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Background <p>Sitosterolemia is an autosomal recessive disorder caused by mutations in <i>ABCG5/8</i>. Previous studies have reported that heterozygous carriers of <i>ABCG5/8</i> 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.</p> Methods <p>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 <i>ABCG5/8</i> genotypes from whole exome sequencing and apolipoprotein levels from Olink proteomics. Selected apolipoproteins identified in Dataset 1 were then independently validated in Dataset 2.</p> Results <p>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.</p> Conclusion <p>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 <i>ABCG5/8</i> heterozygous carriers.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Shijie Xu,
  • Jun Zhang,
  • Lei Xiao,
  • Jialu Li,
  • Luya Wang,
  • Yan Chen,
  • Junfang Wu

摘要

Background

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.

Methods

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.

Results

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.

Conclusion

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.