Patel, ZH; Lu, X; Miller, D; Forney, CR; Lee, J; Lynch, A; Schroeder, C; Parks, L; Magnusen, AF; Chen, X; Pujato, M; Maddox, A; Zoller, EE; Namjou, B; Brunner, HI; Henrickson, M; Huggins, JL; Williams, AH; Ziegler, JT; Comeau, ME; Marion, MC; Glenn, SB; Adler, A; Shen, N; Nath, SK; Stevens, AM; Freedman, BI; Pons-Estel, BA; Tsao, BP; Jacob, CO; Kamen, DL; Brown, EE; Gilkeson, GS; Alarcon, GS; Martin, J; Reveille, JD; Anaya, J; James, JA; Sivils, KL; Criswell, LA; Vila, LM; Petri, M; Scofield, RH; Kimberly, RP; Edberg, JC; Ramsey-Goldman, R; Bang, S; Lee, H; Bae, S; Boackle, SA; Graham, DC; Vyse, TJ; Merrill, JT; Niewold, TB; Ainsworth, HC; Silverman, ED; Weisman, MH; Wallace, DJ; Raj, P; Guthridge, JM; Gaffney, PM; Kelly, JA; Alarcon-Riquelme, ME; Langefeld, CD; Wakeland, EK; Kaufman, KM; Weirauch, MT; Harley, JB; Kottyan, LC. A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Human Molecular Genetics. 2018; 27(13):2392-2404.
The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. Members of the Kottyan, Weirauch, and Harley labs performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Additionally, functional genomic experiments demonstrated genotype-dependent transcription factor binding and transcriptional regulation of STAT1 in B cells. Altogether, this exciting manuscript presents a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus.
Wang, J; Dai, M; Cui, Y; Hou, G; Deng, J; Gao, X; Liao, Z; Liu, Y; Meng, Y; Wu, L; Yao, C; Wang, Y; Qian, J; Guo, Q; Ding, H; Qu, B; Shen, N. Association of Abnormal Elevations in IFIT3 With Overactive Cyclic GMP-AMP SynthaseStimulator of Interferon Genes Signaling in Human Systemic Lupus Erythematosus Monocytes. Arthritis and Rheumatology. 2018; 70(12):2036-2045.
Type I IFN pathway is the critical component for the development of SLE and other interferonopathies. Understanding the molecuar mechanisms underlying the overactivation of this pathway could help us to create novel interventions for these patients.  In this manuscript,  the cGAS-STING signaling pathway, which  senses self-DNA and  produces type I IFN, has been found to be over-activated  in monocytes of SLE patients. The lupus related IFN inducible gene, IFIT3, has been demonstrated to contribute to the over-active cGAS-STING signaling. These data indicate that the interplay between type I IFN and cGAS-STING signaling could form a feedforward loop exacerbating the disease.  These findings suggest  IFIT3 may serve as a distinct and new therapeutic target to control the  type I IFN production  in SLE and other cGAS-STING pathway dependent interferonopathies.
Kottyan, LC; Maddox, A; Braxton, JR; Stucke, EM; Mukkada, V; Putnam, PE; Abonia, JP; Chehade, M; Wood, RA; Pesek, RD; Vickery, BP; Furuta, GT; Dawson, P; Sampson, HA; Martin, LJ; Kelly, JA; Kimberly, RP; Sivils, K; Gaffney, PM; Kaufman, K; Harley, JB; Rothenberg, ME. Genetic variants at the 16p13 locus confer risk for eosinophilic esophagitis. Genes and Immunity. 2019; 20(4):281-292.
In this manuscript CAGE faculty member Leah Kottyan, PhD led a study with Marc Rothenberg, MD, PhD to identify new genetic risk loci for Eosinophilic Esophagitis (EoE). EoE is a food allergic disease that involves chronic eosinophilic inflammation in the esophagus. Together with support from CAGE faculty Kenneth Kaufman, PhD and John Harley, MD, PhD, the team identified a new risk locus at a region of the genome encoding CLEC16A, DEXI, and CIITI. These genes are expressed in immune cells and esophageal epithelial cells and are likely important in the genetic etiology of EoE.
Bernstein, DI; Lummus, ZL; Kesavalu, B; Yao, J; Kottyan, L; Miller, D; Cartier, A; Cruz, M; Lemiere, C; Munoz, X; Quirce, S; Tarlo, S; Sastre, J; Boulet, LP; Weirauch, MT; Kaufman, K. Genetic variants with gene regulatory effects are associated with diisocyanate-induced asthma. Journal of Allergy and Clinical Immunology. 2018; 142(3):959-969.
In this study, CAGE faculty Ken Kaufman, PhD, Matt Weirauch, PhD, and Leah Kottyan, PhD collaborated with David Bernstein, MD from the Department of Allergy & Immunology at the University of Cincinnati to sequence candidate genetic risk loci for occupational asthma. Identified genetic risk variants were prioritized via a computational pipeline and experimentally validated using functional genomic assays.
Miller, DE; Forney, C; Rochman, M; Cranert, S; Habel, J; Rymer, J; Lynch, A; Schroeder, C; Lee, J; Sauder, A; Smith, Q; Chawla, M; Trimarchi, MP; Lu, X; Fjellman, E; Brusilovsky, M; Barski, A; Waggoner, S; Weirauch, MT; Rothenberg, ME; Kottyan, LC. Genetic, Inflammatory, and Epithelial Cell Differentiation Factors Control Expression of Human Calpain-14. G3: Genes, Genomes, Genetics. 2019; 9(3):729-736.
CAPN14 is dynamically up-regulated as a function of EoE disease activity and after exposure of epithelial cells to interleukin-13 (IL-13). In this multidisciplinary project, members from the divisions of Allergy&Immunology and CAGE worked together to elucidate the transcriptional regulation of calpain-14 in esophageal epithelial cells.