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Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease.
- Source :
-
Journal of the American College of Cardiology (JACC) . Aug2021, Vol. 78 Issue 5, p437-449. 13p. - Publication Year :
- 2021
-
Abstract
- <bold>Background: </bold>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.<bold>Objectives: </bold>This study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CORONARY artery disease
*SINGLE nucleotide polymorphisms
*CHRONIC kidney failure
*GENETIC variation
*POLYMERASE chain reaction
*ATHEROSCLEROSIS
*LIPOPROTEINS
*PROTEINS
*RESEARCH
*GENETICS
*RESEARCH methodology
*MEDICAL cooperation
*EVALUATION research
*COMPARATIVE studies
*LONGITUDINAL method
Subjects
Details
- Language :
- English
- ISSN :
- 07351097
- Volume :
- 78
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of the American College of Cardiology (JACC)
- Publication Type :
- Academic Journal
- Accession number :
- 151467004
- Full Text :
- https://doi.org/10.1016/j.jacc.2021.05.037