Familial Hypercholesterolemia and the Founder Effect Among Franco-Americans: A Brief History and Call to Action

Abstract

Familial hypercholesterolemia (FH) is an inherited disorder characterized by chronically elevated low-density lipoprotein cholesterol levels and an increased risk of premature atherosclerotic cardiovascular disease. FH has been shown to disproportionately affect French Canadians and other ethnic populations due to the presence of a founder effect characterized by reduced genetic diversity resulting from relatively few individuals with FH-causing genetic mutations establishing self-contained populations. Beginning in the mid-1800s, approximately 1 million French Canadians immigrated to the Northeastern United States and largely remained in these small, tight-knit communities. Despite extensive genetic- and population-based research involving the French-Canadian founder population, primarily in the Province of Quebec, little is known regarding Franco-Americans in the United States. Concurrent with addressing the underdiagnosis rate of FH in the general population, we propose the following steps to leverage this founder effect and meet the cardiovascular needs of Franco-Americans: (1) increase cascade screening in regions of the United States with a high proportion of individuals of French-Canadian descent; (2) promote registry-based, epidemiological research to elucidate accurate prevalence estimates as well as diagnostic and treatment gaps in Franco-Americans; and (3) validate contemporary risk stratification strategies such as the Montreal-FH-SCORE to enable optimal lipid management and prevention of premature atherosclerotic cardiovascular disease among French-Canadian descendants.

Figure 1

Summarized representation of the origins of the Franco-American founder subpopulation and proposed recommendations for the diagnosis and treatment of familial hypercholesterolemia (FH) and prevention of premature atherosclerotic cardiovascular disease (ASCVD).

Figure 2

Genealogical origins of Cajuns/Acadians in Atlantic Canada (blue) and migration of French-Canadians (magenta) to the United States. Reproduced from Han et al., and data were made available in the public domain (Creative Commons CCO).

Figure 3

Canadian definition for the clinical diagnosis of FH. Secondary causes of high LDL-C should be ruled out (severe or untreated hypothyroidism, nephrotic syndrome, hepatic disease [biliary cirrhosis], and medication, especially antiretroviral agents). ∗∗Causal DNA mutation refers to the presence of a known FH-causing variant in the LDLR, APOB, or PCSK9 gene on the basis of presence of the variant in ClinVar, the Human Gene Mutation Database, or Western Database of Lipid Variants databases, in the proband or a first-degree relative. ASVD, atheroslcerotic vascular disease; LDL-C, low-density lipoprotein cholesterol. Reproduced from Ruel et al. with permission of Elsevier.