Recently the common
adiponutrin (PNPLA3) polymorphism p.I148M has been identified as a genetic determinant of severe forms of
non-alcoholic fatty liver disease and
alcoholic liver disease. Additionally,
insulin resistance - linked to the development of non-
alcoholic steatohepatitis - increases the risk of developing
gallstones. Here we assessed whether the PNPLA3 p.I148M (c.444 C-G) polymorphism affects
glucose and
lipid levels and increases
gallstone risk. We analysed 229 individuals with
gallstones from 108 families (age 24-80 years, BMI 17-55 kg/m(2)) and 258
gallstone-free controls (age 20-70 years, BMI 14-43 kg/m(2)). Fasting
glucose,
triglyceride and
cholesterol serum levels were determined. The p.I148M polymorphism was genotyped using a PCR-based assay with 5'-nuclease and fluorescence detection. Case-control association tests and nonparametric linkage (NPL) analysis in sib-pairs were performed. Individuals carrying the [GG] genotype had significantly (P<0.0001) higher median fasting
glucose levels as compared to [GC] and [CC] carriers. After adjustment for multiple testing, we detected a trend for an association between
triglyceride levels and variant
adiponutrin in
gallstone patients (P=0.032), and
gallstone cases carrying the genotype [CC] presented with significantly higher
triglyceride levels than the corresponding controls (P<0.003). No significant effects on
cholesterol metabolism were detected. Neither genotype distributions nor NPL scores provided evidence for association or linkage between the PNPLA3 variant and
gallstones. In conclusion, homozygous carriers of the PNPLA3 risk allele display higher fasting
glucose. Although this
adiponutrin variant may affect
triglyceride homeostasis, it does not increase the risk of
cholelithiasis.