Format

Send to

Choose Destination
Eur Heart J. 2017 Jun 14;38(23):1823-1831. doi: 10.1093/eurheartj/ehx174.

A novel but frequent variant in LPA KIV-2 is associated with a pronounced Lp(a) and cardiovascular risk reduction.

Author information

1
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Schoepfstrasse 41, 6020 Innsbruck, Austria.
2
Division of Cell Biology, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
3
Division of Genetic Epidemiology, Division of Genetic Epidemiology - Faculty of Medicine and Medical Center - University of Freiburg, Hugstetter Strasse 49, 79106 Freiburg, Germany.
4
Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Peter-Mayr-Strasse 1, 6020 Innsbruck, Austria.
5
German Center for Diabetes Research, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
6
Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
7
Munich Heart Alliance, German Center for Cardiovascular Disease Research, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
8
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
9
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
10
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377 Munich, Germany.
11
Internal Medicine I, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
12
Section of Interventional Oncology - Microinvasive Therapy (SIP), Department of Radiology, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
13
First Department of Internal Medicine, Paracelsus Private Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
14
Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
15
Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

Abstract

Aims:

Lp(a) concentrations represent a major cardiovascular risk factor and are almost entirely controlled by one single locus (LPA). However, many genetic factors in LPA governing the enormous variance of Lp(a) levels are still unknown. Since up to 70% of the LPA coding sequence are located in a difficult to access hypervariable copy number variation named KIV-2, we hypothesized that it may contain novel functional variants with pronounced effects on Lp(a) concentrations. We performed a large scale mutation analysis in the KIV-2 using an extreme phenotype approach.

Methods and Results:

We compiled an discovery set of 123 samples showing discordance between LPA isoform phenotype and Lp(a) concentrations and controls. Using ultra-deep sequencing, we identified a splice site variant (G4925A) in preferential association with the smaller LPA isoforms. Follow-up in a European general population (n = 2892) revealed an exceptionally high carrier frequency of 22.1% in the general population. The variant explains 20.6% of the Lp(a) variance in carriers of low molecular weight (LMW) apo(a) isoforms (P = 5.75e-38) and reduces Lp(a) concentrations by 31.3 mg/dL. Accordingly the odds ratio for cardiovascular disease was reduced from 1.39 [95% confidence interval (CI): 1.17-1.66, P = 1.89e-04] for wildtype LMW individuals to 1.19 [95%CI: 0.92; 1.56, P = 0.19] in LMW individuals who were additionally positive for G4925A. Functional studies point towards a reduction of splicing efficiency by this novel variant.

Conclusion:

A highly frequent but until now undetected variant in the LPA KIV-2 region is strongly associated with reduced Lp(a) concentrations and reduced cardiovascular risk in LMW individuals.

KEYWORDS:

CVD risk; Copy number variation; Kringle IV-type 2; LPA; Lipoprotein(a)

PMID:
28444229
PMCID:
PMC5837733
DOI:
10.1093/eurheartj/ehx174
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center