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COMMON IMMUNE-RELATED FACTORS AND RISK OF
NON-HODGKIN LYMPHOMA
by
Jun Wang
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(EPIDEMIOLOGY)
December 2012
Copyright 2012 Jun Wang
Object Description
| Title | Common immune-related factors and risk of non-Hodgkin lymphomy |
| Author | Wang, Jun |
| Author email | junw@usc.edu;jun.wang73@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Epidemiology |
| School | Keck School of Medicine |
| Date defended/completed | 2012-10-08 |
| Date submitted | 2012-11-19 |
| Date approved | 2012-11-19 |
| Restricted until | 2012-11-19 |
| Date published | 2012-11-19 |
| Advisor (committee chair) | Cozen, Wendy |
| Advisor (committee member) |
Mack, Thomas M. Stern, Mariana C. Berhane, Kiros T. Akbari, Omid |
| Abstract | Non-Hodgkin lymphoma (NHL) is a highly heterogeneous group of neoplasms originating from B- or T- lymphocytes, with the vast majority of B-cell origin. It is believed that immune dysregulation plays an important role in the etiology of NHL. Currently, the strongest risk factor is immune deficiency, including primary or acquired immune deficiency, and immunosuppressive therapy after organ transplant. However, these conditions are rare in the general population and therefore do not account for the majority of the cases. A remaining key question is whether mild to moderate immune dysregulation could also contribute to NHL risk given that immune deficiency, especially severe immune deficiency, has been established as a strong risk factor. ❧ Extensive epidemiological studies have investigated the association between common immune-related diseases/conditions and NHL risk. Autoimmune or atopic diseases and infections are among those most studied. Autoimmune rheumatic conditions have been shown to increased NHL risk despite the debate regarding whether immunosuppressive therapy for autoimmune disease may also contribute to the development of NHL. Atopic diseases, on the other hand, have been consistently reported to be inversely associated with NHL risk in case-control studies although a disease effect cannot be ruled out: NHL may interfere with B-cell’s ability to produce immunoglobulin E (IgE). Surrogates for early life infections, such as later birth order and large sibship size, have been shown to be positively associated with NHL risk. ❧ Progress has also been made on understanding genetic susceptibility to NHL. Currently, the most consistent findings come from immune response genes, with evidence from both candidate gene and genome wide association studies. Particularly, tumor necrosis factor – alpha (TNF-α), interleukin-10 (IL-10), and lymphotoxin alpha (LTA) are among the best characterized and validated genes. ❧ The full spectra of the biologic mechanisms for NHL are not understood. However, the critical role of chronic antigenic stimulation in lymphomagenesis has been largely appreciated. Nevertheless, the nature of the immune dysfunction in terms of lymphomagenesis is still puzzling, e.g. both immune suppression (severe immunodeficiency) and stimulation (chronic B-cell activation) have been implicated in the pathogenesis of NHL. The objective of this dissertation was to understand how common immune-altering factors, including environmental stimulant (e.g. household endotoxin) and immune-related medical history, would affect risk for NHL in the general populations, with emphasis on atopic diseases and infections. ❧ We did not find any association between household endotoxin levels, measured from dust samples collected from participants’ vacuum cleaner bags, and NHL risk in a NCI/SEER multi-center population based case-control study. The null finding could be due to the nature of cross-sectional measurement of endotoxin or a single measurement which may not reflect a long term exposure. ❧ In a case-control study involving like-sexed twins discordant for NHL, common-immune related diseases or conditions were evaluated in terms of NHL risk. We found a strong inverse association between atopic disease, especially seasonal hay fever (OR = 0.28, 95%CI = 0.10-0.75) or allergy to specific substance (OR = 0.29, 95%CI = 0.13-0.68), and NHL risk. The inverse association was even stronger among dizygotic twins than monozygotic twins, which may suggest a potential gene-environment interaction in NHL etiology. A history of infectious mononucleosis was found inversely associated with NHL risk (OR = 0.35, 95%CI = 0.14-0.90). Childhood behaviors associated with risk of infection was positively associated with later life NHL risk, which is consistent with the finding of the positive association between later birth order / large sibship and NHL in current literature. ❧ Finally, to further clarify the true atopy-NHL association, we evaluated the interactions between atopic disease and established NHL-related immune response genes, including TNF-α, IL10 and LTA, on NHL risk. After taking into account of multiple testing, we did not find any significant interactions for all NHL combined. However, significant interactions were observed in subtype analysis after Bonferroni correction. LTA 252A>G may modify the association between asthma and Diffuse Large B-cell Lymphoma (P Interaction = 0.0004) and there was a significant interaction between IL10 -3575T>A and a history of both allergy and eczema on Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma risk (P Interaction = 0.002). ❧ In conclusion, this dissertation has provided some evidence that mild to moderate immune-altering factors, particularly atopic diseases, may also affect risk of NHL. Future studies are needed to understand the underlying mechanisms. |
| Keyword | non-Hodgkin lymphoma; epidemiology; etiology; immunity; endotoxin; atopy; immune-response genes |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Wang, Jun |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume6/etd-WangJun-1308.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Full text | COMMON IMMUNE-RELATED FACTORS AND RISK OF NON-HODGKIN LYMPHOMA by Jun Wang A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (EPIDEMIOLOGY) December 2012 Copyright 2012 Jun Wang |
