Key result
In ADH patients with unexpectedly low LDL-C, 40% carried at least one minor allele for four common APOB variants compared to 1.5% in the general European population, and 6.7% had APOB truncations.
Why the study?
Do loss-of-function mutations or specific common variants in APOB, PCSK9, and ANGPTL3 explain unexpectedly low LDL-C levels in patients with genetically diagnosed Autosomal Dominant Hypercholesterolemia?
Observational (n=75)
Do loss-of-function mutations or specific common variants in APOB, PCSK9, and ANGPTL3 explain unexpectedly low LDL-C levels in patients with genetically diagnosed Autosomal Dominant Hypercholesterolemia?
Absolute Event Rate: 40% vs 1.5%
Unexpectedly low LDL-C levels in some patients with familial hypercholesterolemia mutations may be partially explained by co-inheritance of APOB truncating mutations or specific common APOB haplotypes.
APOB variants may explain low LDL-C in ADH; hypothesis-generating for modifier gene screening in familial hypercholesterolemia.
Autosomal Dominant Hypercholesterolemia (ADH) is caused by LDLR and APOB mutations. However, genetically diagnosed ADH patients do not always exhibit the expected hypercholesterolemic phenotype. Of 4,669 genetically diagnosed ADH patients, identified through the national identification screening program for ADH, 75 patients (1.6%) had LDL-cholesterol (LDL-C) levels below the 50th percentile for age and gender prior to lipid-lowering therapy. The genes encoding APOB, PCSK9, and ANGPTL3 were sequenced in these subjects to address whether monogenic dominant loss-of-function mutations underlie this paradoxical phenotype. APOB mutations, resulting in truncated APOB, were found in five (6.7%) probands, reducing LDL-C by 56%. Rare variants in PCSK9, and ANGPTL3 completely correcting the hypercholesterolemic phenotype were not found. The common variants p.N902N, c.3842+82T>A, p.D2312D, and p.E4181K in APOB, and c.1863+94A>G in PCSK9 were significantly more prevalent in our cohort compared to the general European population. Interestingly, 40% of our probands carried at least one minor allele for all four common APOB variants compared to 1.5% in the general European population. While we found a low prevalence of rare variants in our cohort, our data suggest that regions in proximity of the analyzed loci, and linked to specific common haplotypes, might harbor additional variants that correct an ADH phenotype.
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Huijgen et al. (2011) conducted an observational in Autosomal Dominant Hypercholesterolemia (n=75). Genetic variation in APOB, PCSK9, and ANGPTL3 vs. General European population was evaluated on Carriage of at least one minor allele for all four common APOB variants. In ADH patients with unexpectedly low LDL-C, 40% carried at least one minor allele for four common APOB variants compared to 1.5% in the general European population, and 6.7% had APOB truncations.
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