Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n聽=聽103) and their normolipidemic relatives (NLR; n聽=聽240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p聽<聽0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p聽<聽0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p聽<聽0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p聽<聽0.001).
The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.