JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 卷:78 |
Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease | |
Article | |
Schachtl-Riess, Johanna F.1  Kheirkhah, Azin1  Gruneis, Rebecca1  Di Maio, Silvia1  Schoenherr, Sebastian1  Streiter, Gertraud1  Losso, Jamie Lee1  Paulweber, Bernhard2  Eckardt, Kai-Uwe3,4  Kottgen, Anna5,6  Lamina, Claudia1  Kronenberg, Florian1  Coassin, Stefan1  | |
[1] Med Univ Innsbruck, Dept Genet & Pharmacol, Inst Genet Epidemiol, Schoepfstr 41, A-6020 Innsbruck, Austria | |
[2] Paracelsus Private Med Univ, Dept Internal Med 1, Salzburg, Austria | |
[3] Friedrich Alexander Univ Erlangen Nurnberg, Dept Nephrol & Hypertens, Erlangen, Germany | |
[4] Charite Univ Med Berlin, Dept Nephrol & Med Intens Care, Berlin, Germany | |
[5] Univ Freiburg, Inst Genet Epidemiol, Fac Med, Freiburg, Germany | |
[6] Univ Freiburg, Med Ctr, Freiburg, Germany | |
关键词: cardiovascular disease; cohort study; copy number variation; genetic variability; lipoprotein(a); Mendelian randomization; | |
DOI : 10.1016/j.jacc.2021.05.037 | |
来源: Elsevier | |
【 摘 要 】
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 hyper variable 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. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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