Prevalence, genotype and phenotype of familial hypercholesterolemia in 10,194 Finnish men

Abstract

Abstract Background Familial hypercholesterolemia (FH) is the most frequent monogenic disease with an estimated prevalence of 1:250. The prevalence of different variants varies widely between the populations. According to previous studies, the prevalence of heterozygous FH in Finland has been reported to be 1:400–650, seven Finnish LDLR founder mutations having been considered to cause 80% of FH. Purpose To investigate the genetics of FH in the large Finnish population-based study. Methods The whole exome sequencing using Next Generation Sequencing method was performed for 10,194 men from eastern Finland who participated in the METSIM (Metabolic Syndrome in Men) study. The findings were confirmed by Sanger sequencing. The coding regions of the FH causing genes LDLR, APOB and PCSK9 were sequenced. The pathogenicity of the variants was classified according to the ACMG guidelines, and using the Genome Aggregation Database (gnomAD), and the ClinVar archive. Results Total 22 individuals of 10,194 carry 8 different pathogenic/likely pathogenic (P/LP) FH variants (7 LDLR variants, 1 APOB variant and 0 PCK9 variants). Seven LDLR gene variants classified as P/LP were detected in 21 individuals. Two of the seven variants are founder mutations (p.Pro309Lysfs*59, p.Arg595Gln), four are other previously reported variants (p.Arg124Trp, p.Glu228*, p.Asp266Asn, p.Asp445Glu) and one is a novel variant (p.Gly396Ala). Of the 21 individuals carrying P/LP LDLR variants, 16 carry founder mutations and five other P/LP LDLR variants. Of individuals carrying any P/LP LDLR variant, 28.6% had premature (men <55 years, women <60 years) atherosclerotic cardiovascular disease (CVD): coronary artery disease (CAD) 28.6%, peripheral artery disease (PAD) 0.0%, and stroke or TIA 0.0%. CVD at any age was diagnosed in 38.1% (CAD 33.3%, PAD 4.8%, stroke or TIA 9.5%). Only one individual from 10,194 carry APOB variant which is classified as P/LP. The detected APOB variant is a previously reported variant (p.Gln4494del). None of the 10,194 individuals carry P/LP PCSK9 variants. Thus, the prevalence of P/LP FH variants in the population from eastern Finland was 0.22%, 1 in 463.4 (LDLR variants 0.21%, 1 in 485; APOB variants 0.01%, 1 in 10 194). Of the P/LP variant carriers, 72.7% carry founder mutation of the LDLR, and 27.3% carry other LDLR and APOB variants. Conclusions The prevalence of heterozygous FH in the population-based study of 10,194 men from eastern Finland was 1 in 463.4, which is about the same as previously reported. LDLR variants accounted for the majority of FH cases, and although previously reported Finnish LDLR founder mutations were common, about 30% of the mutations detected were other LDLR and APOB variants. Pathogenic/likely pathogenic APOB variants were, however, rare and PCSK9 variants were not found. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Kuopio university hospital