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Funded by the Austrian Science Fund (FWF)

Project 31458, project start: November 2018

Team

Rebecca Grüneis (PhD Student)

Peter Zöscher (MSc Student)

Monika Summerer (PostDoc)

Background

The KIV-2 copy number variation encodes up to 70% of the LPA gene, but has been a white spot on the genome for a long time due to its repetitive structure (Ebbert et al recently termed it a “camouflaged” gene”; Ebbert et al, Genome Biol 20, 2019). We have recently developed a sequencing approach and a validated bioinformatic analysis pipeline that is able to reliably detect mutations in this region (link to github).

Using this approach, we identified a genetic variant (named LPA KIV-2 4925G>A) that is highly frequent in the population and strongly decreases the Lp(a) levels of individuals presenting a small Lp(a) isoform (Coassin et al, EHJ 38, 2017). This results in small Lp(a) isoforms with unusual low Lp(a) concentrations. Although 22% of the population carries this variant, it had been overlooked in all previous studies due to its location in the KIV-2 region. The mechanism by which 4925G>A lowers Lp(a) is not understood, yet.

Some variants in the KIV-2 region can have large effects on the Lp(a) concentrations. In the figure left-hand, the 4925G>A variant (carriers shown in red) is associated with an up to 30 mg/dL decrease in Lp(a) concentrations (double the median in the general population) compared to non-carriers (“wt”). This effect is most pronounced in the smaller Lp(a) isoforms, which are those which present otherwise the largest cardiovascular risk (Coassin et al, EHJ 38, 2017) .

Project description

In this project we aim at understanding the mechanism by which the LPA KIV-2 4925G>A variant lowers Lp(a) and at investigating the molecular causes of LPA null alleles.

Functional research on Lp(a) is hampered by the fact that it is expressed to a high level exclusively in liver tissue and no cell line expresses Lp(a). In collaboration with the team of the University Hospital for Visceral, Transplant and Thoracic Surgery (Head: Univ. Prof. Dietmar Öfner-Velano; Collabrating partner: Assoc. Prof. Dr. Manuel Maglione) we are collecting tissue samples from donors who undergo liver resection.

All samples are fully genotyped and phenotyped regading their LPA genotypes by PFGE, Western blot, ELISA and targeted genotyping of several functional SNPs, as well as 4925 G>A. These samples will then be used to investigate the impact of 4925 G>A on the transcription of the LPA gene using targeted and whole transcriptome approaches.

Expression profiling ressources like GTEx do not include any LPA phenotype information and are thus of limited utility for LPA genetics. Our project will generate a large collection of liver tissue and liver mRNA from individuals with complete Lp(a) phenotypes and data and provide a new ressource for the scientific community.

Project updates

April 2020

Rebecca will give her first progress seminar for the Innsbruck Genetics, Epigenetics and Genomics PhD School on April 30th 2020. Has been a year with lots of work, indeed…

March 2020

After a great year Peter now leaves the lab to write up his thesis. Great work and looking forward to read it!

May 2019

Welcome in the team to Rebecca!

May 2019

Stefan presented our recent survey on the complete genetic variability in the KIV-2 region (Coassin et al, JLR 60, 2019) and the effects of the LPA KIV-2 R21X null allele in 11,000 individuals at the EAS 2019 in Maastricht.

April and May 2019

Silvia Di Maio presented her master thesis work on the effects of the LPA KIV-2 R21X null allele in 11,000 individuals at the Austrian Atherosclerosis Society meeting 2019 and at the Grainau Workshop on Genetic Epidemiology 2019.

April 2019

Welcome in the team to Monika!

March 2019

Welcome in the team to Peter!

Collaborators

  • Manuel Maglione and the team of the University Hospital for Visceral, Transplant and Thoracic Surgery (Head: Univ. Prof. Dietmar Öfner-Velano)
  • Austrian Drug Screening Institute