Paraoxonase (PON1) is associated with familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder of which the molecular basis still remains to be elucidated. Since the HDL-associated enzyme serum paraoxonase (PON1) is associated with variation in serum lipids and lipoproteins, we determined whether variation in PON1 also contributes to the FCH phenotype. The study population consisted of 32 well-defined families with FCH, including 103 FCH patients and 240 normolipidemic relatives (NLR). In addition to plasma lipids and lipoproteins we determined PON1 activity (arylesterase- and paraoxonase activity) as well as the common genetic variants −107C > T, 55L > M and 192Q > R in the PON1 gene. The arylesterase activity was significantly higher in FCH patients when compared to NLR (P < 0.001). In the total population, the PON1 genetic variants associated with the highest arylesterase activity (−107CC and 55LL) also associated with higher levels of total cholesterol, apolipoprotein B, triglycerides and VLDL-cholesterol and decreased levels of HDL-cholesterol. In support, the combination of the −107CC with the 55LL genotype associated with a significant increased risk for FCH when compared to the −107TT/55MM genotype (odds ratio 5.0 (95% CI, 1.3–19.1, P = 0.02)). In conclusion, in this population of subjects from well-defined families with FCH, PON1 is biochemically and genetically associated with FCH.