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The Role of the HLA Gene Region and Environmental Risk Factors in Follicular Non-Hodgkin Lymphoma

Abstract

The first genome-wide scans searching for follicular lymphoma (FL) risk factors revealed that a section of chromosome 6 powerfully impacts risk of this disease. Common genetic variants within the human leukocyte antigen (HLA) gene region were shown to be associated with an approximate doubling of individual disease odds. This dissertation aims to concurrently improve the resolution of, expand upon, clarify, and take the first steps in explaining these findings. Chapter 1 provides a review of the broadly relevant literature, including the epidemiology of FL and related lymphomas, the molecular immunology of FL, and the HLA gene region. Chapter 2 is a study making use of the highest possible resolution HLA genotyping methodology for its time, applied to an FL case-control study. This study not only increased our knowledge of known risk factors, it also was the first study to demonstrate an association of FL with variation at HLA-DPB1. Chapter 3 describes the method which will soon be used to localize to a single locus the associations which are ambiguously assigned to several genes. Using pilot data, this study demonstrate the feasibility of performing genetic ancestry matching and HLA imputations on historically stored samples. Chapter 4 uses data from several studies to identify two amino-acid positions, which may themselves explain a substantial portion of FL risk. The fact that these amino acid positions lie in the key peptide binding groove of HLA-DRB1 gives some evidence that peptide binding is the mechanism by which these HLA associations are impacting FL development. Finally, in Chapter 5 the peptide binding properties of HLA class II alleles are computationally investigated, examining potential environmental and internal proteomes likely to be encountered by HLA proteins. This approach reveals that certain alleles which impact FL risk are predicted to be exceptionally strong or weak at binding peptides, and several candidate antigens are mined from the data. Concluding in Chapter 6, the state of HLA-FL research is summarized, and future research is recommended.

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