Fine Mapping of <scp>MHC</scp> Region Identifies Novel Susceptibility Loci in Multiple Myeloma When Comparing With Its Precursor Monoclonal Gammopathy of Unknown Significance

Genome-wide association studies have linked major histocompatibility complex (MHC) region loci to immune-related diseases, but their role in multiple myeloma (MM) progression from monoclonal gammopathy of undetermined significance (MGUS) remains unclear. This case-control study included 238 individuals with MGUS (> 5 years follow-up without MM progression) and 618 MM patients from MCW Froedtert Hospital (2011-2020). Using multivariable logistic regression, Omnibus test and conditional haplotype tests, we identified HLA alleles and amino acid positions associated with MM risk compared to MGUS. The HLA-A*30:01 (OR_pooled = 7.90, 95% CI = 3.05-20.00, P_pooled = 2.04 × 10^-5), HLA-B*08:01 (OR_pooled = 0.40, 95% CI = 0.28-0.58, P_pooled = 1.16 × 10^-6) and HLA-DRB1*15:03 (OR_pooled = 0.26, 95% CI = 0.16-0.43, P_pooled 1.14 × 10^-7) were consistently identified to be associated with the risk of MM when compared with MGUS across the four imputed datasets. Additional associations were observed for HLA-A*30:02 (OR_pooled = 0.45, 95% CI = 0.28-0.72, P_pooled = 8.66 × 10^-4) and HLA-C*07:01 (OR_pooled = 0.62, 95% CI = 0.49-0.79, P_pooled = 6.49 × 10^-5) in two or three imputation datasets. Omnibus test identified three amino acid positions associated with MM risk: HLA-A position 152 (P_Omnibus = 0.005), HLA-B position 9 (P_omnibus = 0.034) and HLA-C position 66 (P_omnibus = 0.011). These findings suggest an important role of HLA class I and II molecules in the genetic susceptibility of MM compared with MGUS, suggesting alterations in peptide-binding capabilities may impair immune recognition of malignant cells. Further studies are needed to validate our findings and elucidate the biological mechanisms.