| Title: | Genetic testing in individuals with extreme HDL-C levels: Diagnostic yield and clinical implications from the Tromsø Study |
| Journal: | PLOS ONE |
| Published: | 20 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42008427/ |
| DOI: | https://doi.org/10.1371/journal.pone.0344627 |
Publication 17912
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Abstract
AIM: This study aimed to assess the prevalence of genetic variants responsible for extreme levels of high-density lipoprotein cholesterol (HDL-C) and evaluate the adequacy of current thresholds for genetic testing of HDL-related dyslipidemia.</p>
METHODS: Using data from the Tromsø Study, a population-based cohort in Northern Norway, we identified 210 individuals with HDL-C levels ≤ 0.5 mmol/L or ≥ 3.0 mmol/L. Six HDL-related genes (ABCA1, APOA1, CETP, LCAT, PLTP, SCARB1) were sequenced in these participants. We classified variants according to ACMG guidelines, incorporating functional assays and UK Biobank data for additional phenotype-genotype associations.</p>
RESULTS: We identified 38 variants of interest across six HDL-related genes, of which 10 were considered potentially causative, found in 14 individuals. Genetic causes were detected in 33.3% of individuals with low HDL-C and 5.05% of those with high HDL-C. Sex-specific analyses showed that using HDL-C thresholds aligned with population distributions improved detection of individuals with pathogenic variants, particularly among women with high HDL-C and men with low HDL-C. These findings suggest that current uniform thresholds may overlook clinically relevant cases and that incorporating sex-specific HDL-C distributions could enhance the identification of individuals with suspected genetic HDL disorders.</p>
CONCLUSIONS: Genetic testing for HDL-related dyslipidemia is underutilized, with many individuals not meeting the current extreme HDL-C threshold criteria. Revised sex-specific thresholds for genetic testing will improve the identification of pathogenic variants and provide more accurate diagnoses of HDL-related disorders. Continued research is essential to refine our understanding of HDL genetics and its clinical implications.</p>
16 Keywords
- ATP Binding Cassette Transporter 1
- Adult
- Aged
- Apolipoprotein A-I
- Cholesterol Ester Transfer Proteins
- Cholesterol, HDL
- Cohort Studies
- Dyslipidemias
- Female
- Genetic Testing
- Humans
- Male
- Middle Aged
- Norway
- Phosphatidylcholine-Sterol O-Acyltransferase
- Scavenger Receptors, Class B
7 Authors
- Åsa Schawlann Ølnes
- Marianne Teigen
- Thea Bismo Strøm
- Erik Kristoffer Arnesen
- Antoine Rimbert
- Anne Elise Eggen
- Katrine Bjune
1 Application
| Application ID | Title |
|---|---|
| 49823 | Genetic predisposition to cardiovascular and metabolic diseases |
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