Browsing by Author "Jones, Marcus B."

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    A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation
    (Springer Nature, 2022) Vujkovic, Marijana; Ramdas, Shweta; Lorenz, Kim M.; Guo, Xiuqing; Darlay, Rebecca; Cordell, Heather J.; He, Jing; Gindin, Yevgeniy; Chung, Chuhan; Myers, Robert P.; Schneider, Carolin V.; Park, Joseph; Lee, Kyung Min; Serper, Marina; Carr, Rotonya M.; Kaplan, David E.; Haas, Mary E.; MacLean, Matthew T.; Witschey, Walter R.; Zhu, Xiang; Tcheandjieu, Catherine; Kember, Rachel L.; Kranzler, Henry R.; Verma, Anurag; Giri, Ayush; Klarin, Derek M.; Sun, Yan V.; Huang, Jie; Huffman, Jennifer E.; Townsend Creasy, Kate; Hand, Nicholas J.; Liu, Ching-Ti; Long, Michelle T.; Yao, Jie; Budoff, Matthew; Tan, Jingyi; Li, Xiaohui; Lin, Henry J.; Chen, Yii-Der Ida; Taylor, Kent D.; Chang, Ruey-Kang; Krauss, Ronald M.; Vilarinho, Silvia; Brancale, Joseph; Nielsen, Jonas B.; Locke, Adam E.; Jones, Marcus B.; Verweij, Niek; Baras, Aris; Reddy, K. Rajender; Neuschwander-Tetri, Brent A.; Schwimmer, Jeffrey B.; Sanyal, Arun J.; Chalasani, Naga; Ryan, Kathleen A.; Mitchell, Braxton D.; Gill, Dipender; Wells, Andrew D.; Manduchi, Elisabetta; Saiman, Yedidya; Mahmud, Nadim; Miller, Donald R.; Reaven, Peter D.; Phillips, Lawrence S.; Muralidhar, Sumitra; DuVall, Scott L.; Lee, Jennifer S.; Assimes, Themistocles L.; Pyarajan, Saiju; Cho, Kelly; Edwards, Todd L.; Damrauer, Scott M.; Wilson, Peter W.; Gaziano, J. Michael; O'Donnell, Christopher J.; Khera, Amit V.; Grant, Struan F. A.; Brown, Christopher D.; Tsao, Philip S.; Saleheen, Danish; Lotta, Luca A.; Bastarache, Lisa; Anstee, Quentin M.; Daly, Ann K.; Meigs, James B.; Rotter, Jerome I.; Lynch, Julie A.; Regeneron Genetics Center; Geisinger-Regeneron DiscovEHR Collaboration; EPoS Consortium; VA Million Veteran Program; Rader, Daniel J.; Voight, Benjamin F.; Chang, Kyong-Mi; Medicine, School of Medicine
    Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.
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    The auxiliary protein complex SaePQ activates the phosphatase activity of sensor kinase SaeS in the SaeRS two-component system of Staphylococcus aureus
    (Wiley, 2012) Jeong, Do-Won; Cho, Hoonsik; Jones, Marcus B.; Shatzkes, Kenneth; Sun, Fei; Ji, Quanjiang; Liu, Qian; Peterson, Scott N.; He, Chuan; Bae, Taeok; Microbiology and Immunology, School of Medicine
    In bacterial two-component regulatory systems (TCSs), dephosphorylation of phosphorylated response regulators is essential for resetting the activated systems to the pre-activation state. However, in the SaeRS TCS, a major virulence TCS of Staphylococcus aureus, the mechanism for dephosphorylation of the response regulator SaeR has not been identified. Here we report that two auxiliary proteins from the sae operon, SaeP and SaeQ, form a protein complex with the sensor kinase SaeS and activate the sensor kinase's phosphatase activity. Efficient activation of the phosphatase activity required the presence of both SaeP and SaeQ. When SaeP and SaeQ were ectopically expressed, the expression of coagulase, a sae target with low affinity for phosphorylated SaeR, was greatly reduced, while the expression of alpha-haemolysin, a sae target with high affinity for phosphorylated SaeR, was not, demonstrating a differential effect of SaePQ on sae target gene expression. When expression of SaePQ was abolished, most sae target genes were induced at an elevated level. Since the expression of SaeP and SaeQ is induced by the SaeRS TCS, these results suggest that the SaeRS TCS returns to the pre-activation state by a negative feedback mechanism.
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    Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria
    (SpringerNature, 2016-08-10) Tran, Tuan M.; Jones, Marcus B.; Ongoiba, Aissata; Bijker, Else M.; Schats, Remko; Venepally, Pratap; Skinner, Jeff; Doumbo, Safiatou; Quinten, Edwin; Visser, Leo G.; Whalen, Elizabeth; Presnell, Scott; O’Connell, Elise M.; Kayentao, Kassoum; Doumbo, Ogobara K.; Chaussabel, Damien; Lorenzi, Hernan; Nutman, Thomas B.; Ottenhoff, Tom H. M.; Haks, Mariëlle C.; Traore, Boubacar; Kirkness, Ewen F.; Sauerwein, Robert W.; Crompton, Peter D.; Department of Medicine, IU School of Medicine
    Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria.