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

Trinder, Mark; DeCastro, Maria Liza; Azizi, Hawmid; Cermakova, Luba; Jackson, Leland J.; Fröhlich, Jiří; Mancini, G.B. John; Francis, Gordon A.; Brunham, Liam R.

doi:10.1016/j.jacc.2020.03.065

Cited by 58 publications

(45 citation statements)

References 43 publications

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“…However, after adjusting LDL-C levels for Lp(a) cholesterol to more accurately assess the FH status, those values were similar at 24, 22, and 21 mg/dl, respectively. Similar observations were made when using the make early diagnosis to prevent early deaths or Simon-Broome FH diagnostic criteria (77) as well as in the British Columbia FH cohort using the Dutch Lipid Clinics Network criteria (78), indicating that a substantial proportion of patients clinically diagnosed with FH are in fact hyperlipoprotein(a)emic and not genuine FH.…”

Section: Lipoprotein (A)supporting

confidence: 69%

Lipoprotein metabolism in familial hypercholesterolemia

Chemello

García-Nafría

Gallo

et al. 2021

Journal of Lipid Research

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Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes ( LDLR/APOB/PCSK9/LDLRAP1 ) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to investigate molecular defects affecting the LDL receptor pathway. In addition, we review perturbations in the metabolism of lipoproteins other than LDL in FH, with a major focus on lipoprotein (a). Finally, we discuss the mode of action and efficacy of many of the currently approved hypocholesterolemic agents used to treat patients with FH, with a special emphasis on the treatment of phenotypically more severe forms of FH.

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Section: Lipoprotein (A)supporting

confidence: 69%

Lipoprotein metabolism in familial hypercholesterolemia

Chemello

García-Nafría

Gallo

et al. 2021

Journal of Lipid Research

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“…However, the hypothesis of Lp(a) clearance through the LDLR has been challenged recently. No differences in Lp(a) levels were found between carriers of pathogenic variants of LDLR and APOB vs. noncarriers [ 13 ].…”

Section: Introduction—an Overviewmentioning

confidence: 99%

“…An Italian and Swedish series showed that elevated Lp(a) significantly contributed to the raised CV risk in patients with a genomic diagnosis of FH [ 39 ]. It seems that FH does not cause hyperlipoproteinemia(a), but that a rise in Lp(a) increases the probability that an individual with genetic FH will be clinically recognized [ 13 ].…”

Section: Introduction—an Overviewmentioning

confidence: 99%

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Greco

Sirtori

Corsini

et al. 2020

JCM

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It is well-known that elevated lipoprotein(a)—Lp(a)—levels are associated with a higher risk of cardiovascular (CV) mortality and all-cause mortality, although a standard pharmacotherapeutic approach is still undefined for patients with high CV risk dependent on hyperlipoproteinemia(a). Combined with high Lp(a) levels, familial hypercholesterolemia (FH) leads to a greater CVD risk. In suspected FH patients, the proportion of cases explained by a rise of Lp(a) levels ranges between 5% and 20%. In the absence of a specific pharmacological approach able to lower Lp(a) to the extent required to achieve CV benefits, the most effective strategy today is lipoprotein apheresis (LA). Although limited, a clear effect on Lp(a) is exerted by PCSK9 antagonists, with apparently different mechanisms when given with statins (raised catabolism) or as monotherapy (reduced production). In the era of RNA-based therapies, a new dawn is represented by the use of antisense oligonucleotides APO(a)Lrx, able to reduce Lp(a) from 35% to over 80%, with generally modest injection site reactions. The improved knowledge of Lp(a) atherogenicity and possible prevention will be of benefit for patients with residual CV risk remaining after the most effective available lipid-lowering agents.

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“…These results appear to be compatible with findings obtained in clinical trials using PCSK9 inhibitors. Furthermore, a recent PheWAS focusing on Lipoprotein (a) [LPA] genotypes and thousands of phenotypes showed an inverse relationship between FH and elevated Lp(a) 53) . Lp(a) is elevated in patients with FH, the mechanism of which remains unclear.…”

Section: Phenome In Addition To Genomementioning

confidence: 99%

Challenges of Precision Medicine for Atherosclerotic Cardiovascular Disease Based on Human Genome Information

Tada

Usui

Sakata

et al. 2021

JAT

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The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Review Precision or personalized medicine is currently gaining a lot of attention. Clinical evidence for its effectiveness has been established based on randomized clinical trials accounting for classical risk factors, such as hypertension, diabetes, and serum lipids. However, besides such classical risk factors, the genetic background should be considered, at least for heritable traits, including atherosclerotic cardiovascular disease (ASCVD). Such classical risk factors are almost always incidents that have already occurred in which it may be too late to start treatment, instead of indicators of presymptomatic state. Human genome information is associated with most traits, including ASCVD. Two methods of implementing precision medicine for ASCVD using human genome information are currently being investigated: the use of rare genetic variations that have large effect sizes and polygenic risk scores that are composed of multiple common genetic variations. This review article emphasizes the importance of clinical as well as genetic diagnoses when implementing precision medicine. Precision medicine should be considered based on comprehensive genetic analyses, encompassing rare to common genetic variations. is strongly associated with premature ASCVD 4). A single loss-of-function genetic mutation in the LDL receptor gene is associated with ASCVD via elevation of LDL cholesterol because LDL cholesterol is one of the causal factors of ASCVD 5). However, there are a substantial number of people who are at extremely high risk for inherited ASCVD that is not associated with serum lipids. Causal links between biology and ASCVD development in such inherited risk factors exist. Aim The following review describes conditions beginning with FH in which precision medicine for ASCVD seems to be quite effective, to other conditions in which precision medicine for ASCVD is currently being rigorously examined.

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

Cited by 58 publications

References 43 publications

Lipoprotein metabolism in familial hypercholesterolemia

Lipoprotein metabolism in familial hypercholesterolemia

Lipoprotein(a) Lowering—From Lipoprotein Apheresis to Antisense Oligonucleotide Approach

Challenges of Precision Medicine for Atherosclerotic Cardiovascular Disease Based on Human Genome Information

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