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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. 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. 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. 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. Show less

Severe hypertriglyceridemia can be caused by pathogenic variants in genes encoding proteins involved in the metabolism of triglyceride-rich lipoproteins. A key protein in this respect is lipoprotein lipase (LPL) which hydrolyzes triglycerides in these lipoproteins. Another important protein is glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) which transports LPL to the luminal side of the endothelial cells. Our objective was to identify a genetic cause of hypertriglyceridemia in 459 consecutive unrelated subjects with levels of serum triglycerides ≥20 mmol/l. These patients had been referred for molecular genetic testing from 1998 to 2021. In addition, we wanted to study whether GPIHBP1 autoantibodies also were a cause of hypertriglyceridemia. Molecular genetic analyses of the genes encoding LPL, GPIHBP1, apolipoprotein C2, lipase maturation factor 1 and apolipoprotein A5 as well as apolipoprotein E genotyping, were performed in all 459 patients. Serum was obtained from 132 of the patients for measurement of GPIHBP1 autoantibodies approximately nine years after molecular genetic testing was performed. A monogenic cause was found in four of the 459 (0.9%) patients, and nine (2.0%) patients had dyslipoproteinemia due to homozygosity for apolipoprotein E2. One of the 132 (0.8%) patients had GPIHBP1 autoantibody syndrome. Only 0.9% of the patients had monogenic hypertriglyceridemia, and only 0.8% had GPIHBP1 autoantibody syndrome. The latter figure is most likely an underestimate because serum samples were obtained approximately nine years after hypertriglyceridemia was first identified. There is a need to implement measurement of GPIHBP1 autoantibodies in clinical medicine to secure that proper therapeutic actions are taken. Show less

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters in plasma from high density lipoprotein (HDL) to very low density lipoprotein and low density lipoprotein. Loss-of-function variants in the CETP gene cause elevated levels of HDL cholesterol. In this study, we have determined the functional consequences of 24 missense variants in the CETP gene. The 24 missense variants studied were the ones reported in the Human Gene Mutation Database and in the literature to affect HDL cholesterol levels, as well as two novel variants identified at the Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital in subjects with hyperalphalipoproteinemia. HEK293 cells were transiently transfected with mutant CETP plasmids. The amounts of CETP protein in lysates and media were determined by Western blot analysis, and the lipid transfer activities of the CETP variants were determined by a fluorescence-based assay. Four of the CETP variants were not secreted. Five of the variants were secreted less than 15% compared to the WT-CETP, while the other 15 variants were secreted in varying amounts. There was a linear relationship between the levels of secreted protein and the lipid transfer activities (r = 0.96, p<0.001). Thus, the secreted variants had similar specific lipid transfer activities. The effect of the 24 missense variants in the CETP gene on the lipid transfer activity was mediated predominantly by their impact on the secretion of the CETP protein. The four variants that prevented CETP secretion cause autosomal dominant hyperalphalipoproteinemia. The five variants that markedly reduced secretion of the respective variants cause mild hyperalphalipoproteinemia. The majority of the remaining 15 variants had minor effects on the secretion of CETP, and are considered neutral genetic variants. Show less