The Impact of the NOD2/CARD15 Variant (3020insC) and PSMA6 Polymorphism (-8C>G) on the Development and Outcome of Multiple Myeloma

Introduction. Multiple myeloma (MM) is a hematological malignancy characterized by genetic variety. The 3020insC variant of theNOD2/CARD15gene results in the upregulation of proinflammatory cytokines. Chronic inflammation and abnormal function of the proteasome system may lead to MM development. The polymorphism (-8C>G) in thePSMA6gene affects proteasome activity. The aim of our study was to analyze the possible relationship ofNOD/CARD15andPSMA6genes with the risk of development and outcome of MM, as well as the sensitivity to bortezomib (proteasome inhibitor) in cell cultures derived from MM patients.Objects and Methods. Genomic DNA from 100 newly diagnosed MM patients and 100 healthy blood donors was analyzed by methods such as PCR-RFLP (forPSMA6genotyping) and automated DNA sequencing (forNOD2/CARD15genotyping). In a subgroup of 50 MM patients, nucleated bone marrow cells were treated with bortezomibin vitro.Results. Patients withPSMA6CG+GG genotypes had higher chances for progressive disease (OR=5.0, 95% CI 1.07-23.16,p=0.05), shorter overall survival taking into account the type of treatment (p=0.039), and increased risk of death due to MM at the level of tendency (OR=4.74, 95% CI 1.02-21.97,p=0.06). The presence ofNOD2/CARD153020insC decreased the risk of renal dysfunction in MM (OR=0.23, 95% CI 0.07-0.74,p=0.009). The analyzed changes inNOD2/CARD15andPSMA6genes did not impact the MM risk. In anin vitrostudy, bortezomib increased the number of apoptotic cells at 8 nM and 12 nM between wild-type and 3030insC variants ofNOD2/CARD15(p=0.018andp=0.03, respectively).Conclusion. The presented results suggest a possible impact ofPSMA6CG+GG genotypes on the MM outcome and the association of theNOD2/CARD15variant with bortezomibin vitrosensitivity.