A silent mutation of Niemann-Pick C1-like 1 and apolipoprotein E4 modulate cholesterol absorption in primary hyperlipidemias.

OBJECTIVE: To investigate the influence of the silent mutation c.816C > G (L272) of Niemann-Pick C1-like 1 (NPC1L1) and of apolipoprotein (APO) E alleles on cholesterol absorption markers, sitosterol and campesterol, in 87 patients with primary hyperlipidemias. METHODS: In all subjects genotyped for silent polymorphism in NPC1L1 gene c.816C > G (L272L) and for APO E polymorphism, campesterol and sitosterol were measured by gas chromatography coupled to mass spectrometry. RESULTS: Thirty-eight patients carrying the G allele of NPC1L1 showed significantly greater concentrations (log values) of campesterol (1.86 ± 0.3 vs 1.61 ± 0.3 10(2) μmol/mmol cholesterol, p < .001) and sitosterol (2.03 ± 0.2 vs 1.94 ± 0.2 10(2) μmol/mmol cholesterol, P = .05). Patients with at least one E4 allele showed values of sitosterol greater than those carrying E3E3 or E3E2 (2.05 ± 0.2 10(2) μmol/mmol cholesterol vs 1.95 ± 0.2 10(2) μmol/mmol cholesterol, P = .004). The presence of the G allele (β = .379, P < 0.001) and high-density lipoprotein cholesterol (β = .242, P = .019) was an independent predictor of campesterol values (R of the model = 0.473, P < .001). The E4 allele (β = .293, P = .005) and high-density lipoprotein cholesterol (β = .311, P = .003) were independent predictors of sitosterol values (R 0.416, P of the model <.001). CONCLUSIONS: In patients with hyperlipidemias, G allele of NPC1L1 and APO E4 could account for some of the inter-individual variability in cholesterol absorption.