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Genetic Variants Associated With Obesity and Insulin Resistance in Hispanic Boys With Nonalcoholic Fatty Liver Disease

Rausch, John, C.*; Lavine, Joel, E.*; Chalasani, Naga; Guo, Xiuqing; Kwon, Soonil; Schwimmer, Jeffrey, B.§; Molleston, Jean, P.||; Loomba, Rohit; Brunt, Elizabeth, M.#; Chen, Yii-Der, Ida; Goodarzi, Mark, O.**; Taylor, Kent, D.; Yates, Katherine, P.††; Rotter, Jerome, I.for the NASH Clinical Research Network

Journal of Pediatric Gastroenterology and Nutrition: May 2018 - Volume 66 - Issue 5 - p 789–796
doi: 10.1097/MPG.0000000000001926
Original Articles: Hepatology

Background and Objectives: Nonalcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic boys. Further, obesity and insulin resistance are major risk factors for NAFLD. No gene localization studies had been performed on children with biopsy-proven NAFLD. This study aims to identify genomic variants associated with increased adiposity and insulin resistance in a population of children with varying histologic severity of NAFLD.

Methods: We conducted a genome-wide association scan (GWAS) including 624,297 single-nucleotide polymorphisms (SNPs) distributed among all 22 autosomal chromosomes in 234 Hispanic boys (up to 18 years of age) who were consecutively recruited in a prospective cohort study in the Nonalcoholic Steatohepatitis Clinical Research Network Studies. Traits were examined quantitatively using linear regression. SNPs with P value <10−5 and a minor allele frequency >5% were considered potentially significant.

Results: Evaluated subjects had a median age of 12.0 years, body mass index (BMI) of 31.4, and hemoglobin A1C (Hgb A1C) of 5.3. The prevalence of NAFL, borderline NASH, and definite NASH were 23%, 53%, and 22%, respectively. The GWAS identified 10 SNPs that were associated with BMI z score, 6 within chromosome 2, and 1 within CAMK1D, which has a potential role in liver gluconeogenesis. In addition, the GWAS identified 9 novel variants associated with insulin resistance: HOMA-IR (6) and HbA1c (3).

Conclusions: This study of Hispanic boys with biopsy-proven NAFLD with increased risk for the metabolic syndrome revealed novel genetic variants that are associated with obesity and insulin resistance.

*Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University, New York, NY

Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN

Institute for Translational Genomics and Population Science and Pediatrics, LA BioMed at Harbor-UCLA Medical Center, Los Angeles

§Division of Gastroenterology, Hepatology and Nutrition in the Department of Pediatrics, University of California, San Diego, San Diego, CA

||Division of Gastroenterology, Hepatology and Nutrition; Department of Pediatrics, Indiana University, Indianapolis, IN

Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Diego, San Diego, CA

#Departments of Pathology and Immunology, Washington University, St. Louis, MO

**Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA

††Department of Pediatrics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.

Address correspondence and reprint requests to Joel E. Lavine, MD, PhD, Pediatrics, Columbia University, 622 W. 168th Street, PH17-105F, New York, NY 10032 (e-mail: jl3553@columbia.edu).

Received 5 January, 2017

Accepted 1 December, 2017

The study was supported by NIDDK (U01DK061734, U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061737, U01DK061738, U01DK061730, U01DK061713) and NICHD. It was also supported by NIH CTSA awards (UL1TR000040, UL1RR024989, UL1RR025761, M01RR00188, UL1RR024131, UL1RR025014, UL1RR031990, UL1RR025741, UL1RR029887, UL1RR24156, UL1RR025055, UL1RR031980), and DRC HDK063491.

www.clinicaltrials.gov registration number: NCT01061684.

The authors report no conflicts of interest.

© 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,