Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease
Johanna F. Schachtl‐Riess, Azin Kheirkhah, Rebecca Grüneis, Silvia Di Maio, Sebastian Schoenherr, Gertraud Streiter, Jamie Lee Losso, Bernhard Paulweber, Kai‐Uwe Eckardt, Anna Köttgen, Claudia Lamina, Florian Kronenberg, Stefan Coassin, Kai‐Uwe Eckardt, Heike Meiselbach, Markus P. Schneider, Mario Schiffer, Hans‐Ulrich Prokosch, Barbara Bärthlein, Andreas Beck, André Reis, Arif B. Ekici, Susanne Becker, Dinah Becker-Grosspitsch, Matthias Schmid, Birgit Hausknecht, Anke Weigel, Gerd Walz, Anna Köttgen, Ulla T. Schultheiß, Fruzsina Kotsis, Simone Meder, Erna Mitsch, Ursula Reinhard, Jürgen Floege, Turgay Saritas, Elke Schäeffner, Seema Baid‐Agrawal, Kerstin Theisen, Hermann Haller, Jan Menne, Martin Zeier, Claudia Sommerer, Johanna Theilinger, Günter Wolf, Martin Busch, Rainer Paul, Thomas Sitter, Christoph Wanner, Vera Krane, Antje Börner-Klein, Britta Bauer, Florian Kronenberg, Julia Raschenberger, Barbara Kollerits, Lukas Forer, Sebastian Schönherr, Hansi Weißensteiner, Peter J. Oefner, Wolfram Gronwald, Matthias Schmid, Jennifer Nadal
Abstract
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>A on Lp(a) and CAD. METHODS: We genotyped 4733G>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>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 < 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>A and 4925G>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>A alone and compound heterozygosity with 4925G>A reduced HR for CAD by 9% (95% CI: 7%-11%) and 12% (95% CI: 7%-16%) (both P < 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.