Analysis of HLA and Receptor Gene Polymorphisms in Multiple Myeloma

Date

2024-11-6

Author

Akin, Hasan Yalim

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Multiple myeloma (MM) is a treatable but rarely curable neoplastic plasma-cell disorder, primarily effecting elderly with a male predilection with a higher incidence rate in African ancestry. Natural killer (NK) cells are regulators of immune response against infections and cancer. Tumor cells are recognized through their human leukocyte antigen (HLA) ligands by killer cell immunoglobulin-like (KIR) receptors on NK cells. Due to their highly polymorphic structure, numerous combinations of KIR-HLA pairs result in underpowered statistical significance in KIR/HLA association studies. A few studies reported conflicting associations between KIR/HLA ligands and MM, due to the limited number of participants. In this study, an alternative approach was conducted to increase the sample size by using large existing data from various studies aiming to investigate the effect of KIR and HLA ligands on MM in different populations. Along with the local patients, KIR and HLA genes were imputed from the whole exome sequencing data belong to one of the largest MM datasets. The preliminary findings on a local cohort have revealed the protective role of activating KIR as well as an association between KIR/HLA ligands and age of MM onset. Remarkably, increasing the sample size uncovered the predisposing effect of Bw4 ligand (one of the public epitopes of HLA-B molecules), and a bidirectional interaction between KIR genes 3DL1, 3DS1 and their cognate ligand Bw4, that had not been reported in prior studies. Moreover, low frequencies of the protective genotypes and high frequencies of the predisposing genotypes among African Americans suggests a relationship between KIR/HLA ligands and ethnic disparities in MM. Finally, this study provides a reference model for the association between KIR/ligand genotypes and MM. It also presents a validated methodology for the global integration of large genomic datasets, enabling accurate evaluation of KIR and HLA allotypes across various disease courses.

Subject Keywords

Multiple Myeloma, Innate Immunity, Human Leukocyte Antigen, Killer Cell Immunoglobulin-Like Receptors, Imputation

URI

https://hdl.handle.net/11511/112653

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Graduate School of Natural and Applied Sciences, Thesis