Background and Aims

Background:

The identification of genetic factors responsible for familial hypobetalipoproteinemia (FHBL), such as APOB, PCSK9 or ANGPTL3, has led to the development of lipid lowering drugs. 30 to 50% of patients with LDL-c <5^th percentile present with mutations in causal FHBL genes, while a polygenic origin is suspected for the others. Liver steatosis is the main complication of FHBL.

Aims:

This study aims at evaluating the spectrum of genetic factors that drive LDL-c to very low levels in order to: i) assess consequences on plasma lipids and liver enzymes and ii) identify polygenic FHBL patients for genetic research purposes.

Methods

127 patients with LDL-c<5^th percentile adjusted for age and sex were recruited. Targeted-next generation sequencing was performed to screen for monogenic forms of FHBL. A 12-SNPs polygenic risk score (PRS) has been calculate for all patients and 856 matched-population controls. Chronic liver disease was assessed by liver panel test (ALT, AST, GGT).

Results

41(32%) patients carried a monogenic FHBL. Patients without mutation present a significant lower PRS than controls (p<1.0e-08) whereas no difference was observed between mutation-carriers and controls (p=0.83). 36 (28%) patients display polygenic predispositions for hypocholesterolemia. While mutation carriers did not have lower plasma LDL-c, they had more frequently chronic liver disease (ALT: P<0.01; GGT<0.01) than patients with polygenic FHBL.

Conclusions

Our study shows an important polygenic origin for FHBL that can phenocopy the effect of monogenic forms on plasma LDL-c levels. However, patients with polygenic FHBL present a decreased risk for chronic liver disease than mutation carriers.