Clinical Expression of Familial Hypercholesterolemia in Patients from France and French Canada Carrying Identical-by-Descent Pathogenic LDLR Gene Variants: A Proof-of-Concept Study

Abstract

Background: Studying patients carrying identical-by-descent (IBD) pathogenic gene variants allows us to control for the disease-causing genetic background and to more accurately document the impact of modifiers. Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels and premature atherosclerosis and is often caused by defects in the LDLR gene. There is a high prevalence of FH in French Canada as a result of a founder effect from France in the 17th century. Several FH patients currently living in French Canada (founder population) and in France (colonizing population) carry IBD FH-causing variants. The expression of FH is affected by environmental and genetic modifiers, and patients with IBD variants may present different characteristics. Methods: In this study, we compared FH clinical expression patients carrying IBD LDLR pathogenic variants living in France or Canada. Four IBD variants, namely c.259T>G p.(Trp87Gly), c.2000G>A p.(Cys667Tyr), c.682G>A p.(Glu228Lys), and c.1048C>T p.(Arg350*), were selected. Untreated plasma lipid profiles, the apolipoprotein E (APOE) genotype, cardiovascular risk factors, and the occurrence of symptomatic ASCVD were compared in 105 adult carriers (30 from France and 75 from French Canada). Results: All parameters were similar between the two populations, except for untreated total cholesterol (10.14 ± 1.89 mmol/L vs. 8.65 ± 1.84 mmol/L, p = 0.0006) and LDL-c concentrations (7.94 ± 1.86 mmol/L vs. 6.93 ± 1.78 mmol/L, p = 0.016), which were significantly higher in FH patients living in France, an observation that was revealed across all studied LDLR variants. Conclusions: This study illustrates that FH patients sharing IBD pathogenic LDLR variants that have evolved in different geographic, cultural, and socio-economic environments for hundreds of years differ in terms of cholesterol levels, highlighting the importance of better understanding the interplay between genetic and environmental modulators of FH expression.

Keywords: familial hypercholesterolemia; founder effect; identical-by-descent variant.

Figure 1

Baseline (untreated) total cholesterol and LDL-cholesterol levels in FH carriers of identical-by-descent (IBD) pathogenic LDLR gene variants in 75 FH patients from the French-Canadian founder population and 30 patients from France (colonizing population). Patients from both countries carried either the c.259T>G p.(Trp87Gly) rs121908025, c.2000G>A p.(Cys667Tyr) rs28942083, c.682G>A p.(Glu228Lys) rs121908029, or c.1048C>T p.(Arg350*) rs769737896 LDLR gene variants, all pathogenic, having a proven French founder effect and having evolved in a different environment for 4 centuries. Both groups were comparable for ApoE genotype, smoking habits, anthropometric measurements, diabetes, and other cardiovascular risk factors. Patients were matched for age and sex (≥3:1 for the p.(Trp87Gly) variant). Baseline cholesterol levels were significantly lower among French-Canadians in all genotypes (see text).