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Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent

International Journal of Obesity volume 34, pages 190–194 (2010)Cite this article

Abstract

Context:

The PNPLA3 I148M variant (rs738409) is robustly associated with hepatic steatosis. Intriguingly, initial findings in cohorts with a mean body mass index (BMI) of 30 kg m−2 also suggested that it is associated with elevated liver enzymes but not with insulin resistance and dyslipidaemia.

Objective:

To determine whether the PNPLA3 variant alters the susceptibility of morbidly obese subjects to develop liver injury and metabolic sequelae.

Participants and methods:

The study was carried out in 678 obese Italians (mean BMI=41 kg m−2) who were genotyped for the I148M variant. All participants provided fasting blood samples and then underwent oral glucose tolerance tests.

Main outcome measures:

Indices of liver injury (alanine transaminase (ALT), aspartate transaminase (AST)), glucose tolerance and insulin resistance were measured.

Results:

Markers of hepatic injury such as ALT and AST were significantly higher in carriers of the 148M allele (P=2.2 × 10−5 and 0.001, respectively). In all, 50% of 148M risk allele homozygotes had pathological levels of ALT (>40 U l−1) compared with 25% of 148I allele homozygotes (P=0.005). Glucose tolerance and insulin sensitivity were similar in all three genotypes.

Conclusion:

Obese Southern Europeans carrying the 148M allele have increased indices of liver damage uncoupled from proxy measures of insulin resistance.

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Acknowledgements

This study was supported by grants from the Wellcome Trust (to Drs O’Rahilly and Savage), GlaxoSmithKline (to Dr Savage), the NIHR Cambridge Biomedical Research Centre, The Medical Research Council and Raymond & Beverly Sackler scholarship (to Dr Dash), and by research grants from the University of Cagliari (ex-60% 2006-08) and the Sardinian Regional Government (RAS Research Projects 2006 and 2007) awarded to Marco G Baroni.

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Authors and Affiliations

  1. Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK

    S Romeo, S Dash, G S H Yeo, D B Savage & S O'Rahilly

  2. Department of Medical Sciences, Endocrinology and Metabolism, University of Cagliari, Cagliari, Sardinia, Italy

    S Romeo, F Sentinelli, M Incani & M G Baroni

  3. Department of Clinical Sciences, University of Rome La Sapienza, Rome, Italy

    F Leonetti, D Capoccia & C Maglio

  4. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    M Iacovino

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  1. S Romeo
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  2. F Sentinelli
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  3. S Dash
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Correspondence to S Romeo.

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Supplementary Information accompanies the paper on International Journal of Obesity website (http://www.nature.com/ijo)

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Romeo, S., Sentinelli, F., Dash, S. et al. Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent. Int J Obes 34, 190–194 (2010). https://doi.org/10.1038/ijo.2009.216

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  • DOI: https://doi.org/10.1038/ijo.2009.216

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