Lipoprotein(a) and familial hypercholesterolaemia – Authors' reply

Abstract

We thank Leopoldo Perez de Isla and colleagues for their interest in our study1Langsted A Kamstrup PR Benn M Tybjærg-Hansen A Nordestgaard BG High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study.Lancet Diabetes Endocrinol. 2016; 4: 577-587Summary Full Text Full Text PDF PubMed Scopus (166) Google Scholar and their kind words. The SAFEHEART study2Mata N Alonso R Badimón L et al.Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART).Lipids Health Dis. 2011; 10: 94Crossref PubMed Scopus (105) Google Scholar is very interesting, and includes an impressive number of genetically diagnosed patients with familial hypercholesterolemia.3Alonso R Andres E Mata N et al.Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation.J Am Coll Cardiol. 2014; 63: 1982-1989Crossref PubMed Scopus (234) Google Scholar There are two interesting comparisons to be made with respect to lipoprotein(a) concentrations in clinical familial hypercholesterolaemia (in our study of a general population cohort) and in genetically confirmed familial hypercholesterolaemia (in the SAFEHEART study). First, lipoprotein(a) concentrations in patients with genetic familial hypercholesterolaemia were 12% higher than in relatives without genetic familial hypercholesterolaemia.3Alonso R Andres E Mata N et al.Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation.J Am Coll Cardiol. 2014; 63: 1982-1989Crossref PubMed Scopus (234) Google Scholar By contrast, individuals in the general population with clinical familial hypercholesterolaemia had 52–58% higher lipoprotein(a) concentration than did individuals without clinical familial hypercholesterolaemia. Thus, the much higher lipoprotein(a) concentrations in clinical versus genetic familial hypercholesterolaemia is unlikely to be caused solely by defects in the LDL receptor, as supported by kinetic studies in homozygous familial hypercholesterolaemia.4Rader DJ Mann WA Cain W et al.The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans.J Clin Invest. 1995; 95: 1403-1408Crossref PubMed Scopus (176) Google Scholar Second, the 12% higher lipoprotein(a) concentrations in individuals with versus those without genetic familial hypercholesterolaemia3Alonso R Andres E Mata N et al.Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation.J Am Coll Cardiol. 2014; 63: 1982-1989Crossref PubMed Scopus (234) Google Scholar should be compared with the lack of difference in lipoprotein(a) concentrations when comparing individuals from the general population with a known familial hypercholesterolaemia-causing mutation in LDLR or APOB with those without such mutations.1Langsted A Kamstrup PR Benn M Tybjærg-Hansen A Nordestgaard BG High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study.Lancet Diabetes Endocrinol. 2016; 4: 577-587Summary Full Text Full Text PDF PubMed Scopus (166) Google Scholar We speculate that the 12% difference in lipoprotein(a) concentrations in SAFEHEART might be ascribed to ascertainment bias because index cases of genetic familial hypercholesterolaemia referred to a lipid clinic are likely to have larger increases in LDL cholesterol5Tybjærg-Hansen A Jensen HK Benn M Steffensen R Jensen G Nordestgaard BG Phenotype of heterozygotes for low-density lipoprotein receptor mutations identified in different background populations.Arterioscler Thromb Vasc Biol. 2005; 25: 211-215Crossref PubMed Scopus (31) Google Scholar and probably also in lipoprotein(a) concentrations than do individuals with genetic familial hypercholesterolaemia in the general population. The lipoprotein(a) concentrations reported in SAFEHEART are pooled for genetic familial hypercholesterolaemia index cases (prone to ascertainment bias) and for relatives with genetic familial hypercholesterolaemia, and then compared with relatives without genetic familial hypercholesterolaemia. It would be interesting to know the lipoprotein(a) concentrations comparing relatives with and without genetic familial hypercholesterolaemia, while excluding index cases. In conclusion, we believe that the SAFE-HEART study can help us to understand the role of lipoprotein(a) in familial hypercholesterolaemia, but we also await data from more population-based studies free of ascertainment bias. We declare no competing interests. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort studyHigh lipoprotein(a) concentrations and corresponding LPA risk genotypes represent novel risk factors for clinical familial hypercholesterolaemia. Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction. Full-Text PDF Lipoprotein(a) and familial hypercholesterolaemiaWe read with great interest the excellent article by Anne Langsted and colleagues.1 The reason why lipoprotein(a) concentrations are raised in individuals with familial hypercholesterolaemia is unclear, and in this well designed study, the investigators explore the hypothesis that high lipoprotein(a) concentrations are a possible cause of clinical familial hypercholesterolaemia. Their conclusion in favour of a possible causal role for lipoprotein(a) contradicts other theories suggesting that defects in the LDL receptor gene (LDLR), present in most people with familial hypercholesterolaemia, reduce LDL and lipoprotein(a) plasma clearance, leading to increased LDL and lipoprotein(a) concentrations. Full-Text PDF