| Title: | Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease |
| Journal: | Journal of the American College of Cardiology |
| Published: | 1 Aug 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34325833/ |
| DOI: | https://doi.org/10.1016/j.jacc.2021.05.037 |
Publication 4866
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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.</p>
OBJECTIVES: This study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD.</p>
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.</p>
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.</p>
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.</p>
6 Keywords
- Coronary Artery Disease
- Genetic Variation
- Humans
- Kringles
- Lipoprotein(a)
- Prospective Studies
63 Authors
- 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
- GCKD Investigators
- 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
- Ulrike Alberth-Schmidt
- Birgit Hausknecht
- Anke Weigel
- Gerd Walz
- Anna Köttgen
- Ulla T. Schultheiß
- Fruzsina Kotsis
- Simone Meder
- Erna Mitsch
- Ursula Reinhard
- Jürgen Floege
- Turgay Saritas
- Elke Schaeffner
- Seema Baid-Agrawal
- Kerstin Theisen
- Hermann Haller
- Jan Menne
- Martin Zeier
- Claudia Sommerer
- Johanna Theilinger
- Gunter 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 Oefner
- Wolfram Gronwald
- Matthias Schmid
- Jennifer Nadal
1 Application
| Application ID | Title |
|---|---|
| 62905 | Analyzing unmappable ("camouflaged") genome regions in UK Biobank exome sequencing data using the LPA gene as a model. |
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