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Variation at the Interleukin-6 Locus and Genetic Susceptibility to Blastomycosis
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Variation at the Interleukin-6 Locus and Genetic Susceptibility to Blastomycosis. |
| 개인저자 | Merkhofer, Richard M., Jr. |
| 단체저자명 | The University of Wisconsin - Madison. Cellular & Molecular Bio-LS. |
| 발행사항 | [S.l.]: The University of Wisconsin - Madison., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 225 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-02B. Dissertation Abstract International |
| ISBN | 9781085614610 |
| 학위논문주기 | Thesis (Ph.D.)--The University of Wisconsin - Madison, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
Advisor: Klein, Bruce S. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | We are constantly exposed to fungi that are capable of causing disease. Yet, remarkably, invasive fungal infections are exceptionally rare in the general population. Still, for many fungal diseases, the number at risk greatly exceeds the number affected, suggesting a role for genetic susceptibility. Fine variations in the immune response are likely to explain population-level trends in fungal illness.Blastomycosis is an illness caused by the dimorphic fungus Blastomyces dermatitidis, which is endemic in North America. The majority of infections by B. dermatitidis are asymptomatic, and many of those who develop symptoms do not appear to be at increased risk for fungal infection. Thus, genetic differences are hypothesized to underlie ethnic disparities in incidence rates of the endemic systemic mycoses, including blastomycosis. Individuals of Hmong ancestry display elevated risk for this serious fungal infection.We interrogated the genomes of Wisconsin (WI) Hmong blastomycosis patients to uncover regions of the genome that are likely shared among the greater Hmong population, and filtered for variants with high potential to affect disease susceptibility. This approach uncovered 113 candidate susceptibility variants. Among the most promising are those in genes involved in the interleukin- (IL-)17 response. In particular, we identified 25 linked variants near the gene encoding IL-6 (IL6). We validated differences in cytokine production between Hmong and European volunteers, and formally demonstrated a critical role for IL-6 in the development of adaptive immunity to Blastomyces dermatitidis.We developed a framework for studying variation at the IL6 locus. In silico analysis revealed potential mechanisms by which candidate susceptibility variants may impact IL-6 production via alterations to a regulatory, antisense non-coding RNA named antisense-IL6 (AS-IL6). We harnessed the power of induced pluripotent stem cells (iPSCs) and genome editing to work towards testing the effects of select variants experimentally. Ongoing experiments will also address the role of AS-IL6 in the immune system. Future experiments may elucidate polygenic effects that contribute to the observed health disparity, including other loci that may impact the development of adaptive immune responses to B. dermatitidis. |
| 일반주제명 | Immunology. |
| 언어 | 영어 |
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: 이 자료의 원문은 한국교육학술정보원에서 제공합니다. |
