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Journal of Lipid Research, Vol. 50, 2111-2116, October 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity

Silvia Sookoian^1,*,,**, Gustavo O. Castaño^,**, Adriana L. Burgueño, Tomas Fernández Gianotti, María Soledad Rosselli^*, and Carlos Jose Pirola^1,

^* Laboratory of Clinical and Molecular Hepatology, Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research, University of Buenos Aires-CONICET, Ciudad Autónoma de Buenos Aires, Argentina
Laboratory of Molecular Genetics and Biology of the Metabolic Syndrome, Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research, University of Buenos Aires-CONICET, Ciudad Autónoma de Buenos Aires, Argentina
Research Council of GCBA, Ciudad Autónoma de Buenos Aires, Argentina
^** Department of Medicine and Surgery, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Argentina

¹ To whom correspondence should be addressed. e-mail: ssookoian{at}lanari.fmed.uba.ar or pirola.carlos{at}lanari.fmed.uba.ar

We explored the role of the adiponutrin (PNPLA3) nonsynonymous-rs738409 single nucleotide polymorphism (SNP) in genetic susceptibility to nonalcoholic fatty liver disease (NAFLD) and whether this SNP contributes to the severity of histological disease. Two hundred sixty-six individuals were evaluated in a case-control association study, which included 172 patients with features of NAFLD and 94 control subjects. The rs738409 G allele was significantly associated with NAFLD (P < 0.001; OR 2.8 95%, CI 1.5–5.2), independent of age, sex, body mass index (BMI), and Homeostasis Model Assessment (HOMA) index. When we tested the hypothesis of a relation between the SNP and the histological spectrum of NAFLD, a significant association was observed [chi2 19.9, degree of freedom (df): 2, P < 5 x 10^–5, adjusted for HOMA and BMI]. The degree of liver steatosis, as evaluated by liver biopsy, was significantly associated with the rs738409 G allele. Patients with CC genotype showed a lower steatosis score (14.9% ± 3.9) in comparison with the CG genotype (26.3% ± 3.5) and GG genotype (33.3% ± 4.0) (P < 0.005). The proportion of the total variation attributed to rs738409 genotypes was 5.3% (β 0.23 ± 0.07; P < 0.002). Our data suggest that the rs738409 G allele is associated not only with fat accumulation in the liver but also with liver injury, possibly triggered by lipotoxicity.

Supplementary key words SNP • genetics • replication study • PNPLA3 • fatty liver • nonalcoholic steatohepatitis • NASH

Abbreviations: ADPN, adiponutrin; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BMI, body mass index; df, degree of freedom; GGT, glutamyl-transferase; GWAS, genome-wide association studies; HOMA, Homeostasis Model Assessment; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase domain containing 3 gene; SABP, systolic arterial blood pressure; SNP, single nucleotide polymorphism; US, ultrasonographic

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