Faculty Collaboration Database

Fine Mapping of MHC Region Identifies Novel Susceptibility Loci in Multiple Myeloma When Comparing With Its Precursor Monoclonal Gammopathy of Unknown Significance. HLA 2026 Feb;107(2):e70589

Date

02/13/2026

Pubmed ID

41685425

Pubmed Central ID

PMC12902906

DOI

10.1111/tan.70589

Scopus ID

2-s2.0-105029925738 (requires institutional sign-in at Scopus site)

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.

Author List

Arsang-Jang S, Massat B, Pareek G, Han J, Thapa B, Patek V, Nader Z, Auer PL, Zimmerman MT, Urrutia R, Hari P, D'Souza A, Dhakal B, Janz S, Dong J

Authors

Paul L. Auer PhD Professor in the Data Science Institute department at Medical College of Wisconsin
Anita D'Souza MD Professor in the Medicine department at Medical College of Wisconsin
Binod Dhakal MD, MBBS Professor in the Medicine department at Medical College of Wisconsin
Jing Dong PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Parameswaran Hari MD Adjunct Professor in the Medicine department at Medical College of Wisconsin
Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Alleles
Case-Control Studies
Chromosome Mapping
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
HLA-A Antigens
HLA-B Antigens
HLA-DRB1 Chains
Haplotypes
Humans
Major Histocompatibility Complex
Male
Middle Aged
Monoclonal Gammopathy of Undetermined Significance
Multiple Myeloma