Background:
Autosomal dominant hypercholesterolemia (ADH) is due to deleterious variants in
LDLR
,
APOB
, or
PCSK9
genes. Double heterozygote for these genes induces a more severe phenotype. More recently, a new causative variant of heterozygous ADH was identified in
APOE
. Here we study the phenotype of 21 adult patients, double heterozygotes for rare
LDLR
and rare
APOE
variants (
LDLR+APOE
) in a national wide French cohort.
Methods:
LDLR
,
APOB
,
PCSK9
, and
APOE
genes were sequenced in 5743 probands addressed for ADH genotyping. The lipid profile and occurrence of premature atherosclerotic cardiovascular diseases were compared between the
LDLR+APOE
carriers (n=21) and the carriers of the same
LDLR
causative variants alone (n=22).
Results:
The prevalence of
LDLR+APOE
carriers in this French ADH cohort is 0.4%. Overall, LDL (low-density lipoprotein)-cholesterol concentrations were 23% higher in
LDLR+APOE
patients than in
LDLR
patients (9.14±2.51 versus 7.43±1.59 mmol/L,
P=0
.0221). When only deleterious or probably deleterious variants were considered, the LDL-cholesterol concentrations were 46% higher in
LDLR+APOE
carriers than in
LDLR
carriers (10.83±3.45 versus 7.43±1.59 mmol/L,
P=0
.0270). Two patients exhibited a homozygous familial hypercholesterolemia phenotype (LDL-cholesterol >13 mmol/L). Premature atherosclerotic cardiovascular disease was more common in
LDLR+APOE
patients than in
LDLR
carriers (70% versus 30%,
P=0
.026).
Conclusions:
Although an incomplete penetrance should be taken into account for
APOE
variant classification, these results suggest an additive effect of deleterious
APOE
variants on ADH phenotype highlighting the relevance of
APOE
sequencing.