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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Evaluation of Pathogenic Variants Associated With Monogenic Disorders of Dyslipidemia in Patients With Well
Tae-Hwi Schwantes-An1, Marco A Abreu1, Brent A Neuschwander-Tetri2
1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
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.
Insights
Monogenic dyslipidemia disorders are uncommon in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, carriers of certain pathogenic variants, like those in APOB, showed worse liver histology and altered lipid profiles.
Area of Science:
- Genetics and Genomics
- Hepatology
- Cardiology
Background:
- Dyslipidemia is prevalent in MASLD patients, but inherited dyslipidemia disorders are poorly understood.
- The frequency and clinical significance of monogenic dyslipidemia in MASLD require investigation.
Purpose of the Study:
- To determine the prevalence of pathogenic variants for monogenic dyslipidemia in MASLD patients.
- To assess the impact of these variants on liver histology and lipid profiles.
Main Methods:
- Genotyping for variants in APOB, MTTP, PCSK9, ANGPTL3, LDLR, and LDLRAP1 genes.
- Analysis of liver histology, liver enzymes, and lipid profiles in variant carriers versus matched controls.
Main Results:
- Pathogenic variants were found in 24 of 3358 MASLD patients (0.7%).
- APOB variant carriers exhibited higher steatosis grade and NAS, with significantly lower LDL-c and triglycerides.
- LDLR variant carriers showed trends towards worse liver parameters and higher LDL-c, but without statistical significance.
Conclusions:
- Monogenic dyslipidemia disorders are rare in MASLD.
- APOB variant carriers may experience more severe liver disease.
- Genetic testing for monogenic dyslipidemia in MASLD patients should be considered selectively.
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