@article{cc41f86a03d049ecb67c2e92369653c2,
title = "Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children",
abstract = "Background and Aims: NAFLD is the most common chronic liver disease in children. Large pediatric studies identifying single nucleotide polymorphisms (SNPs) associated with risk and histologic severity of NAFLD are limited. Study aims included investigating SNPs associated with risk for NAFLD using family trios and association of candidate alleles with histologic severity. Approach and Results: Children with biopsy-confirmed NAFLD were enrolled from the NASH Clinical Research Network. The Expert Pathology Committee reviewed liver histology. Genotyping was conducted with allele-specific primers for 60 candidate SNPs. Parents were enrolled for trio analysis. To assess risk for NAFLD, the transmission disequilibrium test was conducted in trios. Among cases, regression analysis assessed associations with histologic severity. A total of 822 children with NAFLD had mean age 13.2 years (SD 2.7) and mean ALT 101 U/L (SD 90). PNPLA3 (rs738409) demonstrated the strongest risk (p = 2.24 × 10−14) for NAFLD. Among children with NAFLD, stratifying by PNPLA3 s738409 genotype, the variant genotype associated with steatosis (p = 0.005), lobular (p = 0.03) and portal inflammation (p = 0.002). Steatosis grade associated with TM6SF2 (p = 0.0009), GCKR (p = 0.0032), PNPLA3 rs738409 (p = 0.0053), and MTTP (p = 0.0051). Fibrosis stage associated with PARVB rs6006473 (p = 0.0001), NR1I2 (p = 0.0021), ADIPOR2 (p = 0.0038), and OXTR (p = 0.0065). PNPLA3 rs738409 (p = 0.0002) associated with borderline zone 1 NASH. Conclusions: This study demonstrated disease-associated SNPs in children with NAFLD. In particular, rs6006473 was highly associated with severity of fibrosis. These hypothesis-generating results support future mechanistic studies of development of adverse outcomes such as fibrosis and generation of therapeutic targets for NAFLD in children.",
author = "{for the NASH Clinical Research Network} and Goyal, {Nidhi P.} and Rosenthal, {Sara B.} and Chanod Nasamran and Behling, {Cynthia A.} and Angeles, {Jorge E.} and Fishbein, {Mark H.} and Harlow, {Kathryn E.} and Jain, {Ajay K.} and Mollewston, {Jean P.} and Newton, {Kimberly P.} and Patricia Ugalde-Nicalo and Xanthankos, {Stavra A.} and Katherine Yates and Schork, {Nicholas J.} and Fisch, {Kathleen M.} and Schwimmer, {Jeffrey B.} and Yates, {Katherine P.} and Tinsay Woreta and Wilson, {Laura A.} and Annette Wagoner and {Van Natta}, {Mark L.} and James Tonascia and Alice Sternberg and Michael Smith and Jacqueline Smith and Sharkey, {Emily P.} and Carrie Shade and Laura Miriel and Jill Meinert and Clark, {Jeanne M.} and Patricia Belt and Peggy Adamo and Robuck, {Patricia R.} and Rebecca Torrance and Sherker, {Averell H.} and Hoofnagle, {Jay H.} and Sherry Hall and Doo, {Edward C.} and Kleiner, {David E.} and Brunt, {Elizabeth M.} and Melissa Young and Matthew Yeh and Randolph Otto and Kara Cooper and Niviann Blondet and Andrew Wang and Patricia Ugalde-Nicalo and Jaret Skonieczny and Schwimmer, {Jeffrey B.} and Newton, {Kimberly P.} and Goyal, {Nidhi P.} and Janis Durelle and Cynthia Behling and Susan Torretta and Jain, {Ajay K.} and Janet Freebersyser and Theresa Cattoor and Danielle Carpenter and Saeed Mohammad and Fishbein, {Mark H.} and Angela Anthony and Cindy Sawyers and Girish Rao and Emily Ragozzino and Wendy Morlan and Molleston, {Jean P.} and Ann Klipsch and Kathryn Harlow and Cummings, {Oscar W.} and Laura Carr and Molly Bozic and Miriam Vos and Saul Karpen and Maria Cordero and Rebecca Cleeton and Adina Alazraki and Stavra Xanthakos and Andrew Trout and Marialena Mouzaki and Meghan McNeill and Kim Cecil and April Carr and Kristin Bramlage and Nicole Triggs and Yen Pham and Alicia Lawson and Paula Hertel and Donna Garner",
note = "Funding Information: The TONIC trial was conducted by the NASH CRN and supported in part by the Intramural Research Program of the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The vitamin E and matching placebo were provided by Pharmavite through a Clinical Trial Agreement with the NIH. The CyNCh trial was conducted by the NASH CRN and supported in part by the Intramural Research Program of the National Cancer Institute and by a Collaborative Research and Development Agreement (CRADA) between NIDDK and Raptor Pharmaceuticals. The project was also supported by the Rady Children's Hospital Academic Enrichment Fund, the UC San Diego Altman Clinical and Translational Research Institute supported by NIH Grants UL1TR000100, UL1TR001442, the UC San Diego Center for Computational Biology & Bioinformatics, and the San Diego Digestive Diseases Research Center supported by NIDDK grant P30 DK120515. Funding Information: Ajay K. Jain advises Mirum Pharma. He consults for and received grants from Camp 4. Jeffrey B. Schwimmer received grants from Intercept, Genfit, and Seraphina. Jean P. Molleston received grants from Gilead, AbbVie, Albireo, and Shire. Stavra A. Xanthankos received grants from Target RWE. Publisher Copyright: {\textcopyright} 2022 American Association for the Study of Liver Diseases.",
year = "2022",
doi = "10.1002/hep.32570",
language = "English",
journal = "Hepatology",
issn = "0270-9139",
}