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Observational Study
. 2020 Jun 2;75(21):2682-2693.
doi: 10.1016/j.jacc.2020.03.065.

Ascertainment Bias in the Association Between Elevated Lipoprotein(a) and Familial Hypercholesterolemia

Mark Trinder  1 , Maria L DeCastro  2 , Hawmid Azizi  2 , Luba Cermakova  2 , Linda M Jackson  2 , Jiri Frohlich  2 , G B John Mancini  3 , Gordon A Francis  4 , Liam R Brunham  5
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Free article
Observational Study

Ascertainment Bias in the Association Between Elevated Lipoprotein(a) and Familial Hypercholesterolemia

Mark Trinder et al. J Am Coll Cardiol. .
Free article

Abstract

Background: Lipoprotein(a) is an atherogenic low-density lipoprotein-like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why.

Objectives: This study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically.

Methods: We investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486).

Results: Patients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH.

Conclusions: These results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.

Keywords: Lp(a); genetic epidemiology; hypercholesterolemia; lipoprotein metabolism; longitudinal cohort study.

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