Lipoprotein(a) Genomics

We are interested in understanding how genetic variants in LPA contribute to the huge variance in lipoprotein(a) concentrations observed between individuals and across ancestries.

Lead

Stefan Coassin, PhD
Associate Professor

+43 512 9003 70576
stefan.coassin@i-med.ac.at

Co-Lead

Florian Kronenberg, MD, MAE
Full Professor

+43 512 9003 70560
florian.kronenberg@i-med.ac.at
Sebastian Schönherr, Dr.techn.
Professor of Computational Genomics

+43 512 9003 70579
sebastian.schoenherr@i-med.ac.at

Team

Stephan Amstler, MSc.
PhD Student

+43 512 9003 70574
stephan.amstler@i-med.ac.at
Silvia Di Maio, PhD
Postdoc

+43 512 9003 70567
silvia.di-maio@i-med.ac.at
Lara Escherich, MSc.
Lab technician

+43 512 9003 70572
lara.escherich@i-med.ac.at
Mohadeseh Ragerdikashani, MSc.
Lab technician (part-time)

mohadeseh.ragerdikashani@i-med.ac.at
Gertraud Streiter, BSc.
Lab technician (BMA)

+43 512 9003 70573
gertraud.streiter@i-med.ac.at

About

Genetic variation in the LPA gene explains up to 90% of lipoprotein(a) [Lp(a)] plasma concentrations in the population but the genetic mechanisms that govern the individual lipoprotein(a) concentrations are poorly understood. We investigate how functional genetic variants in LPA create the huge variance in lipoprotein(a) concentrations that we observe between individuals and across ancestries. A major part of our work concerns the investigation of mutations located in the KIV-2 repeat region of the LPA gene. This repetitive region can encompass up to 70% of the coding sequence of the gene, but, due to its complex structure, it has not been accessible until recently. By combining the computational expertise of the institute in the detection of low-level mutations, advanced molecular techniques genetics and our long-standing experience in Lp(a) research, we have developed a comprehensive genetic toolset capable of adressing many difficult aspects of Lp(a) genetics. Additionally, we enjoy exploring the potential of nanopore sequencing and other emerging genetic technologies to tackle tough genetic questions across disciplines.

Many SNPs have been identified as modifiers of Lp(a) concentrations, including several variants located within the complex KIV-2 VNTR region. The exons are numbered according to the protein domain that they encode (1–10: KIV-1 to KIV-10, L. leader sequence, P. protease domain, 5’: 5′UTR, 3’: 3′ UTR). SNPs that result in a complete loss of protein production (null alleles) are underlined. Figure reproduced from Coassin and Kronenberg, Atherosclerosis 349:17–35, 2022 (https://doi.org/10.1016/j.atherosclerosis.2022.04.003) under CC-BY 4.0 license.
Many SNPs have been identified as modifiers of Lp(a) concentrations, including several variants located within the complex KIV-2 VNTR region. The exons are numbered according to the protein domain that they encode (1–10: KIV-1 to KIV-10, L. leader sequence, P. protease domain, 5’: 5′UTR, 3’: 3′ UTR). SNPs that result in a complete loss of protein production (null alleles) are underlined. Figure reproduced from Coassin and Kronenberg, Atherosclerosis 349:17–35, 2022 (https://doi.org/10.1016/j.atherosclerosis.2022.04.003) under CC-BY 4.0 license.

Nanopore Sequencing

Nanopore sequencing allows sequencing DNA and RNA molecules by monitoring fluctuations in the ionic current while a DNA or RNA strand moves through a protein pore. Unlike other technologies, Nanopore sequencing provides data in real-time, allows up to megabase-sized read lengths, reads directly the native target molecule, provides true single molecule data and keeps information about epigenetic modifications. It also allows direct phasing of variants over long DNA segments, which is of special use in Lp(a) genetics. These features make it an appealing technology to target complex genes with structural variants and extensive homologies like the LPA gene. We explore applications of this technologies in Lp(a) genetics and beyond (human genetics, variant phasing, DNA/RNA epigenetics and metagenomics).

Technologies in our Lab

Other GenEpi Investigators involved

Funding and Projects

Earlier Team Members and Students

Key Publications

Coassin S, Kronenberg F: Lipoprotein(a) beyond the kringle IV repeat polymorphism: The complexity of genetic variation in the LPA gene. Atherosclerosis 349:17-35, 2022. PMID: 35606073   Review

Amstler S, Streiter G, Pfurtscheller C, Forer L, Di Maio S, Weissensteiner H, Paulweber B, Schönherr S, Kronenberg F, Coassin S: Nanopore sequencing with unique molecular identifiers enables accurate mutation analysis and haplotyping in the complex lipoprotein(a) KIV-2 VNTR. Genome Med. 16:117, 2024. PMID: 39380090   Journal Article

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. 63:100306, 2022. PMID: 36309064   Journal Article

Grüneis R, Lamina C, Di Maio S, Schönherr S, Zoescher P, Forer L, Streiter G, Peters A, Gieger C, Köttgen A, Kronenberg F, Coassin S: The effect of LPA Thr3888Pro on lipoprotein(a) and coronary artery disease is modified by the LPA KIV-2 variant 4925G>A. Atherosclerosis 349:151-159, 2022. PMID: 35534298   Journal Article

Schachtl-Riess JF, Kheirkhah A, Grüneis R, Di Maio S, Schoenherr S, Streiter G, Losso JL, Paulweber B, Eckardt KU, Köttgen A, Lamina C, Kronenberg F, Coassin S, GCKD Investigators: Frequent LPA KIV-2 variants lower lipoprotein(a) concentrations and protect against coronary artery disease. J. Am. Coll. Cardiol. 78:437-449, 2021. PMID: 34325833   Journal Article

Di Maio S, Grüneis R, Streiter G, Lamina C, Maglione M, Schoenherr S, Öfner D, Thorand B, Peters A, Eckardt KU, Köttgen A, Kronenberg F, Coassin S: Investigation of a nonsense mutation located in the complex KIV-2 copy number variation region of apolipoprotein(a) in 10,910 individuals. Genome Med. 12:74, 2020. PMID: 32825847   Journal Article

Coassin S, Schönherr S, Weissensteiner H, Erhart G, Forer L, Losso JL, Lamina C, Haun M, Utermann G, Paulweber B, Specht G, Kronenberg F: A comprehensive map of single-base polymorphisms in the hypervariable LPA kringle IV type 2 copy number variation region. J. Lipid Res. 60:186-199, 2019. PMID: 30413653   Journal Article

Coassin S, Erhart G, Weissensteiner H, Eca Guimarães de Araújo M, Lamina C, Schönherr S, Forer L, Haun M, Losso JL, Köttgen A, Schmidt K, Utermann G, Peters A, Gieger C, Strauch K, Finkenstedt A, Bale R, Zoller H, Paulweber B, Eckardt KU, Hüttenhofer A, Huber LA, Kronenberg F: A novel but frequent variant in LPA KIV-2 is associated with a pronounced Lp(a) and cardiovascular risk reduction. Eur. Heart J. 38:1823-1831, 2017. PMID: 28444229   Journal Article