Genetic Variation at PPP1R3B Increases Hepatic CT Attenuation and Interacts With Prandial Status on Plasma Glucose

Abstract

Abstract Context A common genetic variant near PPP1R3B (rs4841132G > A) has been associated with increased hepatic computed tomography (CT) attenuation and with plasma levels of glucose and liver enzymes. Objective To elucidate the association of rs4841132 with hepatic CT attenuation, and to test if synergistic 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 General Population 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 liver enzymes. 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 attenuation in the range above 65 Hounsfield units, but remained constant at the range below (P = 4 × 10−8 for nonlinearity). Rs4841132-A was associated with up to 0.17 mmol/L higher plasma glucose in fasting individuals, but with up to 0.17 mmol/L lower glucose in postprandial individuals (P = 6 × 10−5 for interaction between rs4841132 and time since last meal on plasma glucose). Finally, rs4841132-A was associated with up to 2 U/L higher plasma alanine transaminase (P = 3 × 10−6). This association was not modified by adiposity, alcohol intake, or steatogenic genetic risk. Conclusions Rs4841132-A associates with higher hepatic CT attenuation in a distinctly nonlinear manner, and its association with plasma glucose depends on prandial status. The overall association pattern supports that rs4841132-A promotes hepatic glycogen synthesis postprandially.