A newly discovered LPA splicing variant lowers Lp(a) by 13.6 mg/dL and cuts coronary disease risk by 9%, found in 4,673 Germans and validated in 440,234 UK Biobank participants (J Am Coll Cardiol 2021)

Original title: Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease

J Am Coll Cardiol · 3 August 2021 · 8

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 et al.

Studying the hypervariable, previously hard-to-access kringle IV type 2 (KIV-2) region of LPA, which comprises up to 70% of the gene coding sequence, the authors identified a new, common splicing variant, 4733G>A (38.2% carrier frequency), in the German Chronic Kidney Disease study (n=4,673). This variant reduces Lp(a) by 13.6 mg/dL (95% CI 12.5-14.7, P<0.0001), the strongest Lp(a)-lowering factor after isoform size itself. Compound heterozygosity with another KIV-2 splicing variant, 4925G>A (4.6% of the population), reduced Lp(a) by 31.8 mg/dL and narrowed the interquartile range 9-fold (from 42.1 to 4.6 mg/dL). In the UK Biobank (n=440,234), 4733G>A alone and compound heterozygosity with 4925G>A reduced coronary artery disease hazard by 9% (95% CI 7%-11%) and 12% (95% CI 7%-16%) respectively (both P<0.001). The findings show that functional variants within the previously inaccessible LPA KIV-2 region meaningfully shape both Lp(a) levels and coronary disease risk, and that even modest lifelong genetic Lp(a) reduction translates into detectable cardiovascular benefit.

Original 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.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.