The Prkar1b P.R115k Variant Is Associated With Lipoprotein Profile In African American Youth With Metabolic Challenges

Context: High childhood obesity rates coincide with increased incidence of nonalcoholic fatty liver disease (NAFLD) and other comorbidities. Understanding the genetics of susceptibility to obesity and its comorbidities could guide intervention.The cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) signaling pathway regulates energy balance, glucose homeostasis, and lipid metabolism.Objective: We hypothesized that PKA-related gene variants may be associated with obesity or associated metabolic conditions.Methods: We included 457 youths from theYale Obesity Clinic into the Pathogenesis of Youth-Onset Diabetes cohort (NCT01967849); a variety of clinical tests were performed to characterize NAFLD. Exon sequencing of 54 PKA pathway genes was performed. Variants were confirmed by Sanger sequencing. Clinical data were analyzed, correcting for NAFLD status and body mass index z-score with adjustments for multiple comparisons. Fluorescence resonance energy transfer (FRET) and PKA enzymatic assays were performed in HEK293 cells transfected with the PRKAR1B p.R115K construct. In silico structural analysis for this variant was done.Results: We identified the variant PRKAR1B p.R115K in 4 unrelated, African American patients. Analyses compared this variant group to other African American patients in the cohort. PRKAR1B p.R115K was associated with favorable circulating lipoprotein levels. Analysis of FRET and PKA enzymatic assay showed stronger interaction between the R1 beta mutant and PKA catalytic subunit Ca and decreased basal PKA activity compared with the wildtype (P< .0001). Structural analysis revealed that p.R115K may hinder conformational changes resulting from cAMP binding at cAMP binding domain A.Conclusion: Data suggest PRKAR1 B p.R115K affects cAMP signaling and may favorably modulate lipoprotein profile in African American youth, protecting them from some adverse metabolic outcomes.