The frequent PNPLA3 risk variant p.I148 M is associated with decreased pruritus in cholestasis: novel role of a prosteatotic polymorphism
Background and aims: The common PNPLA3 (adiponutrin) variant p.I148 M is associated with severe forms of liver diseases1. Of note, the minor allele [M] at this locus promotes the conversion of lysophosphatidic acid (LPA) into phosphatidic acid (PA)2, resulting in increased cellular diacylglycerol synthesis. Since LPA functions as a mediator of cholestatic pruritus3, we now investigate the effects of the PNPLA3 variant on itching in patients with primary biliary cirrhosis (PBC) and intrahepatic cholestasis of pregnancy (ICP).
Methods: We recruited 186 PBC patients (age range 22 – 83 years, 165 females, 68 with liver cirrhosis) and 201 females with ICP (age range 17 – 46 years). PBC symptoms were quantified with the PBC-27 and PBC-40 questionnaires. The PNPLA3 polymorphism was genotyped using a PCR-based assay with 5′-nuclease and fluorescence detection. Genotype and allele frequencies were compared with PBC- and ICP-free control cohorts (N = 250 and N = 198, respectively).
Results: The PBC patients who tested positive for the ‘gain-of-function’ PNPLA3 allele [M] reported significantly less itching in the PBC-27 (3.4 ± 0.5 vs. 5.1 ± 0.5, P = 0.02) and PBC-40 tests (3.6 ± 0.5 vs. 5.03 ± 0.50, P = 0.05) as compared to homozygous wild-type allele carriers. Of note, the wild-type allele substantially increased the odds (OR = 7.05, P = 0.04) to require plasmapheresis for refractory pruritus. In the ICP patients, the [M] allele was less frequent (19.7%) as compared to controls (27.0%, P < 0.05). Hence, carriers of the [MM] and [IM] genotypes were at reduced risk (OR = 0.58, 95% CI = 0.38 – 0.86, P = 0.007) of symptomatic ICP as compared to the carriers of the common genotype [II].
Conclusions: The PNPLA3 p.I148 M risk allele, previously associated with more severe hepatic phenotypes1, might be associated with decreased pruritus in patients with cholestasis. Conversely, the major allele [I] increases the risk of treatment refractory pruritus. This novel finding could be related to increased acyltransferase activity2 in liver and/or skin, which eventually results in decreased levels of LPA, the critical mediator of pruritus in chronic cholestasis.
 Sookoian et al. Hepatology 2011
 Kumari et al. Cell Metabolism 2012
 Kremer et al. Gastroenterology 2010