TY - JOUR
T1 - Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride
AU - Stender, Stefan
AU - Smagris, Eriks
AU - Lauridsen, Bo K.
AU - Kofoed, Klaus F.
AU - Nordestgaard, Børge G.
AU - Tybjærg-Hansen, Anne
AU - Pennacchio, Len A.
AU - Dickel, Diane E.
AU - Cohen, Jonathan C.
AU - Hobbs, Helen H.
N1 - Funding Information:
Received August 15, 2017; accepted December 18, 2017. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.29751/suppinfo. S.S. was supported by a Sapere Aude grant from the Danish Medical Research Council (4004-00398). J.C.C. and H.H.H. were supported by grants from the National Institutes of Health (RO1 DK090066 and PO1 HL20948). Copyright VC 2017 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.29751
Funding Information:
Acknowlegments: We thank Fang Xu, Liangcai Nie, and Vanessa Schmid for excellent technical assistance, Mohammed Kanchwala for analyzing the RNA-sequencing data, and Dermot Reilly (Merck, Inc.) for providing us data from the MGH-liver eQTL database. This work was supported by National Institutes of Health grants to R24HL123879, R01HG003988, and UM1HG009421, and research was conducted at the E.O. Lawrence Berkeley National Laboratory and performed under Department of Energy Contract DE-AC02-05CH11231, University of California.
Funding Information:
We thank Fang Xu, Liangcai Nie, and Vanessa Schmid for excellent technical assistance, Mohammed Kanchwala for analyzing the RNA-sequencing data, and Dermot Reilly (Merck, Inc.) for providing us data from the MGH-liver eQTL database. This work was supported by National Institutes of Health grants to R24HL123879, R01HG003988, and UM1HG009421, and research was conducted at the E.O. Lawrence Berkeley National Laboratory and performed under Department of Energy Contract DE-AC02-05CH11231, University of California.
Publisher Copyright:
© 2017 by the American Association for the Study of Liver Diseases.
PY - 2018/6
Y1 - 2018/6
N2 - 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. (Hepatology 2018;67:2182-2195).
AB - 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. (Hepatology 2018;67:2182-2195).
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U2 - 10.1002/hep.29751
DO - 10.1002/hep.29751
M3 - Article
C2 - 29266543
AN - SCOPUS:85042730750
VL - 67
SP - 2182
EP - 2195
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 6
ER -