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Grüneis, R.* ; Weissensteiner, H.* ; Lamina, C.* ; Schönherr, S.* ; Forer, L.* ; Di Maio, S.* ; Streiter, G.* ; Peters, A. ; Gieger, C. ; Kronenberg, F.* ; Coassin, S.*

The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat.

J. Lipid Res. 63, 11:100306 (2022)
Verlagsversion Forschungsdaten DOI PMC
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Lipoprotein(a) [Lp(a)] concentrations are regulated by the LPA gene mainly via the large kringle IV-type 2 (KIV-2) copy number variation and multiple causal variants. Early studies suggested an effect of long pentanucleotide repeat (PNR) alleles (10 and 11 repeats, PNR10 and PNR11) in the LPA promoter on gene transcription and found an association with lower Lp(a). Subsequent in-vitro studies showed no effects on mRNA transcription, but the association with strongly decreased Lp(a) remained consistent. We investigated the isolated and combined effect of PNR10, PNR11 and the frequent splice site variant KIV-2 4925G>A on Lp(a) concentrations in the Cooperative Health Research in the Region of Augsburg (KORA) F4 study by multiple quantile regression in single-SNP and joint models. Data on Lp(a), apolipoprotein(a) Western blot isoforms and variant genotypes were available for n=2,858 individuals. We found a considerable linkage disequilibrium (LD) between KIV-2 4925G>A and the alleles PNR10 and PNR11. In single variant analysis adjusted for age, sex, and the shorter apo(a) isoform we determined that both PNR alleles were associated with a highly significant Lp(a) decrease (PNR10: β=-14.43 mg/dL, 95% CI: -15.84,-13.02, p=3.33e-84; PNR11: β=-17.21 mg/dL, 95% CI: -20.19,-14.23, p=4.01e-29). However, a joint model, adjusting the PNR alleles additionally for 4925G>A abolished the effect on Lp(a) (PNR10: β=+0.44 mg/dL, 95% CI: -1.73,2.60, p=0.69; PNR11: β=-1.52 mg/dL, 95% CI: -6.05,3.00, p=0.51). Collectively, we conclude that the previously reported Lp(a) decrease observed in pentanucleotide alleles PNR10 or PNR11 carriers results from an LD with the frequent splicing mutation KIV-2 4925G>A.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Apolipoproteins ; Free Keywords: Kringle Iv-2 Repeat ; Genomics ; Lipoprotein(a) Metabolism ; Lipoprotein(a) Regulation ; Lipoproteins ; Listed Keywords: Lipoprotein(a) ; Apolipoprotein(a) ; Complex Genome Region ; Short Tandem Repeat; KORA, Herz-Kreislauf, Genetik
ISSN (print) / ISBN 0022-2275
e-ISSN 1539-7262
Zeitschrift Journal of Lipid Research
Quellenangaben Band: 63, Heft: 12, Seiten: 11, Artikelnummer: 100306 Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Verlagsort Radarweg 29, 1043 Nx Amsterdam, Netherlands
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
Förderungen Austrian Science Fund (FWF)
State of Bavaria
Helmholtz Zentrum Munchen -German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
Austrian Atherosclerosis Society