The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat
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 promot...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227522001390 |
| _version_ | 1797979811486892032 |
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| author | Rebecca Grüneis Hansi Weissensteiner Claudia Lamina Sebastian Schönherr Lukas Forer Silvia Di Maio Gertraud Streiter Annette Peters Christian Gieger Florian Kronenberg Stefan Coassin |
| author_facet | Rebecca Grüneis Hansi Weissensteiner Claudia Lamina Sebastian Schönherr Lukas Forer Silvia Di Maio Gertraud Streiter Annette Peters Christian Gieger Florian Kronenberg Stefan Coassin |
| author_sort | Rebecca Grüneis |
| collection | DOAJ |
| description | 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 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 2,858 individuals. We found a considerable linkage disequilibrium 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 a linkage disequilibrium with the frequent splicing mutation KIV-2 4925G>A. |
| first_indexed | 2024-04-11T05:44:33Z |
| format | Article |
| id | doaj.art-7ca7fd1b9f194420b10ece6fefb904c3 |
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| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-04-11T05:44:33Z |
| publishDate | 2022-12-01 |
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| series | Journal of Lipid Research |
| spelling | doaj.art-7ca7fd1b9f194420b10ece6fefb904c32022-12-22T04:42:17ZengElsevierJournal of Lipid Research0022-22752022-12-016312100306The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeatRebecca Grüneis0Hansi Weissensteiner1Claudia Lamina2Sebastian Schönherr3Lukas Forer4Silvia Di Maio5Gertraud Streiter6Annette Peters7Christian Gieger8Florian Kronenberg9Stefan Coassin10Department of Genetics, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Genetics, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Genetics, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Genetics, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Genetics, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Genetics, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Genetics, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, AustriaGerman Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-University Munich, Munich, GermanyGerman Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyDepartment of Genetics, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Genetics, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria; For correspondence: Stefan CoassinLipoprotein(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 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 2,858 individuals. We found a considerable linkage disequilibrium 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 a linkage disequilibrium with the frequent splicing mutation KIV-2 4925G>A.http://www.sciencedirect.com/science/article/pii/S0022227522001390lipoprotein(a)lipoprotein(a) metabolismapolipoproteinsgenomicslipoproteinsapolipoprotein(a) |
| spellingShingle | Rebecca Grüneis Hansi Weissensteiner Claudia Lamina Sebastian Schönherr Lukas Forer Silvia Di Maio Gertraud Streiter Annette Peters Christian Gieger Florian Kronenberg Stefan Coassin The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat Journal of Lipid Research lipoprotein(a) lipoprotein(a) metabolism apolipoproteins genomics lipoproteins apolipoprotein(a) |
| title | The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat |
| title_full | The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat |
| title_fullStr | The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat |
| title_full_unstemmed | The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat |
| title_short | The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat |
| title_sort | kringle iv type 2 domain variant 4925g a causes the elusive association signal of the lpa pentanucleotide repeat |
| topic | lipoprotein(a) lipoprotein(a) metabolism apolipoproteins genomics lipoproteins apolipoprotein(a) |
| url | http://www.sciencedirect.com/science/article/pii/S0022227522001390 |
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