Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children

Nidhi P. Goyal; Sara B. Rosenthal; Chanod Nasamran; Cynthia A. Behling; Jorge E. Angeles; Mark H. Fishbein; Kathryn E. Harlow; Ajay K. Jain; Jean P. Molleston; Kimberly P. Newton; Patricia Ugalde-Nicalo; Stavra A. Xanthankos; Katherine Yates; Nicholas J. Schork; Kathleen M. Fisch; Jeffrey B. Schwimmer

doi:10.1002/hep.32570

Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children

Nidhi P. Goyal, Sara B. Rosenthal, Chanod Nasamran, Cynthia A. Behling, Jorge E. Angeles, Mark H. Fishbein, Kathryn E. Harlow, Ajay K. Jain, Jean P. Molleston, Kimberly P. Newton, Patricia Ugalde-Nicalo, Stavra A. Xanthankos, Katherine Yates, Nicholas J. Schork, Kathleen M. Fisch, Jeffrey B. Schwimmer^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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 Ã - 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.

Original language	English (US)
Pages (from-to)	197-212
Number of pages	16
Journal	Hepatology
Volume	77
Issue number	1
DOIs	https://doi.org/10.1002/hep.32570
State	Published - Jan 2023

Funding

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. 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.

ASJC Scopus subject areas

Hepatology

Access to Document

10.1002/hep.32570

Cite this

Goyal, N. P., Rosenthal, S. B., Nasamran, C., Behling, C. A., Angeles, J. E., Fishbein, M. H., Harlow, K. E., Jain, A. K., Molleston, J. P., Newton, K. P., Ugalde-Nicalo, P., Xanthankos, S. A., Yates, K., Schork, N. J., Fisch, K. M., & Schwimmer, J. B. (2023). Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children. Hepatology, 77(1), 197-212. https://doi.org/10.1002/hep.32570

@article{371fbe21784b44929fb39cccf3657261,

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 {\~A} - 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 = "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 Molleston, \{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.\}",

year = "2023",

month = jan,

doi = "10.1002/hep.32570",

language = "English (US)",

volume = "77",

pages = "197--212",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Lippincott Williams and Wilkins",

number = "1",

}

Goyal, NP, Rosenthal, SB, Nasamran, C, Behling, CA, Angeles, JE, Fishbein, MH, Harlow, KE, Jain, AK, Molleston, JP, Newton, KP, Ugalde-Nicalo, P, Xanthankos, SA, Yates, K, Schork, NJ, Fisch, KM & Schwimmer, JB 2023, 'Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children', Hepatology, vol. 77, no. 1, pp. 197-212. https://doi.org/10.1002/hep.32570

TY - JOUR

T1 - Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children

AU - Goyal, Nidhi P.

AU - Rosenthal, Sara B.

AU - Nasamran, Chanod

AU - Behling, Cynthia A.

AU - Angeles, Jorge E.

AU - Fishbein, Mark H.

AU - Harlow, Kathryn E.

AU - Jain, Ajay K.

AU - Molleston, Jean P.

AU - Newton, Kimberly P.

AU - Ugalde-Nicalo, Patricia

AU - Xanthankos, Stavra A.

AU - Yates, Katherine

AU - Schork, Nicholas J.

AU - Fisch, Kathleen M.

AU - Schwimmer, Jeffrey B.

PY - 2023/1

Y1 - 2023/1

N2 - 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 Ã - 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.

AB - 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 Ã - 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.

UR - https://www.scopus.com/pages/publications/85132322638

UR - https://www.scopus.com/inward/citedby.url?scp=85132322638&partnerID=8YFLogxK

U2 - 10.1002/hep.32570

DO - 10.1002/hep.32570

M3 - Article

C2 - 35560106

AN - SCOPUS:85132322638

SN - 0270-9139

VL - 77

SP - 197

EP - 212

JO - Hepatology

JF - Hepatology

IS - 1

ER -

Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this