Journal of Lipid Research
Volume 50, Issue 10, October 2009, Pages 2111-2116
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Patient-Oriented and Epidemiological Research
A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity

https://doi.org/10.1194/jlr.P900013-JLR200Get rights and content
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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 × 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.

SNP
genetics
replication study
PNPLA3
fatty liver
nonalcoholic steatohepatitis
NASH

Cited by (0)

This work was supported in part by grants UBACYT M055 (Universidad de Buenos Aires), PICT 05-25920 and PICT 2006-124 (Agencia Nacional de Promoción Científica y Tecnológica) and Consejo de Investigación de la Ciudad Autonóma de Bs.As. SS, ALB and CJP belong to Consejo Nacional de Investigaciones Científicas (CONICET).

    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