Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease
Schachtl-Riess JF, Kheirkhah A, Grüneis R, Di Maio S, Schoenherr S, Streiter G, Losso JL, Paulweber B, Eckardt KU, Köttgen A, Lamina C, Kronenberg F, Coassin S (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 78
Pages Range: 437-449
Journal Issue: 5
DOI: 10.1016/j.jacc.2021.05.037
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.
Authors with CRIS profile
Involved external institutions
Medizinische Universität Innsbruck
Austria (AT)
Paracelsus Medizinische Privatuniversität
Austria (AT)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Austria (AT)
Paracelsus Medizinische Privatuniversität
Austria (AT)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
How to cite
APA:
Schachtl-Riess, J.F., Kheirkhah, A., Grüneis, R., Di Maio, S., Schoenherr, S., Streiter, G.,... Coassin, S. (2021). Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease. Journal of the American College of Cardiology, 78(5), 437-449. https://doi.org/10.1016/j.jacc.2021.05.037
MLA:
Schachtl-Riess, Johanna F., et al. "Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease." Journal of the American College of Cardiology 78.5 (2021): 437-449.
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