The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life

Romeo, Stefano; Sentinelli, Federica; Cambuli, Valentina M; Incani, Michela; Congiu, Tiziana; Matta, Vanessa; Pilia, Sabrina; Huang-Doran, Isabel; Cossu, Efisio; Loche, Sandro; Baroni, Marco G

doi:10.1016/j.jhep.2010.02.034

« Previous Next »Journal of Hepatology
Volume 53, Issue 2 , Pages 335-338, August 2010

The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life

Stefano Romeo
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
- These authors contributed equally to this work.
Federica Sentinelli
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
- These authors contributed equally to this work.
Valentina M Cambuli
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
Michela Incani
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
Tiziana Congiu
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
Vanessa Matta
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
Sabrina Pilia
- Pediatric Endocrine Unit, Regional Hospital for Microcitemia, Cagliari, Italy
Isabel Huang-Doran
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
Efisio Cossu
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
Sandro Loche
- Pediatric Endocrine Unit, Regional Hospital for Microcitemia, Cagliari, Italy
Marco G Baroni
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
- Corresponding author. Address: Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Policlinico Universitario, 09042 Cagliari, Italy. Tel.: +39 070 6754068; fax: +39 070 51096044.

Received 30 December 2009; received in revised form 18 February 2010; accepted 19 February 2010. published online 05 May 2010.

Background & aims

Childhood obesity is a growing problem worldwide. Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity in children. Recently, the PNPLA3 gene I148M (rs738409) variant was demonstrated to be strongly associated with hepatic steatosis in obese adults. In this study we add further insight into the role of PNPLA3 by exploring whether this association begins early in life in obese children or becomes manifest only in adulthood.

Methods

Four hundred and seventy-five obese/overweight children and adolescents were genotyped for the I148M allele. Clinical and biochemical parameters were collected for all participants, including indices of hepatic injury, glucose tolerance and insulin resistance. Ultrasound imaging of the liver was obtained to assess the degree of steatosis in a subset of children.

Results

Carriers of two 148M alleles had a 52% increase in circulating ALT levels compared to carriers of two 148I alleles, with individuals with one 148M allele showing a 9.5% increase (p=0.001). AST concentration was also significantly higher in carriers of two and one M alleles (17.4% and 4%, respectively, p=0.022). A total of 36% of carries of two 148M alleles showed elevated ALT, defined as >30U/L, compared to only 10% of carriers of two 148I alleles (p<0.001). Liver steatosis was more prevalent in carriers of two 148M alleles. Glucose tolerance and insulin sensitivity were similar across all three genotypes.

Conclusions

Our data show that the PNPLA3 gene I148M variant is associated with increased levels of ALT/AST in obese children and adolescents, suggesting that it confers genetic susceptibility to liver damage from a young age.

Abbreviations: NAFLD, non-alcoholic fatty liver disease, ALT, alanine transaminase, AST, aspartate transaminase, BMI, body mass index, HOMA-IR, homeostasis model assessment for insulin resistance, MAF, minor allele frequency