Genetics of Fatty Liver Disease in Children

Genetics of Fatty Liver Disease in Childhood Obesity.

This is a study to investigate genetic predisposition to hepatic steatosis and the expression of gluconeogenic and lipogenic genes in livers of obese children and adolescents.

Hypothesis 1: Common variants recently associated with variation in plasma TG levels identified in Genome Wide Association Studies (GWAS) (such as GCKR, PNPLA3) can affect accumulation of fat and subsequent development of Non Alcoholic Fatty Liver Disease (NAFLD). Gene variants act in additive or synergistic manner with progressive liver fat accumulation per additional risk allele.

Hypothesis 2: With increase in hepatic fat content NASH and fibrosis will increase. Furthermore, expression of lipogenic markers (SREBP1c) will increase.

Study Overview

• Status: Completed
• Conditions: Non Alcoholic Fatty Liver Disease
• Intervention / Treatment: Other: ogtt; Other: genotyping; Other: abdominal and liver magnetic resonance imaging; Other: stool sample; Other: liver biopsy

Detailed Description

To establish a cohort of obese youths to prospectively analyze potential factors (genetic and nutritional factors) that might affect the expression and progression of NAFLD. This study will determine genetic markers and their ability to convey susceptibility to NAFLD in obese children and adolescents. Furthermore, potential mechanisms that might contribute to the accumulation of hepatic Triglyceride (TG) accumulation will be, for the first time, assessed by genotyping. Additionally, we will examine the presence of intestinal microbiome in the development of fatty liver through stool collection.

• Study Type: Observational
• Enrollment (Actual): 381

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The majority of the research subjects will be recruited from the Yale Pediatric Obesity Clinic and the Endocrine Clinic.

Description

Inclusion Criteria:

• between 7 and 18 years of age,
• overweight or obese with a BMI greater than the 85th percentile for age and gender, and
• be otherwise healthy.

Exclusion Criteria:

• the use of any medication that alters liver function, blood pressure, glucose or lipid metabolism and
• no use of any antipsychotic medication
• Youth on chronic anti-inflammatory medications or who consume alcohol are also excluded.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Pediatric NAFLD Cohort; Overweight and obese children and adolescents at risk for non alcoholic fatty liver disease will undergo oral glucose tolerance testing (ogtt), genotyping, abdominal and liver magnetic resonance imaging (mri), and will provide a stool sample at baseline and at 2 year follow up. A small subset will undergo liver biopsy to test for hepatic steatosis and nonalcoholic steatohepatitis.

Other: ogtt; oral glucose tolerance test; Other: genotyping; genotyping to look for risk alleles; Other: abdominal and liver magnetic resonance imaging; magnetic resonance imaging scan of abdomen and liver - abdominal and liver mri; Other: stool sample; stool sample taken to investigate metabolites; Other: liver biopsy; liver biopsy to examine for cellular change and steatosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
gene expression	gene mutation allele variation identification measure via gene extraction	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hepatic fat content	Abdominal MRI to measure liver fat and subcutaneous and visceral fat ratio done at baseline and 2 year follow up	2 years
glucose tolerance	glucose tolerance status measured by 3 hour oral glucose tolerance test done at baseline and 2 year follow up	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
DNA gene sequencing of intestinal bacteria's	Measure microbiota diversity via stool samples to understand variance of triglycerides accumulation in liver	2 years
Use liver biopsy specimen to assess differences in gene expression, as well as inflammation.	liver biopsy tissue obtained when subject is scheduled for pre-ordered biopsy by hepatologist	As indicated by Pediatric Hepatolgist

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Sonia Caprio, M.D., Yale University

Publications and helpful links

General Publications

• Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, Constable RT, Weiss R, Tamborlane WV, Savoye M, Seyal AA, Caprio S. Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab. 2006 Nov;91(11):4287-94. doi: 10.1210/jc.2006-1010. Epub 2006 Aug 15.
• Trico D, Caprio S, Rosaria Umano G, Pierpont B, Nouws J, Galderisi A, Kim G, Mata MM, Santoro N. Metabolic Features of Nonalcoholic Fatty Liver (NAFL) in Obese Adolescents: Findings From a Multiethnic Cohort. Hepatology. 2018 Oct;68(4):1376-1390. doi: 10.1002/hep.30035.

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: July 15, 2013
• First Submitted That Met QC Criteria: October 16, 2013
• First Posted (Estimate): October 21, 2013

Study Record Updates

• Last Update Posted (Actual): December 8, 2017
• Last Update Submitted That Met QC Criteria: December 6, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: childhood obesity; non alcoholic fatty liver; genetic variants
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Hematinics; Liver Extracts
• Other Study ID Numbers: 1104008388; R01HD040787 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No