Proprotein convertase subtilisin/kexin 9 V4I variant with LDLR mutations modifies the phenotype of familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is caused by mutations in the genes encoding low-density lipoprotein receptor (LDLR), apolipoprotein B, or proprotein convertase subtilisin/kexin 9 (PCSK9). However, FH shows variability of the clinical phenotype modified by other genetic variants or environmental factors.,Our objective was to determine the distribution of PCSK9 variants in Japanese FH heterozygotes and to clarify whether those variants and the combination of those variants and LDLR mutations modify the clinical phenotypes.,A direct sequence analysis was performed for all 18 exons of LDLR gene and 12 exons of PCSK9 gene in 269 clinically diagnosed FH heterozygotes. The serum lipid levels of the carriers of each variant were compared to those of noncarriers. We also assessed Achilles tendon xanthoma and the prevalence of coronary artery disease (CAD) in the patients aged ≥30 years.,Eleven PCSK9 variants were detected. There were 4 frequent PCSK9 variants: L21_22insL, A53 V, V4I, and E32 K. The PCSK9 L21_22insL and A53 V were in linkage disequilibrium with each other. There were no significant differences in serum lipids levels and the prevalence of CAD at the age of ≥ 30 years between PCSK9 V4I, L21_22insL/A53 V, or E32 K variant carriers and noncarriers without LDLR mutations. In the patients carrying LDLR mutations and aged ≥ 30 years, the additional PCSK9 V4I variant was linked to a significantly increased prevalence of CAD in accord with the elevation of the LDL-cholesterol level.,The addition of the PCSK9 V4I was suggested to modify the phenotype of patients carrying LDLR mutations by affecting their LDLR metabolism.