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Browsing by Author "Myers, Robert P."
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Item 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 MedicineNonalcoholic 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.Item Attribution of Nonalcoholic Steatohepatitis as an Etiology of Cirrhosis for Clinical Trials Eligibility: Recommendations from the Multi-stakeholder Liver Forum(Elsevier, 2020) Noureddin, Mazen; Chan, Jean L.; Barradas, Katherine; Dimick-Santos, Lara; Schabel, Elmer; Omokaro, Stephanie O.; Anania, Frank A.; Myers, Robert P.; Miller, Veronica; Sanyal, Arun J.; Chalasani, Naga; Medicine, School of MedicineItem Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis(Wiley, 2022) Sanyal, Arun J.; Anstee, Quentin M.; Trauner, Michael; Lawitz, Eric J.; Abdelmalek, Manal F.; Ding, Dora; Han, Ling; Jia, Catherine; Huss, Ryan S.; Chung, Chuhan; Wong, Vincent Wai-Sun; Okanoue, Takeshi; Romero-Gomez, Manuel; Muir, Andrew J.; Afdhal, Nezam H.; Bosch, Jaime; Goodman, Zachary; Harrison, Stephen A.; Younossi, Zobair M.; Myers, Robert P.; Medicine, School of MedicineBackground and aims: Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis. Approach and results: Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events. Conclusions: In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.Item Spontaneous fluctuations in liver biochemistries in patients with compensated NASH cirrhosis: Implications for drug hepatotoxicity monitoring(SpringerLink, 2020-03) Shamseddeen, Hani; Vilar, Eduardo; Chalasani, Naga; Myers, Robert P.; Subramanian, G. Mani; Shlevin, Harold H.; Allgood, Adam E.; Orman, Eric S.; Medicine, School of MedicineIntroduction: Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. Objective: We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. Methods: We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. Results: In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy's law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34-299) and 56 U/L (47-85)] than for those with normal baseline values [median 26.5 U/L (range 18-33) and 29 U/L (25.5-30.5)] in both studies, respectively, with p < 0.001. Conclusion: Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.