Objective: Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 (ABCG5) or ATP-binding cassette sub-family G member 8 (ABCG8). There are only few data on the pathogenicity of ABCG5 and ABCG8. This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia. Methods: This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targetedsequenced data on ABCG5 or ABCG8 (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. ABCG5 or ABCG8 variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL. Results: Twenty-three ABCG5 or ABCG8 variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5–17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5–4.1] µg/mL) in 14 individuals. Conclusion The scheme proposed for assessing the pathogenicity of genetic variations (ABCG5 and ABCG8) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in ABCG5 or ABCG were classified.

BACKGROUND: CETP(Cholesteryl ester transfer Protein) is the essential protein for 'reverse cholesterol transport' which transfers cholesteryl ester from HDL particles to other lipoproteins. The subjects with CETP deficiency caused by genetic mutation in the CETP gene have very high HDL levels that CETP deficiency implies anti-atherogenic effect. A missense mutation in the exon 15(D442G) and a splicing defect in the intron 14(Int 14A) in the CETP gene are reported to be popular among Japanese population which overall prevalence of both mutations is up to 10%. METHODS: To identify the CETP mutaion such as D442G or Int 14A among Koreans, seven subjects who have high HDL level above 80mg/dl and 14 first-degree relatives of them were included in this study. RESULTS: Of 21 subjects in 7 familes, 5 subjects in 2 families were confirmed as D442G mutation of CETP gene, but Int 14A mutation is not found. Subjects with D442G mutation have high apo A-I levels as well as HDL levels. CONCLUSION: The D442G mutation of CETP gene is firstly confirmed in Koreans. The CETP deficiency caused by genetic mutation in the CETP gene seems to be prevalent among Korean population.
Apolipoprotein A-I ; Asian Continental Ancestry Group ; Cholesterol ; Exons ; Humans ; Introns ; Korea ; Lipoproteins ; Mutation, Missense ; Prevalence