Genetic variation at PPP1R3B increases hepatic CT attenuation and interacts with prandial status on plasma glucose

Abstract

Context: A common genetic variant near PPP1R3B (rs4841132G > A) has been associated withincreased hepatic computed tomography (CT) attenuation and with plasma levels of glucoseand liver enzymes.Objective: To elucidate the association of rs4841132 with hepatic CT attenuation, and to test ifsynergistic effects modify the association of the variant with plasma glucose and liver enzymes.Design: Population-based cohort study.Setting and Participants: The Copenhagen City Heart Study and the Copenhagen GeneralPopulation Study combined, totaling 107 192 individuals from the Danish general population.Hepatic CT scans were available in 6445 individuals.Main Outcome Measures: Hepatic CT attenuation and plasma levels of glucose and liverenzymes.Results: The rs4841132 A-allele (rs4841132-A) was associated with higher hepatic CT attenuation(P = 5 × 10-6). The probability of carrying rs4841132-A increased with higher hepatic CT attenuationin the range above 65 Hounsfield units, but remained constant at the range below (P = 4 × 10-8 fornonlinearity). Rs4841132-A was associated with up to 0.17 mmol/L higher plasma glucose in fastingindividuals, but with up to 0.17 mmol/L lower glucose in postprandial individuals (P = 6 × 10-5 forinteraction between rs4841132 and time since last meal on plasma glucose). Finally, rs4841132-Awas associated with up to 2 U/L higher plasma alanine transaminase (P = 3 × 10-6). This associationwas not modified by adiposity, alcohol intake, or steatogenic genetic risk.Conclusions: Rs4841132-A associates with higher hepatic CT attenuation in a distinctlynonlinear manner, and its association with plasma glucose depends on prandial status. Theoverall association pattern supports that rs4841132-A promotes hepatic glycogen synthesispostprandially.