Abstract 1922: APOA5 Missense Mutations Associated with Chylomicronemia Sensitive to Fibrate Therapy
Apolipoprotein A5 (APOA5) was recently identified as a major regulator of plasma triglycerides (TG) with specific roles still debated in human. We describe a patient, APOA5 compound heterozygote for a novel A239D mutation altering the heparin-binding domain and for the common signal-peptide S19W variant, previously found associated with high plasma TG and low APOA5 expression in liver. 12h fasting plasma APOA5 was measured by ELISA (Genfit). LPL activity was measured by spectrofluorimetry (Progen). APOA5, APOE and LPL genes were analyzed by DNA sequencing (ABI 3130, Applera) and sequences interpreted with Gensearch (Phenosystems). Genomic rearrangements were analysed by MLPA (MRC-Holland) The patient, a 48-yr old woman free of CVD, had personal history of cholecystectomy, liver steatosis, and metabolic syndrome treated since age 38 with fibrates. Upon medication interruption, she had acute pancreatitis, chylomicronemia, plasma TG =40 mmol/L, and low LPL activity (≥20% LLN). Plasma ApoA5 conc. (2781 ng/ml) was >10X normal (200 ng/ml), however twice lower that of a LPL deficient patient (G188E LPL homozygote; TG= 35 mmol/L, ApoA5= 4281 ng/ml, LPL act. <5% LLN). The LPL gene was normal, and APOE genotype was E2E3. Fasting plasma TG were unchanged by statin or fish-oil therapy, but were steadily controlled below 3 mmol/lL under fibrate monotherapy over 10yrs (see figure⇓ below). Partial APOA5 deficiency may cause chylomicronemia, pancreatitis, lowered plasma LPL and ApoA5, all strongly responsive to fibrate therapy, a feature useful for diagnosis. This points APOA5 as a PPAR-alpha sensitive regulator of TG-rich lipoproteins in human.