Evaluation of Pathogenic Variants Associated With Monogenic Disorders of Dyslipidemia in Patients With Well Characterised MASLD

BACKGROUND AND AIMS: Dyslipidemia is common in patients with MASLD, but the frequency and significance of inherited disorders of dyslipidemia are unclear. We investigated the prevalence and significance of pathogenic variants associated with selected monogenic disorders of dyslipidemia in 3358 patients with well-characterised MASLD. APPROACH: We identified clinically relevant variants in APOB, MTTP, PCSK9, ANGPTL3, LDLR and LDLRAP1 genes which can cause hypobetalipoproteinemia (HBL) and familial hypercholesterolemia (FH). Using ClinVar annotations as initial variant selection, we identified 2027 variants in those 6 genes which are reported as 'pathogenic' or 'likely pathogenic' (P/LP). We first assessed for the presence of P/LP variants in the study cohort and then investigated the effect of carrying P/LP variants on liver histology, by comparing ~4 matched controls for each APOB and LDLR carrier. As interpretative analyses, we also looked at the difference between liver enzymes, lipid measures and outcomes between the carriers and matched controls. RESULTS: Twenty-two variants among these 2027 P/LP variants were present in 24 out of 3358 patients (12 ApoB, 10 LDLR, 1 ANGPTL3 and 1 MTTP variant carriers). Compared to controls, APOB carriers had higher steatosis grade (2.4 vs. 1.7, p-value 0.0028), higher NAFLD activity score (NAS) (4.9 vs. 3.8, p-value 0.04), and numerically higher but statistically not significant fibrosis stage (1.2 vs. 1.1, p-value 0.75) and ALT (87.4 vs. 58.1 U/L, p-value 0.06). Their LDL-c (51 vs. 147.8 mg/dL, p-value 6.1E-09) and triglycerides (91.5 vs. 160.6 mg/dL, p-value 2.8E-03) were significantly lower. Compared to controls, LDLR carriers had numerically higher steatosis grade, NAS, fibrosis stage and LDL-c levels, but these were not statistically different. CONCLUSIONS: Monogenic disorders of dyslipidemia are rarely present in patients with MASLD and are sometimes associated with worse liver histology. Testing for these conditions may be considered on a case-by-case basis.