IL-10-592 Polymorphism Predicts the Clinical Outcome of Japanese Patients with Multiple Myeloma and MGUS.

Introduction: Interleukin 10 (IL-10) has been reported as an anti-inflammatory cytokine and B-cell proliferation factor, and has been implicated in autoimmunity, tunorigenesis and stem cell transplantation tolerance. IL-10 is also reported to be involved in multiple myeloma (MM) cell proliferation and survival. The polymorphism of position-592, -819, and -1082 in the promoter of IL-10 gene is a strong determinant of IL-10 expression. However, it is unclear whether IL-10 polymorphisms alter the incidence and clinical outcome of MM. We examined the single nucleotide polymorphism (SNPs) located within the promoter region of IL-10 genes in patients with MM, monoclonal gammopathy of undetermined significance (MGUS) and healthy controls in Japan.

Methods: Seventy nine patients with MM [age range, 40–83 years; stage I (n=9), stage II (n=20), stage III (n=50); IgG(n=47), IgA(n=12), IgD(n=1), non-secretory (n=3), Bence Jones(n=16)], 46 patients with MGUS (age range, 44–86 years), and 200 healthy controls were included. Fifteen patients with transformation of MGUS to MM were included in MM group. Genotyping in IL-10 -1082G/A, -819C/T, -592A/C was determined by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. Genotype and allele frequencies were compared between the study groups using χ²-test. The characteristics and laboratory features of MM patients with each IL-10 promoter polymorphism were compared using χ²-tests and student t-tests. Probability values <0.05 were considered statistically significant. The Kaplan-Meier method was used in the calculation of overall survival. Overall survival curves were compared with the log-rank test.

Results: IL-10-592 A/A, A/C and C/C genotype frequencies were not significantly different between MM patients (51%, 34%, and 15%) and controls (42%, 43%, and 15%). Higher frequency of −592A/A genotype was seen in our Asian control compared with Caucasian. The frequency of IL-10 -1082 and -819 were also not significantly different between MM patients and healthy controls. The IL-10-592A/C genotype was detected in 10 of 16 patients (63%) with transformation of MGUS to MM and 20 of 46 patients (43%) with MGUS who did not progress to MM (odds ratio [OR], 2.2; 95% confidence interval [95% CI], 0.7–7.0; p=0.15). In MM patients who received autologous stem cell transplantation (ASCT), the overall survival was similar among 3 genotype groups. However, in patients who did not received ASCT, patients with IL-10-592A/C and C/C genotype had shorter overall survival compared with patients with IL-10-592A/A genotype (median survival, 32 months vs. not reached).

Conclusion: It is reported that IL-10-592 A/C and C/C genotype are high producer of IL-10. Our results suggested that the IL-10-592 A/C and C/C genotype was not associated with the susceptibility to MM, however associated with poor prognosis in MM patients who did not receive ASCT. In addition, IL-10-592 A/C and C/C genotype may contribute to transformation of MGUS to MM. According these data, IL-10 may be implicated in the progression of MM and MGUS, and SNPs of IL-10 is one of prognostic factors in patients with MGUS and MM.