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

ABSTRACT 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.