Dataset Information

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.

SUBMITTER: Saadatagah S

PROVIDER: S-EPMC8046820 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Genetic basis of hypercholesterolemia in adults.

Saadatagah Seyedmohammad S Jose Merin M Dikilitas Ozan O Alhalabi Lubna L Miller Alexandra A AA Fan Xiao X Olson Janet E JE Kochan David C DC Safarova Maya M Kullo Iftikhar J IJ

NPJ genomic medicine 20210414 1

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 Du ...[more]

PMID: 33854068

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Project description:BackgroundMortality from familial hypercholesterolemia (FH) remains high due to late diagnosis, and the rate of timely diagnosis remains low (< 10% globally and < 1% in China). Early screening and treatment could significantly reduce mortality risk, especially among young adults. This study aims to evaluate the cost-effectiveness of universal genetic screening of young adults aged 18-40 years compared to universal cholesterol screening or current passive screening strategies (opportunistic cholesterol screening and genetic cascade testing) for FH in China.MethodsA decision-analytic Markov model was constructed to simulate the lifetime (until 100 years old or 99% of patients died) coronary heart disease (CHD) events, discounted costs, gains in quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) of different screening strategies. The model targeted the general population aged 18-40 years (226,869,800 males and 209,030,180 females) from a healthcare provider's perspective. Model parameters were derived from published literatures and the largest nationwide screening program of FH in China. The willingness-to-pay threshold (US$38,042) was chosen as three times the Chinese per-capita gross domestic product (GDP) in 2023. Sensitivity analyses and threshold analyses were conducted to assess the robustness of the results.ResultsUniversal genetic screening of young adults aged 18-40 years is cost-effective when compared to both current passive screening strategies and universal cholesterol screening. Compared with current passive screening, universal genetic screening could prevent 172,956 CHD events (88,766 non-fatal, 84,191 fatal) with additional costs of US$40.45 billion and gaining additional 1.23 million QALYs, corresponding to an ICER of US$32,960/QALY gained. Implementing universal genetic screening at younger ages would reduce the ICER from US$36,901/QALY to US$28,910/QALY. The model was most sensitive to the cost and sensitivity of genetic testing. If the cost of genetic testing decreased from US$96.50 to US$38.83 or $2.76, universal genetic screening would become very cost-effective or even cost-saving.ConclusionsUniversal FH genetic screening in young adults has the potential to be cost-effective in China, compared to current passive screening strategy and universal cholesterol screening strategy. Performing screening in younger age would result in better cost-effectiveness benefit.

Dataset Information

Genetic basis of hypercholesterolemia in adults.

Publications

Genetic basis of hypercholesterolemia in adults.

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