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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.*

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

Atherosclerosis 349, 151-159 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Apolipoprotein(a) ; Coronary Artery Disease ; Kringle Iv-2 Repeat ; Lipoprotein(a) ; Mutation ; Snp Interaction
ISSN (print) / ISBN 0021-9150
e-ISSN 1879-1484
Journal Atherosclerosis
Quellenangaben Volume: 349, Issue: , Pages: 151-159 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Grants UK Biobank