Evaluation of plasma apolipoproteins in heterozygous carriers of ABCG5/8 mutations

Sitosterolemia is an autosomal recessive disorder caused by mutations in ABCG5/8 . Previous studies have reported that heterozygous carriers of ABCG5/8 mutations (Sito_het) are at an increased risk of coronary heart disease. Given the established role of apolipoproteins in lipid-related disorders, this study aimed to characterize the biological alterations in Sito_het and to explore diagnostic models to identify Sito_het individuals based on plasma apolipoprotein profiles. Two datasets were analyzed: Dataset 1 comprised 14 Sito_het, 16 hyperlipidemia (HC) and 96 healthy (Con) individuals, with 12 apolipoproteins and Lp(a) quantified by liquid chromatography mass spectrometry. Dataset 2 included 1121 Sito_het participants from the UK Biobank, with ABCG5/8 genotypes from whole exome sequencing and apolipoprotein levels from Olink proteomics. Selected apolipoproteins identified in Dataset 1 were then independently validated in Dataset 2. Two nomogram models were developed using multivariable logistic regression: the first incorporated ApoB, ApoM, and ApoC2 for discriminating Sito_het from Controls, and the second incorporated ApoC2 and Lp(a) for discriminating Sito_het from HC patients. Both models demonstrated good performance with respect to calibration, precision–recall, receiver-operating characteristic analysis, decision curve analysis, and clinical impact assessment. External validation using the UK Biobank cohort confirmed the differences in plasma levels of shared apolipoproteins among the Sito_het, Con, and HC groups. The nomogram models demonstrated promising discriminative performance in distinguishing Sito_het from both HC and healthy controls in this retrospective derivation cohort. Although these findings are exploratory and require further prospective evaluation in larger, independent cohorts, our work provides a useful analytical framework for future research related to ABCG5/8 heterozygous carriers.