Relationship between Genetic Variation at PPP1R3B and Liver Glycogen and Triglyceride Levels

Abstract

Genetic variation at rs4240624 on chromosome 8 is associated with an attenuated signal on hepatic computerized tomography (CT), which has been attributed to changes in hepatic fat. The closest coding gene to rs4240624, PPP1R3B, encodes a protein that promotes hepatic glycogen synthesis. Here we performed studies to determine if the X-ray attenuation associated with rs4240624 is due to changes in hepatic glycogen or hepatic triglyceride content (HTGC). A sequence variant in complete linkage disequilibrium (LD) with rs4240624, rs4841132, was genotyped in the Dallas Heart Study (DHS), the Dallas Liver Study, and the Copenhagen Cohort (n=112,428) of whom 1,539 had non-viral liver disease. The minor A-allele of rs4841132 was associated with increased hepatic X-ray attenuation (n=1,572, P=4 × 10⁻⁵), but not with HTGC (n=2,674, P=0.58). Rs4841132-A was associated with modest, but significant elevations in serum ALT in the Copenhagen Cohort (P=3x10⁻⁴) and the DHS (P=0.004), and with odds ratios for liver disease of 1.13 (95% CI, 0.97-1.31) and 1.23 (1.01-1.51), respectively. Mice lacking PPP1R3B were deficient in hepatic glycogen, whereas HTGC was unchanged. Hepatic overexpression of PPP1R3B caused accumulation of hepatic glycogen and elevated plasma levels of ALT, but did not change HTGC. Conclusion: These observations are consistent with the notion that the minor allele of rs4841132 promotes a mild form of hepatic glycogenosis that is associated with hepatic injury. This article is protected by copyright. All rights reserved.

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