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

## TL;DR

This study finds that inherited lipid disorders are rare in MASLD patients and may be linked to worse liver health in some cases.

## Contribution

The study evaluates the prevalence and impact of monogenic dyslipidemia variants in a large MASLD cohort.

## Key findings

- 24 out of 3358 MASLD patients carried pathogenic variants in dyslipidemia-related genes.
- APOB carriers showed worse liver steatosis and lower LDL-c and triglycerides compared to controls.
- LDLR carriers had numerically worse outcomes, but differences were not statistically significant.

## Abstract

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.

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.

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.

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.

Genetic variants that cause dysregulation of lipids are not more prevalent among the patients with MASLD, liver diseases driven by metabolic dysfunctions such as lipid accumulation. Some of the variants (e.g., APOB) do increase risk for worse liver histology. Although these variants may explain some of the etiologies in MASLD, additional studies are required to elucidate their role in MASLD.