A common LPA gene variant only raises Lp(a) and coronary disease risk in the 96% of people who do not also carry a specific splicing mutation, a genetic study of 184,283 people (Atherosclerosis 2022)

Original title: The effect of LPA Thr3888Pro on lipoprotein(a) and coronary artery disease is modified by the LPA KIV-2 variant 4925G>A

Atherosclerosis · 26 April 2022 · 7

Grüneis R, Lamina C, Di Maio S, Schönherr S, Zoescher P, Forer L, Streiter G, Peters A, Gieger C, Köttgen A, Kronenberg F, Coassin S

Studying the LPA missense variant rs41272110 (Thr3888Pro) and the KIV-2 splicing variant 4925G>A across the German Chronic Kidney Disease study, KORA-F3/F4 (combined n=10,405), and the UK Biobank 200k exome dataset (n=173,878), the authors found a significant SNP-SNP interaction in all cohorts (P=1.26e-05 to 3.03e-04). Considered alone, rs41272110 showed no effect on Lp(a) (beta -0.06, P=0.879) or coronary artery disease (CAD) risk (HR 1.01, CI0.97-1.04, P=0.731). But in a joint model accounting for both variants, rs41272110 was associated with markedly higher Lp(a) (beta +9.40 mg/dL, CI6.45-12.34, P=4.07e-10), and rs41272110 carriers who did not also carry 4925G>A, about 4% of the population, had increased CAD risk (HR 1.10, CI1.04-1.16, P=6.9e-04). The findings show that ignoring genetic subgroup structure can mask or dilute true Lp(a)-CAD genetic associations.

Original abstract

Background And Aims: High lipoprotein(a) [Lp(a)] concentrations are associated with increased coronary artery disease (CAD) risk. Lp(a) is regulated mainly genetically by the LPA gene but involved genetic variants have not been fully elucidated. Improved understanding of the entanglements of genetic Lp(a) regulation may enhance genetic prediction of Lp(a) and CAD risk. We investigated an interaction between the well-known LPA missense SNP rs41272110 (known as Thr3888Pro) and the frequent LPA splicing mutation KIV-2 4925G>A.

Methods: Effects on Lp(a) concentrations were investigated by multiple quantile regression in the German Chronic Kidney Disease (GCKD) study, KORA-F3 and KORA-F4 (ntotal = 10,405) as well as in the UK Biobank (UKB) 200k exome dataset (n = 173,878). The impact of the interaction on CAD risk was assessed by survival analysis in UKB.

Results: We observed a significant SNP-SNP interaction in all studies (p = 1.26e-05 to 3.03e-04). In quantile regression analysis, rs41272110 as a predictor shows no impact on Lp(a) (β = -0.06 [-0.79; 0.68], p = 0.879), but in a joint model including both SNPs as predictors, rs41272110 is associated with markedly higher Lp(a) (β = +9.40 mg/dL [6.45; 12.34], p = 4.07e-10). Similarly, rs41272110 shows no effect on CAD in UKB (HR = 1.01 [0.97; 1.04], p = 0.731), while rs41272110 carriers not carrying 4925G>A show an increased CAD risk (HR = 1.10 [1.04; 1.16], p = 6.9e-04). This group corresponds to 4% of the population. Adjustment for apolipoprotein(a) isoforms further modified the effect estimates markedly.

Conclusions: This work emphasizes the complexity of the genetic regulation of Lp(a) and the importance to account for genetic subgroups in Lp(a) association studies and when interpreting genetic cardiovascular risk profiles.

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