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G,WAS going on? Putative regulatory function of GWAS-identified markers of susceptibility to acute appendicitis

Orlova, Ekaterina (2015) G,WAS going on? Putative regulatory function of GWAS-identified markers of susceptibility to acute appendicitis. Master's Thesis, University of Pittsburgh. (Unpublished)

[img] Microsoft Excel (Table 5. Motifs Identified within the Region of Interest on Chromosome 3 and their Targets.)
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[img] Microsoft Excel (Table 6. Motifs Identified within the Region of Interest on Chromosome 15 and their Targets.)
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[img] Microsoft Excel (Table 7. Motifs Identified within the Region of Interest on Chromosome 4 (at 111.7 Mb) and their Targets.)
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[img] Microsoft Excel (Table 8. Motifs Identified within the Region of Interest on Chromosome 4 (at 112.7 Mb) and their Targets.)
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Appendicitis affects 7-9% of Americans and is the most common diagnosis requiring hospitalization of both children and adults. Several etiologies of appendicitis have been hypothesized, but definitive mechanisms remain elusive – a critical review of the literature does not support a primary role of fecaliths or lymphoid hyperplasia, as is commonly believed. It is known that appendicitis has heritable components, and so we collaborated with 23andMe Inc., a personal genomics company, to identify genetic determinants of susceptibility to acute appendicitis. 23andMe performed a genome-wide association study (GWAS) of 18,773 appendectomy cases and 114,907 controls, and identified one locus with genome-wide significance. In addition, the GWAS identified eight highly significant SNPs that did not reach genome-wide significance. Most of the SNPs identified using this analysis fell outside of protein-coding genes, thus bioinformatic analysis using RegulomeDB was done to interrogate the SNPs’ putative regulatory capacity of nearby or distant genes, or proteins.
This analysis identified 921 targets of putative regulatory elements in the same LD blocks as the four of nine lead SNPs identified in the GWAS and chosen for follow-up study. Of these, 299 targets were unique when targets from all four genomic regions were combined. These targets were organized according to the distance of their putatively egulatory SNP from the given lead SNP, and based on overlap of elements’ targets within one region with targets of elements within the rest of the genomic regions. Ultimately, the following list of 17 proteins was generated for priority in further studies: CEBPB, CTCF, EP300, EVI-1, FOS, FOXJ3, FOXP1, GATA1, HNF4A, JUN, MYC, NFKB, PPARG, RAD21, SPI1, STAT1, and STAT3. This list includes several proteins that directly interact with, or influence the expression of very specific inflammatory markers known to be strongly associated with appendicitis, including IL-8, IL-1B, and IL-6. This outcome supports the utility of RegulomeDB in the interpretation of GWAS-generated non-coding variants.
This compiled resource and the ongoing parallel studies born of the appendectomy GWAS may help to elucidate the pathogenesis of acute appendicitis, thereby providing opportunities to improve the diagnosis, treatment, and prevention of this extremely common disease. The public health significance of appendicitis and its genetics are addressed, and a theoretical public health program that integrates the multiple factors involved in appendicitis etiology is proposed.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Orlova, Ekaterinaeko8@pitt.eduEKO80000-0002-7129-5796
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorMorowitz, Michaelmichael.morowitz@chp.eduMJM226
Committee CoChairShaffer, Johnjrs51@pitt.eduJRS51
Committee MemberFinegold, Daviddnf@pitt.eduDNF
Date: 28 September 2015
Date Type: Publication
Defense Date: 7 August 2015
Approval Date: 28 September 2015
Submission Date: 2 September 2015
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 106
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: appendicitis, appendectomy, GWAS, genome-wide association study, 23andMe, personalized medicine, genetic screening, genetic counseling, public health genetics, direct-to-consumer, genotyping, RegulomeDB, StringDB, complex disease, multifactorial disease
Date Deposited: 28 Sep 2015 18:33
Last Modified: 28 Sep 2018 05:15


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