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Multiple myeloma (MM) is a hematological malignancy characterized by genetic variety. The 3020insC variant of the  NOD2/CARD15  gene 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 the  PSMA6  gene affects proteasome activity. The aim of our study was to analyze the possible relationship of  NOD/CARD15  and  PSMA6  genes 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 (for  PSMA6  genotyping) and automated DNA sequencing (for  NOD2/CARD15  genotyping). In a subgroup of 50 MM patients, nucleated bone marrow cells were treated with bortezomib  in vitro .Results   Patients with  PSMA6  CG+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 of  NOD2/CARD15  3020insC decreased the risk of renal dysfunction in MM (OR = 0.23, 95% CI 0.07-0.74,  p  = 0.009). The analyzed changes in  NOD2/CARD15  and  PSMA6  genes did not impact the MM risk. In an  in vitro  study, bortezomib increased the number of apoptotic cells at 8 nM and 12 nM between wild-type and 3030insC variants of  NOD2/CARD15  ( p  = 0.018 and  p  = 0.03, respectively).Conclusion   The presented results suggest a possible impact of  PSMA6  CG+GG genotypes on the MM outcome and the association of the  NOD2/CARD15  variant with bortezomib  in vitro  sensitivity.

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