Patients With LDLR and PCSK9 Gene Variants Experienced Higher Incidence of Cardiovascular Outcomes in Heterozygous Familial Hypercholesterolemia

Background Patients with familial hypercholesterolemia who harbored both low‐density lipoprotein receptor (LDLR ) andPCSK9 (proprotein convertase subtilisin/kexin type 9) gene variants exhibit severe phenotype associated with substantially high levels of low‐density lipoprotein cholesterol. In this study, we investigated the cardiovascular outcomes in patients with bothLDLR andPCSK9 gene variants.Methods and Results A total of 232 unrelated patients withLDLR and/orPCSK9 gene variants were stratified as follows: patients withLDLR andPCSK9 (LDLR/PCSK9 ) gene variants, patients withLDLR gene variant, and patients withPCSK9 gene variant. Clinical demographics and the occurrence of primary outcome (nonfatal myocardial infarction) were compared. The observation period of primary outcome started at the time of birth and ended at the time of the first cardiac event or the last visit. Patients withLDLR/PCSK9 gene variants were identified in 6% of study patients. They had higher levels of low‐density lipoprotein cholesterol (P =0.04) than those withLDLR gene variants. On multivariate Cox regression model, they experienced a higher incidence of nonfatal myocardial infarction (hazard ratio, 4.62; 95% CI, 1.66–11.0;P =0.003 versus patients withLDLR gene variant). Of note, risk for nonfatal myocardial infarction was greatest in male patients withLDLR/PCSK9 gene variants compared with those withLDLR gene variant (86% versus 24%;P <0.001).Conclusions Patients withLDLR/PCSK9 gene variants were high‐risk genotype associated with atherogenic lipid profiles and worse cardiovascular outcomes. These findings underscore the importance of genetic testing to identify patients withLDLR/PCSK9 gene variants, who require more stringent antiatherosclerotic management.