Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease
Creators: name: Schachtl-Riess, Johanna F.
name: Kheirkhah, Azin
name: Grüneis, Rebecca
name: Di Maio, Silvia
name: Schoenherr, Sebastian
name: Streiter, Gertraud
name: Losso, Jamie Lee
name: Paulweber, Bernhard
name: Eckardt, Kai-Uwe
name: Köttgen, Anna
name: Lamina, Claudia
name: Kronenberg, Florian
name: Coassin, Stefan
name: For The GCKD Investigators, 
name: Eckardt, Kai-Uwe
name: Meiselbach, Heike
name: Schneider, Markus P.
name: Schiffer, Mario
name: Prokosch, Hans-Ulrich
name: Bärthlein, Barbara
name: Beck, Andreas
name: Reis, André
name: Ekici, Arif B.
name: Becker, Susanne
name: Becker-Grosspitsch, Dinah
name: Alberth-Schmidt, Ulrike
name: Hausknecht, Birgit
name: Weigel, Anke
name: Walz, Gerd
name: Köttgen, Anna
name: Schultheiß, Ulla T.
name: Kotsis, Fruzsina
name: Meder, Simone
name: Mitsch, Erna
name: Reinhard, Ursula
name: Floege, Jürgen
name: Saritas, Turgay
name: Schaeffner, Elke
name: Baid-Agrawal, Seema
name: Theisen, Kerstin
name: Haller, Hermann
name: Menne, Jan
name: Zeier, Martin
name: Sommerer, Claudia
name: Theilinger, Johanna
name: Wolf, Gunter
name: Busch, Martin
name: Paul, Rainer
name: Sitter, Thomas
name: Wanner, Christoph
name: Krane, Vera
name: Börner-Klein, Antje
name: Bauer, Britta
name: Kronenberg, Florian
name: Raschenberger, Julia
name: Kollerits, Barbara
name: Forer, Lukas
name: Schönherr, Sebastian
name: Weissensteiner, Hansi
name: Oefner, Peter J.
name: Gronwald, Wolfram
name: Schmid, Matthias
name: Nadal, Jennifer
Publisher: name: Universität Regensburg
Year: 2021
Subjects: subject: Mendelian randomization; cardiovascular disease; cohort study; copy number variation; genetic variability; lipoprotein(a)
subject: 610 Medizin

description: Background: Lipoprotein(a) (Lp(a)) concentrations are a major independent risk factor for coronary artery disease (CAD) and are mainly determined by variation in LPA. Up to 70% of the LPA coding sequence is located in the hypervariable kringle IV type 2 (KIV-2) region. It is hardly accessible by conventional technologies, but may contain functional variants. Objectives: This study sought to investigate the new, very frequent splicing variant KIV-2 4733G&gt;A on Lp(a) and CAD. Methods: We genotyped 4733G&gt;A in the GCKD (German Chronic Kidney Disease) study (n = 4,673) by allele-specific polymerase chain reaction, performed minigene assays, identified proxy single nucleotide polymorphisms and used them to characterize its effect on CAD by survival analysis in UK Biobank (n = 440,234). Frequencies in ethnic groups were assessed in the 1000 Genomes Project. Results: The 4733G&gt;A variant (38.2% carrier frequency) was found in most isoform sizes. It reduces allelic expression without abolishing protein production, lowers Lp(a) by 13.6 mg/dL (95% CI: 12.5-14.7; P &lt; 0.0001) and is the strongest variance-explaining factor after the smaller isoform. Splicing of minigenes was modified. Compound heterozygosity (4.6% of the population) for 4733G&gt;A and 4925G&gt;A, another KIV-2 splicing mutation, reduces Lp(a) by 31.8 mg/dL and most importantly narrows the interquartile range by 9-fold (from 42.1 to 4.6 mg/dL) when compared to the wild type. In UK Biobank 4733G&gt;A alone and compound heterozygosity with 4925G&gt;A reduced HR for CAD by 9% (95% CI: 7%-11%) and 12% (95% CI: 7%-16%) (both P &lt; 0.001). Frequencies in ethnicities differ notably. Conclusions: Functional variants in the previously inaccessible LPA KIV-2 region cooperate in determining Lp(a) variance and CAD risk. Even a moderate but lifelong genetic Lp(a) reduction translates to a noticeable CAD risk reduction.