MTTP gene variants and lomitapide response in a cohort of patients with homozygous familial hypercholesterolemia

Abstract Background: Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder of lipoprotein metabolism caused by pathogenic variants in both alleles of key low-density lipoprotein receptor (LDLR)-mediated pathway genes, resulting in very high LDL cholesterol (LDL-C) levels from birth. The microsomal triglyceride transfer protein (MTTP) inhibitor, lomitapide, is an effective treatment for lowering LDL-C in HoFH that acts independently of LDLR. This study investigated the potential impact of MTTP gene variants on the response to lomitapide treatment in a cohort of patients with HoFH. Methods: Data were extracted from medical records of patients diagnosed with HoFH and receiving treatment with lomitapide in addition to background statin + ezetimibe therapy. Data were collected from patient medical histories, and LDL-C levels before and after lomitapide treatment. Genetic sequencing of all exonic and intronic flanking regions of the MTTP gene was carried out for all patients with genomic DNA isolated whole blood. Results: A total of 13 patients with a diagnosis of HoFH were identified (mean ± standard deviation age, 47.3 ± 17.3 years). In all patients, the median (range) dose of lomitapide was 20 mg/day (10 to 60 mg/day). Median (range) baseline LDL-C at initiation of lipid-lowering treatment (before lomitapide) was 240 mg/dL (162 to 478 mg/dL). Following lomitapide treatment the median (range) LDL-C level was 119 mg/dL (56 to 305 mg/dL), and all patients reported a reduction in LDL-C with lomitapide. A total of 151 MTTP gene variants were identified encompassing 50 distinct variants. There were significantly more variants per patient with LDL-C reduction >50% vs patients with LDL-C reduction ≤50% (P=0.08). Several MTTP gene variants (rs17533489, rs79194015, rs745075, rs41275715, rs1491246, and rs17533517) previously identified as potentially associated with a greater response to lomitapide treatment were significantly more common in patients with a reduction in LDL-C >50% than those with a reduction in LDL-C ≤50% (P<0.001). Conclusions: This study builds upon previous findings by our group suggesting that variants in the MTTP gene may be predictors of response to lomitapide. Further research into the effect of MTTP variants on response to lomitapide is warranted to aid treatment personalization in patients with HoFH.