PNPLA3/adiponutrin genotype is strongly associated with metabolic syndrome components and liver damage in patients with Nonalcoholic Fatty Liver Disease
Abstract
Data di Pubblicazione:
2009
Abstract:
Background: Inherited factors play a major role in the predisposition
to develop nonalcoholic fatty liver disease (NAFLD),
the hepatic manifestation of the metabolic insulin resistance syndrome
and a leading cause of liver disease. Recently, genomewide
association studies identified the I148M single nucleotide
polymorphism (SNP) of the phospholipase PNPLA3 expressed
in the liver and adipose tissue (also known as adiponutrin) as
the principal determinant of liver fat content and ALT levels at
population level. However, the function of PNPLA3 is still
unknown, and the effect of the I148M SNP on histological liver
damage has not been evaluated. Aim: To determine whether
the I148M PNPLA3 SNP is associated with liver damage in Italian
patients with NAFLD. Methods: 261 patients with complete
metabolic and histological characterization, and 179 healthy
controls with normal liver enzymes and metabolic parameters.
The I148M PNPLA3 SNP was determined by Taqman assay
(Applied Biosystems). Liver histology was scored according to
Kleiner. Hepatic expression of FasL, proapoptotic molecule
induced by NASH and insulin resistance, was evaluated by
qRT-PCR in 52 patients. Results: the prevalence of the mutant
M148 allele was significantly higher in patients vs. controls
(41%II 45%IM 14%MM vs. 66%II 31%IM 3%MM, p<.0001).
In patients with NAFLD, despite similar age, sex distribution,
and BMI, the M148 allele was associated with dyslipidemia
(higher triglycerides, and lower HDL cholesterol), and insulin
resistance (insulin, HOMA-R index) in a dose-dependent manner
(p<.0001 for each comparison). In addition, the M148
allele was associated with higher ALT (33±23II 45±39IM
69±54MM, p<.0001), but not GGT levels, and higher histological
severity of steatosis (24±24%II 30±25%IM
37±27%MM, p=.03). Homozygosity for the M148 allele was
associated with significantly higher steatosis grade, necroinflammation,
and ballooning (p<.05), and higher prevalence of
fibrosis stage > 1 (10.6%II 18.2%IM 32.4%MM, p=.008) and
> 2 (4.4%II 6.6%IM 18.9%MM, p=.01), and with significantly
higher FasL expression (.8±.7 II, 1±.8 IM, 1.7±1.2 MM,
HEPATOLOGY, VOLUME 50, NUMBER 4 (SUPPL) AASLD ABSTRACTS 765A
p=.02). The association between the 148MM genotype and
fibrosis>1 (OR 2.33 95%CI 1.3-4.1) and fibrosis>2 (OR 3.82
95%CI 1.6-9.4) was independent of age, BMI, and diabetes.
Conclusion: the I148M PNPLA3 SNP is strongly associated with
metabolic syndrome components and liver damage in patients
with NAFLD. PNPLA3 likely plays a pivotal role in the progression
of liver damage in NAFLD.
Tipologia CRIS:
04E-Meeting abstract in rivista
Elenco autori:
L. Valenti; E. Galmozzi; P. Dongiovanni; R. Rametta; E. Lattuada; M. Zappa; E. Mozzi; G. Roviaro; M. Maggioni; E. Vanni; E. Bugianesi; A. L. Fracanzani; S. Fargion
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