Protein Phosphatase 1 Regulatory Subunit 3B Genotype at rs4240624 Has a Major Effect on Gallbladder Bile Composition.

The protein phosphatase 1 regulatory subunit 3B () gene is a target of farnesoid X receptor (), which is a major regulator of bile acid metabolism. Both and have been suggested to take part in glycogen metabolism, which may explain the association of gene variants with altered hepatic computed tomography attenuation. We analyzed the effect of rs4240624 variant on bile acid composition in individuals with obesity. The study cohort consisted of 242 individuals from the Kuopio Obesity Surgery Study (73 men, 169 women, age 47.6 ± 9.0 years, body mass index 43.2 ± 5.4 kg/m) with genotype and liver RNA sequencing (RNA-seq) data available. Fasting plasma and gallbladder bile samples were collected from 50 individuals. Bile acids in plasma did not differ based on the rs4240624 genotype. However, the concentration of total bile acids (109 ± 55 vs. 35 ± 19 mM;  = 1.0 × 10) and all individual bile acids (also 7α-hydroxy-4-cholesten-3-one [C4]) measured from bile were significantly lower in those with the AG genotype compared to those with the AA genotype. In addition, total cholesterol ( = 0.011) and phospholipid ( = 0.001) levels were lower in individuals with the AG genotype, but cholesterol saturation index did not differ, indicating that the decrease in cholesterol and phospholipid levels was secondary to the change in bile acids. Liver RNA-seq data demonstrated that expression of , tankyrase (), chromosome 8 clone RP11-10A14.5 ( []), chromosome 8 clone RP11-375N15.1 (), and chromosome 8, clone RP11-10A14 () associated with the genotype. In addition, genes enriched in transmembrane transport and phospholipid binding pathways were associated with the genotype. The rs4240624 variant in has a major effect on the composition of gallbladder bile. Other transcripts in the same loci may be important mediators of the variant effect.