Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease

Schachtl-Rieß, J.F.; Kheirkhah, Azin; Grüneis, Rebecca; Maio, Silvia Di; Schoenherr, Sebastian; Streiter, Gertraud; Losso, Jamie Lee; Paulweber, Bernhard; Eckardt, Kai‐Uwe; Köttgen, Anna; Lamina, Claudia; Kronenberg, Florian; Coassin, Stefan; Meiselbach, Heike; Schneider, Markus P.; Schiffer, Mario; Prokosch, Hans‐Ulrich; Bärthlein, Barbara; Beck, Andreas; Reis, André; Ekici, Arif B.; Becker, Susanne; Becker-Grosspitsch, Dinah; Alberth-Schmidt, Ulrike; Hausknecht, Birgit; Weigel, Anke; Walz, Gerd; Schultheiß, Ulla T.; Kotsis, Fruzsina; Meder, Simone; Mitsch, Erna; Reinhard, Ursula; Floege, Jürgen; Saritas, Turgay; Schaeffner, Elke; Baid-Agrawal, Seema; Theisen, Kerstin; Haller, Hermann; Menne, Jan; Zeier, Martin; Sommerer, Claudia; Theilinger, Johanna; Wolf, G; Busch, M.; Paul, Rainer; Sitter, Thomas; Wanner, Christoph; Krane, Vera; Börner-Klein, Antje; Bauer, Britta; Raschenberger, Julia; Kollerits, Barbara; Forer, Lukas; Schönherr, Sebastian; Weißensteiner, Hansi; Oefner, Peter J.; Gronwald, Wolfram; Schmid, Matthias; Nadal, Jennifer

doi:10.1016/j.jacc.2021.05.037

Cited by 50 publications

(66 citation statements)

References 36 publications

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“…In the CCHS, participants in the highest Lp(a) tertile (>42 mg/dL) had an OR of femoral stenosis of 1.6 (95% CI, 1.3-2.0). Several large prospective population-based studies have since replicated these associations and in recent years, two common splice site mutations (G4925A and G4733A with 22% and 38% carrier frequencies, respectively) in the LPA KIV2 repeat region have been discovered and shown to have a pronounced Lp (a) decreasing effect, with a concomitant lower risk of CAD in carriers [5,33,34]. Although most genetic association studies investigating the potential discordance between apo(a) isoform size and Lp(a) levels on CAD risk provided evidence for a causal role of Lp(a) levels in CAD…”

Section: Coronary Artery Diseasementioning

confidence: 87%

Lipoprotein(a) and cardiovascular and valvular diseases: A genetic epidemiological perspective

Arsenault

Kamstrup

2022

Atherosclerosis

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Section: Coronary Artery Diseasementioning

confidence: 87%

Lipoprotein(a) and cardiovascular and valvular diseases: A genetic epidemiological perspective

Arsenault

Kamstrup

2022

Atherosclerosis

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“…34 In datasets with genetic information but not directly measured Lp(a), the Lp(a) GRS might thus be a valid surrogate for Lp(a) plasma levels, as the effect of the GRS on cardiovascular risk appears fully mediated by its effect on Lp(a) concentrations. 34–37…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Characterization of a Highly Penetrant Form of Hyperlipoprotein(a)emia Associated With Genetically Elevated Cardiovascular Risk

Coassin

Chemello

Khantalin

et al. 2022

Circ: Genomic and Precision Medicine

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Background: Lp(a) (lipoprotein [a]) is a highly atherogenic lipoprotein strongly associated with coronary artery disease (CAD). Lp(a) concentrations are chiefly determined genetically. Investigation of large pedigrees with extreme Lp(a) using modern whole-genome approaches may unravel the genetic determinants underpinning this pathological phenotype. Methods: A large family characterized by high Lp(a) and increased CAD incidence was recruited by cascade screening. Plasma lipids, lipoproteins, and apolipoproteins concentrations, as well as the size of apo(a) isoforms, were determined enzymatically by high-resolution mass spectrometry and Western blot, respectively. Whole-exome sequencing was performed to search for rare defects in modifier genes. Genetic risk scores (GRS) for Lp(a) and CAD were calculated and their discriminative power was assessed. Results: Seventeen individuals displayed extreme Lp(a) levels including 6 with CAD. Whole-exome sequencing showed no hint for genetic defects outside the LPA locus. The extreme Lp(a) phenotype segregated with the presence of a short apo(a) isoform containing 21 Kringle IV domains. This allele was characterized by the presence of three rare strongly Lp(a) increasing single nucleotide polymorphisms and a significantly increased load of oxidized phospholipids per Lp(a) particle. An Lp(a) GRS consisting of 48 single nucleotide polymorphisms that represent 2001 genome-wide significant LPA single nucleotide polymorphisms, efficiently captured the hyper-Lp(a) phenotype and discriminated affected and nonaffected individuals with great accuracy. The genome-wide GRS for CAD, encompassing 6.6 million single nucleotide polymorphisms, was very high for most family members (>97.5 percentile of the reference population), but this observation was no longer valid when the contribution of the LPA locus was omitted. Conclusions: High-Lp(a) phenotypes can be successfully captured using the Lp(a) GRS even among closely related family members. In hyper-Lp(a) individuals, LPA can be a major locus driving a very high CAD GRS. This underpins the large contribution of the LPA locus to the cardiovascular genetic risk in families.

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“…Fig. 2D provides an example of such a strongly Lp(a)-modifying SNP (KIV-2 4925G>A) [ 24 , 29 , 30 ]. Because of the differing maturation efficiencies and the modifying SNPs, the two LPA alleles of heterozygous individuals are not necessarily equally secreted to plasma.…”

Section: Lipoprotein(a) Plasma Concentrations – An Enigmatic Traitmentioning

confidence: 99%

“…Nevertheless, the causality of Lp(a) has been debated for a long time [ 36 ] until numerous genetic studies underscored the causality of Lp(a) concentrations using genetic variants strongly associated with high Lp(a) concentrations and subsequent cardiovascular disease [ 37 – 44 ]. Several studies showed also that variants associated with low Lp(a) exert a protective effect on cardiovascular disease [ 29 , 30 , 38 , 45 , 46 ]. On the other hand, it still takes some efforts to find the right genetic instrument to investigate a causal association between extremely low Lp(a) concentrations and diabetes mellitus [ 38 , 47 – 49 ].…”

Section: Why Are We Keen To Understand the Genetic Regulation Of Lp(a)?mentioning

confidence: 99%

“… Lp(a) concentrations show pronounced differences across ancestries, which we do not completely understand yet. There is evidence that SNPs with a strong influence on Lp(a) concentrations show a wide frequency variability across ancestries [ 24 , 29 , 30 , 51 ]. Others also suggested a role of environmental exposures, respectively differing inflammatory burden [ 52 , 53 ].…”

Section: Why Are We Keen To Understand the Genetic Regulation Of Lp(a)?mentioning

confidence: 99%

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Lipoprotein(a) beyond the kringle IV repeat polymorphism: The complexity of genetic variation in the LPA gene

Coassin

Kronenberg

2022

Atherosclerosis

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Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease

Cited by 50 publications

References 36 publications

Lipoprotein(a) and cardiovascular and valvular diseases: A genetic epidemiological perspective

Lipoprotein(a) and cardiovascular and valvular diseases: A genetic epidemiological perspective

Genome-Wide Characterization of a Highly Penetrant Form of Hyperlipoprotein(a)emia Associated With Genetically Elevated Cardiovascular Risk

Lipoprotein(a) beyond the kringle IV repeat polymorphism: The complexity of genetic variation in the LPA gene

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