Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.
Inherited factors play a major role in the predisposition to nonalcoholic fatty liver disease (NAFLD), and the rs738409 C-->G polymorphism of PNPLA3/adiponutrin, encoding for the isoleucine-to-methionine substitution at residue 148 (I148M) protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P = 0.001). In Italian and United Kingdom patients, adiponutrin genotype influenced alanine aminotransferase levels and the severity of steatosis. Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule Fas ligand. In the whole series combined, adiponutrin genotype was associated with steatosis grade >1 (OR = 1.35, 95% CI = 1.04-1.76), nonalcoholic steatohepatitis (OR = 1.5, 95% CI = 1.12-2.04), and fibrosis stage >1 (OR = 1.5, 95% CI = 1.09-2.12), independent of age, body mass index, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes.


CONCLUSIONS
In patients with NAFLD, adiponutrin rs738409 C-->G genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis.
Valenti
Luca
L
Department of Internal Medicine, Università degli Studi Milano, UO Medicina Interna 1B, Fondazione Ospedale Policlinico MaRE Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
Al-Serri
Ahmad
A
Daly
Ann K
AK
Galmozzi
Enrico
E
Rametta
Raffaela
R
Dongiovanni
Paola
P
Nobili
Valerio
V
Mozzi
Enrico
E
Roviaro
Giancarlo
G
Vanni
Ester
E
Bugianesi
Elisabetta
E
Maggioni
Marco
M
Fracanzani
Anna Ludovica
AL
Fargion
Silvia
S
Day
Christopher P
CP
D000328:Adult; D000368:Aged; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008103:Liver Cirrhosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent