Schachtl-Riess Johanna F, Kheirkhah Azin, Grüneis Rebecca, Di Maio Silvia, Schoenherr Sebastian, Streiter Gertraud, Losso Jamie Lee, Paulweber Bernhard, Eckardt Kai-Uwe, Köttgen Anna, Lamina Claudia, Kronenberg Florian, Coassin Stefan
Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
First Department of Internal Medicine, Paracelsus Private Medical University, Salzburg, Austria.
J Am Coll Cardiol. 2021 Aug 3;78(5):437-449. doi: 10.1016/j.jacc.2021.05.037.
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.
This study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD.
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.
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.
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.
脂蛋白(a)[Lp(a)]浓度是冠状动脉疾病（CAD）的主要独立危险因素，主要由LPA基因变异决定。LPA编码序列中高达70%位于高变的kringle IV 2型（KIV-2）区域。传统技术很难获取该区域信息，但它可能包含功能变异。
本研究旨在探究新型且非常常见的剪接变异KIV-2 4733G>A与Lp(a)及CAD的关系。
我们在德国慢性肾脏病（GCKD）研究（n = 4673）中通过等位基因特异性聚合酶链反应对4733G>A进行基因分型，进行小基因分析，鉴定代理单核苷酸多态性，并利用它们在英国生物银行（n = 440234）中通过生存分析来表征其对CAD的影响。在千人基因组计划中评估了不同种族中的频率。
在大多数异构体大小中都发现了4733G>A变异（携带频率为38.2%）。它降低等位基因表达但不消除蛋白质产生，使Lp(a)降低13.6mg/dL（95%CI：12.5 - 14.7；P < 0.0001），是仅次于较小异构体的最强变异解释因子。小基因的剪接发生了改变。4733G>A与另一个KIV-2剪接突变4925G>A的复合杂合性（占人群的4.6%）使Lp(a)降低31.8mg/dL，最重要的是与野生型相比，四分位间距缩小了9倍（从42.1mg/dL降至4.6mg/dL）。在英国生物银行中，单独的4733G>A以及与4925G>A的复合杂合性使CAD的风险比（HR）分别降低了9%（95%CI：7% - 11%）和12%（95%CI：7% - 16%）（两者P < 0.001）。不同种族中的频率差异显著。
之前难以获取信息的LPA KIV-2区域中的功能变异共同决定Lp(a)变异和CAD风险。即使是适度但终身的遗传性Lp(a)降低也会导致CAD风险显著降低。
