Gastroenterology
Volume 137, Issue 4 , Page 1536, October 2009

Heritability of Nonalcoholic Fatty Liver Disease

  • Martijn C.G.J. Brouwers

      Affiliations

    • Laboratory of Vascular Metabolism and Biology, Department of Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
    • ,
  • Marleen M.J. van Greevenbroek

      Affiliations

    • Laboratory of Vascular Metabolism and Biology, Department of Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
    • ,
  • Rita M. Cantor

      Affiliations

    • Departments of Human Genetics and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California

published online 31 August 2009.

Article Outline

 

Dear Sir:

With great interest we read the article by Schwimmer et al,1 who demonstrated that nonalcoholic fatty liver disease (NAFLD), as determined with magnetic spectroscopy, is a heritable trait in families with children who have biopsy-proven NAFLD. The authors conclude that their study warrants the pursuit of linkage and association studies that will eventually lead to the identification of genes that contribute to an increased risk to develop NAFLD.

Of interest, we previously reported a 20%–37% heritability of NAFLD, as determined with plasma alanine aminotransferase levels, in Caucasian pedigrees with a genetic dyslipidemia.2 This heritability estimate is within the confidence limits of the adjusted liver fat fraction of 39% observed by Swimmer et al. Any differences may be explained by the less accurate measure for NAFLD and the genetic background (ie, Caucasian only) of the population that we used in our study.

Subsequent quantitative trait locus (QTL) analysis for fatty liver (as measured by ultrasound) and plasma alanine aminotransferase levels revealed 3 significant loci on chromosome 1q42, 7p14, and 22q11 in these dyslipidemic families.2 As discussed by Schwimmer et al, it is likely that genes affecting the hepatic input of fat (ie, free fatty acid influx and de novo lipogenesis) or hampering the output of fat (ie, suppression of β-oxidation and very low-density lipoprotein production) account for the heritability of NAFLD and thus for these QTLs.

More recently, the QTL on chromosome 7p14 (P = .0002) was replicated in another dyslipidemic cohort when a marker for stearoyl-CoA desaturase 1, a key enzyme in de novo lipogenesis, was used as a trait (P = .03).3 This region therefore merits further fine-mapping and association studies. Of interest, neuropeptide Y, a peptide that is involved in food intake and hepatic lipid metabolism,4 is located on chromosome 7p14 and could serve as a plausible candidate.

Taken together, the emerging incidence of NAFLD in Western society has led to increased efforts to elucidate its pathogenesis. We believe that heritability studies, as presented by our laboratory and by Swimmer and colleagues, provide the essential rationale for further linkage and association studies to unravel the complex genetic background of NAFLD. These studies are now eagerly awaited.

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References 

  1. Schwimmer JB, Celedon MA, Lavine JE, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136:1492–1492
  2. Brouwers MC, Cantor RM, Kono N, et al. Heritability and genetic loci of fatty liver in familial combined hyperlipidemia. J Lipid Res. 2006;47:2799–2807
  3. Mar-Heyming R, Miyazaki M, Weisglas-Volkov D, et al. Association of stearoyl-CoA desaturase 1 activity with familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 2008;28:1193–1199
  4. van den Hoek AM, Voshol PJ, Karnekamp BN, et al. Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin. Diabetes. 2004;53:2529–2534

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported in part by National Institutes of Health Grant HL-28481.

PII: S0016-5085(09)01397-3

doi:10.1053/j.gastro.2009.03.065

Gastroenterology
Volume 137, Issue 4 , Page 1536, October 2009

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