Lp(a) is highest in APOB-dependent familial hypercholesterolaemia, 36.5 mg/dL, versus 21.9 mg/dL in the LDLR-dependent form, a Spanish study of 2,419 people (Atherosclerosis 2022)

Original title: Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation

Atherosclerosis · 23 August 2021 · 6

Marco-Benedí V, Cenarro A, Laclaustra M, Larrea-Sebal A, Jarauta E, Lamiquiz-Moneo I, Calmarza P, Bea AM, Plana N, Pintó X, Martín C, Civeira F

In a cross-sectional study across Spanish lipid clinics, adjusted geometric mean Lp(a) was 14.9 mg/dL in healthy controls (n=1,059), 21.9 mg/dL in genetically diagnosed heterozygous familial hypercholesterolaemia (heFH, n=500), and 37.4 mg/dL in mutation-negative hypercholesterolaemia subjects (n=860), all comparisons P<0.001. Among heFH patients, those with APOB-dependent FH had the highest Lp(a) (36.5 mg/dL), followed by LDLR-dependent FH (21.7 mg/dL), a pattern replicated in a validation cohort from the Spanish Atherosclerosis Society Dyslipidemia Registry. Neither LPA kringle IV type-2 repeat number, a hypercholesterolaemia polygenic score, nor LDL cholesterol explained these gene-specific differences, and within LDLR-dependent FH, Lp(a) did not differ by affected protein domain. The findings show Lp(a) elevation in heFH varies by the specific causal gene, independent of LDL cholesterol level.

Original abstract

Background And Aims: Lipoprotein(a) [Lp(a)] concentration in heterozygous familial hypercholesterolemia (heFH) is not well established. Whether the genetic defect responsible for heFH plays a role in Lp(a) concentration is unknown. We aimed to compare Lp(a) in controls from a healthy population, in genetically diagnosed heFH and mutation-negative hypercholesterolemia subjects, and to assess the influence on Lp(a) of the genetic defect responsible for heFH.

Methods: We conducted a cross-sectional study, performed in a lipid clinic in Spain. We studied adults with suspected heFH and a genetic study of FH genes (LDLR, APOB, APOE and PCSK9) and controls from de Aragon Workers' Health Study. HeFH patients from the Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) were used as validation cohort.

Results: Adjusted geometric means (95% confidence interval) of Lp(a) in controls (n = 1059), heFH (n = 500), and mutation-negative subjects (n = 860) were 14.9 mg/dL (13.6, 16.4), 21.9 mg/dL (18.1, 25.6) and 37.4 mg/dL (33.3, 42.1), p < 0.001 in all comparisons. Among heFH subjects, APOB-dependent FH showed the highest Lp(a), 36.5 mg/dL (22.0, 60.8), followed by LDLR-dependent FH, 21.7 mg/dL (17.9, 26.4). These differences were also observed in heFH from the SEA cohort. The number of plasminogen-like kringle IV type-2 repeats of LPA, the hypercholesterolemia polygenic score or LDLc concentration did not explain these differences. In LDLR-dependent FH, Lp(a) levels were not different depending on the affected protein domain.

Conclusions: Lp(a) is elevated in mutation-negative subjects and in heFH. The concentration of Lp(a) in heFH varies in relation to the responsible gene. Higher Lp(a) in heFH is not explained by their higher LDLc.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.