Key result
Dual CYP27A1 and FH variants are linked to ~2.3 μg/mL higher cholestanol levels.
Why the study?
It remains unclear whether pathogenic CYP27A1 variants modify the clinical manifestations of familial hypercholesterolemia caused by LDL receptor or related gene defects.
Does the presence of a pathogenic CYP27A1 variant increase Achilles tendon thickness and serum cholestanol levels in patients with monogenic heterozygous familial hypercholesterolemia?
Cross-Sectional (n=644)
No
Does the presence of a pathogenic CYP27A1 variant increase Achilles tendon thickness and serum cholestanol levels in patients with monogenic heterozygous familial hypercholesterolemia?
Mean Difference: 2.3 (95% CI 1.4–3.2)
Absolute Event Rate: 3.7% vs 2.3%
p-value: p=<0.001
A pathogenic CYP27A1 variant acts as a phenotype-modulating accessory variant in patients with monogenic familial hypercholesterolemia, exacerbating Achilles tendon thickening and elevating serum cholestanol levels independently of LDL cholesterol pathways.
May modify xanthoma severity in monogenic FH; leaves open CYP27A1 screening or targeted therapy pending prospective validation.
OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disorder caused by pathogenic variants of cytochrome P450 family 27 subfamily A member 1 (CYP27A1). It remains unclear whether such variants modify the clinical manifestations of familial hypercholesterolemia (FH) caused by defects in the low-density lipoprotein (LDL) receptor or other related genes. We aimed to clarify the impact of the pathogenic variants of CYP27A1 on the clinical phenotypes of patients with FH. METHODS: We analyzed clinical data from 644 patients with a clinical diagnosis of monogenic FH who underwent genotyping for CYP27A1 and phenotypic assessment, including the serum sterol levels. Multivariate linear regression analyses, adjusted for age and sex, were conducted to assess the impact of pathogenic CYP27A1 variants on the serum cholestanol levels. RESULTS: Among these individuals, 22 (3.4%) carried pathogenic CYP27A1 variants. Patients harboring a pathogenic variant showed significantly higher median cholestanol concentrations than non-carriers (3.7 vs. 2.3 μg/mL, p ＜0.001). A single pathogenic CYP27A1 variant was associated with an increase in serum cholestanol of 2.3 μg/mL (95% confidence interval: 1.4-3.2 μg/mL, p ＜0.001) and an Achilles tendon thickness of 0.4 mm (95% confidence interval: 0.1-0.7 mm, p = 0.02). Furthermore, carriers exhibited significantly greater Achilles tendon thickness than non-carriers (9.6 vs. 8.9 mm, p ＜0.001). CONCLUSIONS: We identified a substantial number of patients with pathogenic CYP27A1 variants among the patients with monogenic FH, which influenced their Achilles tendon thickness and serum cholestanol levels.
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Tada et al. (2026) conducted a cross-sectional in Monogenic Heterozygous Familial Hypercholesterolemia (n=644). Pathogenic CYP27A1 variant vs. Non-carriers (monogenic FH only) was evaluated on Serum cholestanol level (MD 2.3, 95% CI 1.4-3.2, p=<0.001). Carrying a single pathogenic CYP27A1 variant in addition to a familial hypercholesterolemia-causing variant was associated with a 2.3 μg/mL increase in serum cholestanol and a 0.4 mm increase in Achilles tendon thickness.
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