Investigation of the molecular effects of the LPA KIV-2 mutation 4925 G>A
- Stefan Coassin (PI)
- Rebecca Grüneis (PhD Student)
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. 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 otherwise present the largest cardiovascular risk (Coassin et al, EHJ 38, 2017) .
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.
- Manuel Maglione and the team of the University Hospital for Visceral, Transplant and Thoracic Surgery (Head: Univ. Prof. Dietmar Öfner-Velano)
- Institute of Pathology Innsbruck
- Austrian Drug Screening Institute