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Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride
Author(s) -
Stender Stefan,
Smagris Eriks,
Lauridsen Bo K.,
Kofoed Klaus F.,
Nordestgaard Børge G.,
TybjærgHansen Anne,
Pennacchio Len A.,
Dickel Diane E.,
Cohen Jonathan C.,
Hobbs Helen H.
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29751
Subject(s) - medicine , endocrinology , minor allele frequency , biology , glycogen , triglyceride , liver disease , linkage disequilibrium , allele , haplotype , allele frequency , gene , cholesterol , biochemistry
Genetic variation at rs4240624 on chromosome 8 is associated with an attenuated signal on hepatic computerized tomography, 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 whether the x‐ray attenuation associated with rs4240624 is due to differences in hepatic glycogen or hepatic triglyceride content (HTGC). A sequence variant in complete linkage disequilibrium 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 nonviral 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 alanine aminotransferase (ALT) in the Copenhagen Cohort ( P = 3 × 10 –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 protein phosphatase 1 regulatory subunit 3B (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. (H epatology 2018;67:2182‐2195).