma (MM) patients treated with thalidomide, with rates varying between trials from 15% to 70%. Peripheral neuropathy can often lead to ongoing impairment of quality of life and can lead to discontinuation of treatment. Identifying patients at risk of neuropathy and understanding its pathogenesis would be a significant step forward in the management of thalidomide based therapy. Proposed mechanisms have included: Anti-angiogeneic properties of thalidomide leading to a reduction in nerve blood supply; direct toxic effects of thalidomide on neurons of the posterior root ganglia and dysregulation of neurotrophin activity through effects of thalidomide on NFkB. Genetic variation in genes important in the mechanism of thalidomide neurotoxicity are likely to impact on whether an individual patient develops this adverse effect. Taking a nested case control approach we used peripheral blood DNA from 388 Caucasian MM patients all who had received induction thalidomide (200mg) as part of the Myeloma IX trial. Samples from 80 patients that developed sensory-motor peripheral neuropathy in response to thalidomide therapy were available for this analysis, these were age and sex matched with a ratio of one case to 4 controls. We assayed 3403 SNPs in coding and predicted regulatory regions selected in 1266 genes previously shown to be involved in the pathogenesis, treatment response and side effects associated with myeloma and its therapy. SNPs were present on a custom-built Affymetrix® targeted genotyping chip (designed by “Bank on a Cure” (BOAC)), which utilizes molecular inversion probe technologies. We carried out a univariate analysis by Fischer exact tests. Due to the large number of SNPs and relatively small number of samples, we chose to correct for multiple testing using label swapping permutation using the program PLINK. The most significant SNPs associated with thalidomide related peripheral neuropathy are listed with p=permutated empirical p-value and OR=Odds Ratio: ABCC2-Ile1324Ile (p<9.71x10-5;OR=1.972,1.39-2.8); DGKH-Ala1201Val (p<1.05x10-3;OR =4.267,1.85-9.87); EXO1-Arg354His (p<1.4x10-3;OR=1.79,1.25-2.55) and NPC2-3’UTR (p<1.6x10-3,OR=0.42,0.24-0.75). DGKH, EXO and NPC2 are genes previously reported to play a role in peripheral neurotoxicity. The ABCC2- Ile1324Ile SNP forms part of previously reported functional haplotype. Significant associations were also seen in a number of other ADME genes (drug absorption, distribution, metabolism, and excretion): ABCB1, ABCB11, ABCC1, CYP1A1, CYP20A1, CYP20A1, CYP2C9, CYP3A7, CYP4F2, FMO2, FMO3, FMO6, SLC12A6, SLC22A3 and SLC7A7. Significant associations were also seen in genes important in neurological system processes and central nervous system development: ERBB2, NQO1, MY03A, PPARD, DBH, NGFR, GSTP1, TCF8 and ICF1R. Our results indicate the importance of thalidomide dose and cumulative exposure, and highlight the metabolism of thalidomide as playing a pivotal role in dictating neuropathy events and open the way for predictive testing and dose adjustment. The results also implicate a direct toxicity mechanism for thalidomide related peripheral neuropathy, as we see a number of associations with SNPs in genes with known importance in peripheral neuron function.