Physicians' Academy for Cardiovascular Education

Elevated MI risk in patients with HeFH with gene variants in both LDLR and PCSK9

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

Literature - Doi T, Hori M, Harada-Shiba M, et al. - J Am Heart Assoc. 2021;10:e018263. doi: 10.1161/JAHA.120.018263.

Introduction and methods

Familial hypercholesterolemia (FH) is caused by genetic variants in the LDLR, PCSK9, and APOB genes, and leads to elevated LDL-c levels, tendon or skin xanthomas, and an increased risk for ASCVD [1-4]. Genetic analyses have identified patients with variants in both LDLR and PCSK9 genes [5-6]. This genotype could potentially result in higher elevated LDL-c levels, which would lead to an additionally higher risk for ASCVD in these patients and is therefore considered a severe form of FH by the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel [3]. However, the demographics and clinical outcomes in these patients are unknown. This study investigated the prevalence, clinical characteristics, and CV outcomes of patients with both LDLR and PCSK9 genes variants.

This retrospective study analyzed unrelated patients with clinically diagnosed heterozygous FH (HeFH) who underwent genetic testing to identify variants in the LDLR and/or PCSK9 gene(s) at the National Cerebral and Cardiovascular Center in Osaka, Japan, between 2005 and 2016. HeFH was clinically defined as patients having ≥2 of the following features: LDL-c ≥180 mg/dL, tendon/skin xanthoma, and a family history of FH or premature CAD within second degree relatives. In total, 232 unrelated patients with FH and a gene variant in LDLR gene (n=183), PCSK9 gene (n=35), or both genes (n=14) were included in the study. The primary endpoint was nonfatal MI. Death from any cardiac cause was not observed in the study subjects during the observational period and was therefore not included in the primary outcome. The mean observational period was 53±17 years.

Main results


This study in a cohort of patients with HeFH and genetic variant(s) in LDLR and/or PCSK9 demonstrated that patients with both LDLR and PCSK9 gene variants had an increased atherogenic lipid profile and higher incidence of nonfatal MI compared to patients with a single LDLR gene variant. Risk for nonfatal MI was highest in men with LDLR/PCSK9 gene variants compared to men with a LDLR variant.

The authors suggest that risk stratification according to genotype and sex may potentially identify severe high-risk patients with HeFH who need more intense lipid lowering therapies.


Show references

Find this article online at J Am Heart Assoc.

Share this page with your colleagues and friends: