Key result
Lp(a) levels do not differ by FH-causing variant status in familial hypercholesterolemia.
Why the study?
It remains unclear why patients with familial hypercholesterolemia have elevated lipoprotein(a) levels and how ascertainment affects this association.
Does elevated lipoprotein(a) confound the clinical diagnosis of familial hypercholesterolemia, and do Lp(a) levels differ based on the presence of an FH-causing variant?
Observational (n=521)
Yes
Does elevated lipoprotein(a) confound the clinical diagnosis of familial hypercholesterolemia, and do Lp(a) levels differ based on the presence of an FH-causing variant?
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“[L]ipoprotein(a) levels are elevated in patients with FH due to increased frequency of LPA variants contributing to increased levels of reported LDL-C, premature coronary artery disease, and a positive family history for heart disease that leads to ascertainment bias. Clinical and laboratory investigations for differentiating FH, elevated lipoprotein(a), or the combination of both are important for accurate diagnosis, risk stratification, and treatment strategies.”
Elevated lipoprotein(a) confounds established clinical diagnostic criteria for familial hypercholesterolemia, reinforcing the necessity of concurrent genetic and Lp(a) testing for accurate evaluation.
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.
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Trinder et al. (2020) conducted an observational in Familial hypercholesterolemia (FH) (n=521). Presence of an FH-causing variant vs. Absence of an FH-causing variant was evaluated on Mean lipoprotein(a) level (log mg/dl) (1.43 log mg/dl vs. 1.42 log mg/dl, p=0.97). In the FH cohort, lipoprotein(a) levels did not significantly differ based on the presence or absence of an FH-causing genetic variant (1.43 vs. 1.42 log mg/dl; p=0.97), suggesting FH does not intrinsically cause elevated Lp(a).
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