Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically

Abstract

F amilial hypercholesterolemia (FH) is a relatively common disorder, previously thought to have a monogenic basis. 1 The paradigmatic heterozygous form of FH (HeFH) is characterized by lifelong elevations in plasma low-density lipoprotein (LDL) cholesterol, typically >5.0 mmol/L (194 mg/dL), sometimes occurring with characteristic physical signs and frequently with a personal or family history of early cardiovascular disease (CVD).1 Recent populationbased surveys, including screening with DNA sequencing, suggest that HeFH has a prevalence of ≈1 in 217 individuals in Northern Europe.2 Large-scale whole-exome sequencing efforts indicate that ≈4% of individuals with early coronary heart disease have HeFH resulting from one of several lossof-function mutations in the LDLR gene encoding the LDL receptor.3 Other large-scale sequencing efforts indicate that within subgroups of individuals with severe hypercholesterolemia, defined as untreated LDL cholesterol >5.0 mmol/L (>194 mg/dL), only ≈2% had a pathogenic mutation in an autosomal dominant FH gene. Objective-Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic. Approach and Results-We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5.0 mmol/L (>194 mg/dL). We found that (1) monogenic familial hypercholesterolemia-causing mutations detected by targeted next-generation sequencing were present in 47.3% of individuals; (2) the percentage of individuals with monogenic mutations increased to 53.7% when copy number variations were included; (3) the percentage further increased to 67.1% when individuals with extreme polygenic scores were included; and (4) the percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as low-density lipoprotein cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL). Conclusions-In a clinically ascertained sample with severe hypercholesterolemia, we found that most patients had a discrete genetic basis detected using a comprehensive screening approach that includes targeted next-generation sequencing, an assay for copy number variations, and polygenic trait scores.

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

“…The overall detection rate of pathogenic/likely pathogenic variants was around 60%, a figure which is comparable to that obtained in other studies [12,13]. The assignment of pathogenicity was based on in silico analysis using several algorithms [4] and information available in the published variant databases.…”

“…Several reports have shown that a variable percentage (20e40%) of patients with the clinical diagnosis of heterozygous FH do not carry mutations in the candidate genes mentioned above [12]. Some of these patients were found to carry a burden of LDL-cholesterol (LDL-C) increasing gene variants which cumulatively raise LDL-C levels into the heterozygous FH range [12,13]. However, there are patients in whom the polygenic effect does not explain the high LDL-C levels, indicating the possible presence of other genes yet to be identified [13].…”

Eligibility for alirocumab or evolocumab treatment in 1090 hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol ≥70 mg/dL despite maximal-tolerated LDL-cholesterol-lowering therapy

“…Large-scale, whole-exome sequencing studies suggest that HeFH has a prevalence of ~1 in 217 (0.46%) northern European individuals 39. At the upper end of the number of patients with HeFH eligible for ALI or EVO, in 313 patients with severe hypercholesterolemia (LDLC >194 mg/dL), Wang et al40 reported that 47.3% had monogenic familial hypercholesterolemia, 53.7% if polygenic scores were present, and 67.1% with extreme polygenic scores.…”

Recent Advances in the Genetics of Atherothrombotic Disease and Its Determinants

“…53 For instance, in 313 patients with FH who were evaluated using a targeted next-generation sequencing panel and an assay to detect large-scale copy-number variation, Wang et al 54 found a genetic basis for extremely elevated LDL-C in ≈67% of patients. Of these individuals, 45% had a monogenic largeeffect variant, 6% had a copy-number variation, and 17% had a strong polygenic component, as defined by accumulation of common GWAS-identified SNPs associated with LDL-C levels.…”

“…Of these individuals, 45% had a monogenic largeeffect variant, 6% had a copy-number variation, and 17% had a strong polygenic component, as defined by accumulation of common GWAS-identified SNPs associated with LDL-C levels. 54 Thus, several types of genetic variants need to be considered when assessing patients with elevated LDL-C, including those contributing to both monogenic and polygenic risk. 55 Furthermore, in clinical assessment of patients with severe hypercholesterolemia, it is critical to rule out the contribution of secondary factors, 56 including drugs such as cyclosporine, which can raise LDL-C through both LDL receptor and nonreceptor mechanisms.…”