Genetic basis of hypercholesterolemia in adults

Abstract

We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.

The burden of severe hypercholesterolemia and familial hypercholesterolemia in a population-based setting in the US

“…Our results highlight potential strategies to reduce the burden of ASCVD from SH: at the individual level, increasing awareness of the risk from SH, and adopting healthy lifestyle choices (AHA's Simple 7) [5] ; at the provider level, such as by clinical decision support that encourages achievement of target LDL-C levels [33] ; and at the population level, such as the Million Hearts initiative [34] . In the subset of patients with FH, cascade testing of family members may enable early detection and treatment [ 35 , 36 ]. An important finding of our study is the relatively low proportion of individuals reaching goal LDL-C levels despite relatively high use of LLT.…”

A pragmatic implementation research study for In Our DNA SC: a protocol to identify multi-level factors that support the implementation of a population-wide genomic screening initiative in diverse populations

“…A Tier 1 designation indicates that there is sufficient evidence and that established interventions are available to reduce morbidity and mortality of individuals who are identified with these conditions. Combined, Tier 1 conditions affect 1-2% of the US population; however, few know their risk or receive information about their genetic condition at the time of disease diagnosis [3][4][5][6].…”

LDL-C Concentrations and the 12-SNP LDL-C Score for Polygenic Hypercholesterolaemia in Self-Reported South Asian, Black and Caribbean Participants of the UK Biobank

“…The validity of this score has been confirmed in samples of no-mutation FH adults and children from more than 8 countries with White European populations ( Futema et al, 2018 ). Other studies applied the score to define a polygenic cause of high LDL-C in patients with hypercholesterolaemia ( Amor-Salamanca et al, 2017 ; Saadatagah et al, 2021 ). Two of the current NHS Genomic Laboratory Hubs (GLHs) (South West and North East) are including the 12-SNP score within their diagnostic pipelines ( George et al, 2021 ), demonstrating feasibility of implementation.…”