Serum sitosterol level predicting ABCG5 or ABCG8 genetic mutations

Currently, serum concentrations of sitosterol above 10 μg/ml are considered to be one of the major diagnostic criteria of sitosterolemia. We retrospectively investigated consecutive 206 Japanese dyslipidemic subjects (mean age = 46 yr, male n = 94) with the assessments of serum sitosterol level and the presence of ABCG5 or ABCG8 genetic mutations in our institute since 2009–2018. We divided the subjects into 3 groups based on the number of pathogenic mutations in ABCG5 or ABCG8 genes. We compared serum lipids and serum sitosterol among those groups, and tried to validate the cutoff value discriminating patients of sitosterolemia with double mutations from others. We identified 8 individuals with sitosterolemia with double mutations (affected), 26 individuals with a single mutation (carrier), and 172 individuals without any mutations (wildtype control). Serum sitosterol level of patients with sitosterolemia with double mutations (affected) exhibited significantly higher than those of any other groups (45.2. vs. 7.9 μg/ml, p = 2.5 × 10-2, 45.2 vs. 3.1 μg/ml, p = 1.8 × 10-2). Under these conditions, a cutoff value of sitosterol 10 μg/ml could discriminate the patients with sitosterolemia with double mutations in ABCG5 or ABCG8 gene from no mutation carrier (wildtype control) perfectly, although 6 heterozygous mutation carries exhibited sitosterol level greater than 10 μg/ml. Receiver-operating characteristic (ROC) analysis predicting double mutation status showed that the best cut-off value was 14.81 μg/ml. We suggest a cutoff value of sitosterol 15 μg/ml that shows higher positive predictive value than 10 μg/ml.