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Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically

Arteriosclerosis, thrombosis, and vascular biology, 2016-12, Vol.36 (12), p.2439-2445 [Peer Reviewed Journal]

2016 American Heart Association, Inc. ;ISSN: 1079-5642 ;EISSN: 1524-4636 ;DOI: 10.1161/ATVBAHA.116.308027 ;PMID: 27765764

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Title:
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically
Author: Wang, Jian ; Dron, Jacqueline S ; Ban, Matthew R ; Robinson, John F ; McIntyre, Adam D ; Alazzam, Maher ; Zhao, Pei Jun ; Dilliott, Allison A ; Cao, Henian ; Huff, Murray W ; Rhainds, David ; Low-Kam, Cécile ; Dubé, Marie-Pierre ; Lettre, Guillaume ; Tardif, Jean-Claude ; Hegele, Robert A
Subjects: Adult ; Aged ; Biomarkers - blood ; Cholesterol, LDL - blood ; DNA Copy Number Variations ; DNA Mutational Analysis ; Female ; Gene Dosage ; Genetic Markers ; Genetic Predisposition to Disease ; Genetic Testing - methods ; Heredity ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Humans ; Hyperlipoproteinemia Type II - blood ; Hyperlipoproteinemia Type II - diagnosis ; Hyperlipoproteinemia Type II - genetics ; Male ; Middle Aged ; Multifactorial Inheritance ; Mutation ; Ontario ; Phenotype ; Predictive Value of Tests ; Risk Factors ; Severity of Illness Index
Is Part Of: Arteriosclerosis, thrombosis, and vascular biology, 2016-12, Vol.36 (12), p.2439-2445
Description: 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.
Publisher: United States: American Heart Association, Inc
Language: English
Identifier: ISSN: 1079-5642
EISSN: 1524-4636
DOI: 10.1161/ATVBAHA.116.308027
PMID: 27765764
Source: GFMER Free Medical Journals
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Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically

2016 American Heart Association, Inc. ;ISSN: 1079-5642 ;EISSN: 1524-4636 ;DOI: 10.1161/ATVBAHA.116.308027 ;PMID: 27765764

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