Browsing by Author "Griffiths, Anne M."

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    Mucosal Inflammatory and Wound Healing Gene Programmes Reveal Targets for Stricturing Behaviour in Paediatric Crohn’s Disease
    (Oxford University Press, 2020-08-08) Haberman, Yael; Minar, Phillip; Karns, Rebekah; Dexheimer, Phillip J.; Ghandikota, Sudhir; Tegge, Samuel; Shapiro, Daniel; Shuler, Brianne; Venkateswaran, Suresh; Braun, Tzipi; Ta, Allison; Walters, Thomas D.; Baldassano, Robert N.; Noe, Joshua D.; Rosh, Joel; Markowitz, James; Dotson, Jennifer L.; Mack, David R.; Kellermayer, Richard; Griffiths, Anne M.; Heyman, Melvin B.; Baker, Susan S.; Moulton, Dedrick; Patel, Ashish S.; Gulati, Ajay S.; Steiner, Steven J.; LeLeiko, Neal; Otley, Anthony; Oliva-Hemker, Maria; Ziring, David; Gokhale, Ranjana; Kim, Sandra; Guthery, Stephen L.; Cohen, Stanley A.; Snapper, Scott; Aronow, Bruce J.; Stephens, Michael; Gibson, Greg; Dillman, Jonathan R.; Dubinsky, Marla; Hyams, Jeffrey S.; Kugathasan, Subra; Jegga, Anil G.; Denson, Lee A.; Pediatrics, School of Medicine
    Background and aims: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). Conclusion: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
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    Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression
    (Elsevier, 2021) Mo, Angela; Nagpal, Sini; Gettler, Kyle; Haritunians, Talin; Giri, Mamta; Haberman, Yael; Karns, Rebekah; Prince, Jarod; Arafat, Dalia; Hsu, Nai-Yun; Chuang, Ling-Shiang; Argmann, Carmen; Kasarskis, Andrew; Suarez-Farinas, Mayte; Gotman, Nathan; Mengesha, Emebet; Venkateswaran, Suresh; Rufo, Paul A.; Baker, Susan S.; Sauer, Cary G.; Markowitz, James; Pfefferkorn, Marian D.; Rosh, Joel R.; Boyle, Brendan M.; Mack, David R.; Baldassano, Robert N.; Shah, Sapana; LeLeiko, Neal S.; Heyman, Melvin B.; Griffiths, Anne M.; Patel, Ashish S.; Noe, Joshua D.; Davis Thomas, Sonia; Aronow, Bruce J.; Walters, Thomas D.; McGovern, Dermot P.B.; Hyams, Jeffrey S.; Kugathasan, Subra; Cho, Judy H.; Denson, Lee A.; Gibson, Greg; Pediatrics, School of Medicine
    An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.