Lipoprotein(a) and familial hypercholesterolemia: Partners in crime in heritable hyperlipidemia

Familial hypercholesterolemia (FH), affecting an estimated 1 in 200–250 individuals globally, represents a well-known, heritable hyperlipidemia characterized by lifelong elevations in low-density lipoprotein (LDL) cholesterol levels and a concomitant markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD) [ [1] Mach F. Baigent C. Catapano A.L. et al. ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J. 2019; 41 (2020): 111-188 Crossref Scopus (2987) Google Scholar ]. In contrast, genetically determined high lipoprotein(a) (Lp(a)) levels represent a somewhat less known heritable hyperlipidemia despite high prevalence and increased attention in recent years [ 2 Reyes-Soffer G. Ginsberg H.N. Berglund L. et al. Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American heart association. Arterioscler. Thromb. Vasc. Biol. 2022; 42: e48-e60 Crossref PubMed Scopus (37) Google Scholar , 3 Kronenberg F. Mora S. Stroes E.S.G. et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur. Heart J. 2022; 43: 3925-3946 Crossref PubMed Scopus (18) Google Scholar , 4 Kamstrup P.R. Lipoprotein(a) and cardiovascular disease. Clin. Chem. 2021; 67: 154-166 Crossref PubMed Scopus (39) Google Scholar ]. Lp(a) consists of a cholesterol-laden LDL-like particle identified as a unique lipoprotein by the addition of the plasminogen-like glycoprotein, apolipoprotein(a) (apo(a)) [ [5] Schmidt K. Noureen A. Kronenberg F. Utermann G. Structure, function, and genetics of lipoprotein (a). J. Lipid Res. 2016; 57: 1339-1359 Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar ]. Lp(a) levels vary widely between individuals and are primarily genetically determined by variation in the LPA gene coding for apo(a). Approximately 20% of European descent populations thus have genetically determined high Lp(a) levels (>42 mg/dL, >88 nmol/L), with levels in the top 10% of the concentration distribution associating with (and likely causally) two-to threefold increases in risk of coronary heart disease and aortic valve stenosis, but also increased risk of peripheral artery disease, ischemic stroke, and heart failure [ [4] Kamstrup P.R. Lipoprotein(a) and cardiovascular disease. Clin. Chem. 2021; 67: 154-166 Crossref PubMed Scopus (39) Google Scholar , [6] Arsenault B.J. Kamstrup P.R. Lipoprotein(a) and cardiovascular and valvular diseases: a genetic epidemiological perspective. Atherosclerosis. 2022; 349: 7-16 Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar ]. Accordingly, “hyper-Lp(a)-emia” may be considered the most common heritable hyperlipidemia affecting >1 billion individuals worldwide, although a substantially higher Lp(a) level than that found in 20% of the population is needed to equate the risk of heterozygous FH [ [7] Hedegaard B.S. Bork C.S. Kaltoft M. et al. Equivalent impact of elevated lipoprotein(a) and familial hypercholesterolemia in patients with atherosclerotic cardiovascular disease. J. Am. Coll. Cardiol. 2022; 80: 1998-2010 Crossref Scopus (1) Google Scholar ]. Further, as the Lp(a) cholesterol content is included in LDL cholesterol measurements, regardless of LDL cholesterol levels being measured directly or calculated from total and HDL cholesterol measurements, high Lp(a) levels may contribute to clinically diagnosed (using scoring systems) FH through points given based on LDL cholesterol levels, as well as through points for index patient and/or family history of premature ASCVD [ [2] Reyes-Soffer G. Ginsberg H.N. Berglund L. et al. Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American heart association. Arterioscler. Thromb. Vasc. Biol. 2022; 42: e48-e60 Crossref PubMed Scopus (37) Google Scholar , [8] Langsted A. Kamstrup P.R. Benn M. Tybjaerg-Hansen A. Nordestgaard B.G. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study. Lancet Diabetes Endocrinol. 2016; 4: 577-587 Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar , [9] Kronenberg F. Lipoprotein(a) measurement issues: are we making a mountain out of a molehill?. Atherosclerosis. 2022; 349: 123-135 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ]. Indeed, on this background variation in the LPA gene causing high Lp(a) has previously been suggested as the second most frequent cause of genetic FH, with the most frequent being mutations in the LDL receptor gene, LDLR [ [8] Langsted A. Kamstrup P.R. Benn M. Tybjaerg-Hansen A. Nordestgaard B.G. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study. Lancet Diabetes Endocrinol. 2016; 4: 577-587 Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar ].