Abstract
AbstractWe 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.
Funder
U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute
U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
Mayo Clinic
Publisher
Springer Science and Business Media LLC
Subject
Genetics(clinical),Genetics,Molecular Biology
Reference41 articles.
1. Yusuf, P. S. et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet 364, 937–952 (2004).
2. Virani, S. S. et al. Heart disease and stroke statistics—2020 update: A report from the American Heart Association. Circulation 14, E139–E596 (2020).
3. Mercado, C. et al. Prevalence of cholesterol treatment eligibility and medication use among adults—United States, 2005–2012. Morb. Mortal. Wkly. Rep. 64, 1305–1311 (2015).
4. Heller, D. A., de Faire, U., Pedersen, N. L., Dahlen, G. & McClearn, G. E. Genetic and environmental influences on serum lipid levels in twins. N. Engl. J. Med. 328, 1150–1156 (1993).
5. Anderson, J. T. et al. Scoring systems for evaluating dietary pattern effect on serum cholesterol. Prev. Med. (Balt.). 8, 525–537 (1979).
Cited by
24 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献