Serum sitosterol levels and ABCG5 and ABCG8 genetic mutations among Japanese dyslipidemic subjects

Abstract Background Sitosterolemia, which is caused by ABCG5 or ABCG8 genetic mutations, is involved with marked increased concentrations of cholesterol as well as non-cholesterol plant sterols including sitosterol. Assessments of serum sitosterol level is critical to discriminate this disease from familial hypercholesterolemia (FH), which exhibits similar phenotypes except for elevated sitosterol levels. However, no prior data exist regarding the optimal cutoff value of serum sitosterol predicting the presence of sitosterolemia with double pathogenic mutations in ABCG5 or ABCG8 genes. Methods We retrospectively investigated consecutive 253 Japanese dyslipidemic subjects (mean age = 47.02 yr, male = 48.6%) with the assessments of serum sitosterol level as well as the presence of ABCG5 or ABCG8 genetic mutations in our institute since 2009 to 2018. Exome lesions of those 2 genes were sequenced, and pathogenicity of the identified genetic variants were determined using standard variant filtering schema, including minor allele frequency, in silico annotation tools. We divided the subjects into 3 groups based on the number of pathogenic mutations in ABCG5 or ABCG8 genes. We compared serum lipid values, including LDL cholesterol as well as serum sitosterol among those groups, and tried to determine the optimal cutoff value discriminating patients of sitosterolemia with double mutations from others. Results We identified 11 individuals with sitosterolemia with double mutations, 27 individuals with a single mutation, and 215 individuals without any mutations. Distribution of serum sitosterol exhibited skewed to the right (Figure). There was no significant correlation between serum sitosterol and other lipids, including LDL cholesterol. As expected, serum sitosterol level of patients with sitosterolemia exhibited significantly higher than those of any other groups (52.0 vs. 7.9 μg/ml, p=2.22×10–6, 52.0 vs. 2.8 μg/ml, p=2.275×10–8). 15 μg/ml was the optimal cut-off value, the sensitivity and specificity of which were 100%, and 99.6%, respectively. Histgram of serum sitosterol Conclusion We suggest the cutoff sitosterol value of 15 μg/ml predicting the presence of sitosterolemia with double pathogenic ABCG5 or ABCG8 genetic mutations.