Johanna F. Schachtl-Riess (Austria)

Medical University of Innsbruck Institute of Genetic Epidemiology
Johanna F. Schachtl-Riess is a third-year PhD student at the Institute of Genetic Epidemiology of the Medical University of Innsbruck under the supervision of Dr. Florian Kronenberg. She acquired her Bachelor and Master degree in Molecular Medicine (Medical University of Innsbruck, 2012-2018) and already started working on lipoprotein(a) with Dr. Stefan Coassin (Institute of Genetic Epidemiology Innsbruck) during her Bachelor thesis. In 2019 she received a fellowship of the Dr. Legerlotz foundation. As a PhD student within the HOROS Doctoral Programme of Excellence her current research focuses on the functionality of HDL in chronic kidney disease, genome-wide association studies and the genetics of lipoprotein(a).

Presenter of 1 Presentation

O014 - Highly frequent variants hidden in the KIV-2 region of LPA regulate lipoprotein(a) concentrations and lower coronary artery disease risk (ID 196)

Session Type
Genetics
Session Time
15:00 - 16:30
Date
Mon, 31.05.2021
Room
Live Streamed
Lecture Time
15:49 - 15:57

Abstract

Background and Aims

The lipoprotein(a) [Lp(a)] plasma concentration is largely determined by variation in the LPA gene. However, the repetitive KIV-2 domain is difficult to analyze by conventional PCR-based technologies. The KIV-2 variant 4733G>A is a novel and frequent putative splicing modifier but its function, impact on Lp(a) and coronary artery disease (CAD) risk and, importantly, its combined effect with the 4925G>A, another frequent functional KIV-2 variant, have not been characterized.

Methods

We typed the 4733G>A variant in the German Chronic Kidney Disease (GCKD) study (n=4,673) using a novel allele-specific assay. Its function was analyzed by minigene assays. Ethnic frequencies were assessed in 1000Genomes. Proxy SNPs were identified in GCKD and used to analyze the effect of 4733G>A and the combined effect with 4925G>A on CAD in UK Biobank (n=440,234).

Results

The 4733G>A variant has a carrier frequency of 38%, lowers Lp(a) by 14.0 mg/dL ([15.3-12.6], p=4.82e-184) and was the second strongest genetic factor after the apolipoprotein(a) isoforms. It is found in all isoforms and reduces the expression of the mutated allele. Frequencies differ strongly between ethnicities. Compound heterozygous carriers of 4733G>A and 4925G>A have low Lp(a) concentrations (median=7.2 mg/dL) with little variance left (IQR=4.6 mg/dL), independently from the isoform present. 4733G>A alone and compound heterozygosity with 4925G>A are associated with a significantly lower hazard ratio for CAD (0.91 [0.89-0.93], p<0.001 and 0.88 [0.84-0.93], p<0.001).

Conclusions

Hidden functional LPA variants profoundly modulate Lp(a) concentrations and CAD risk. Furthermore, the 4733G>A variant is a novel instrument to dissect the effect of Lp(a) concentrations and apolipoprotein(a) isoforms.

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Presenter of 1 Presentation

O014 - Highly frequent variants hidden in the KIV-2 region of LPA regulate lipoprotein(a) concentrations and lower coronary artery disease risk (ID 196)

Session Type
Genetics
Session Time
15:00 - 16:30
Date
Mon, 31.05.2021
Room
Live Streamed
Lecture Time
15:49 - 15:57

Abstract

Background and Aims

The lipoprotein(a) [Lp(a)] plasma concentration is largely determined by variation in the LPA gene. However, the repetitive KIV-2 domain is difficult to analyze by conventional PCR-based technologies. The KIV-2 variant 4733G>A is a novel and frequent putative splicing modifier but its function, impact on Lp(a) and coronary artery disease (CAD) risk and, importantly, its combined effect with the 4925G>A, another frequent functional KIV-2 variant, have not been characterized.

Methods

We typed the 4733G>A variant in the German Chronic Kidney Disease (GCKD) study (n=4,673) using a novel allele-specific assay. Its function was analyzed by minigene assays. Ethnic frequencies were assessed in 1000Genomes. Proxy SNPs were identified in GCKD and used to analyze the effect of 4733G>A and the combined effect with 4925G>A on CAD in UK Biobank (n=440,234).

Results

The 4733G>A variant has a carrier frequency of 38%, lowers Lp(a) by 14.0 mg/dL ([15.3-12.6], p=4.82e-184) and was the second strongest genetic factor after the apolipoprotein(a) isoforms. It is found in all isoforms and reduces the expression of the mutated allele. Frequencies differ strongly between ethnicities. Compound heterozygous carriers of 4733G>A and 4925G>A have low Lp(a) concentrations (median=7.2 mg/dL) with little variance left (IQR=4.6 mg/dL), independently from the isoform present. 4733G>A alone and compound heterozygosity with 4925G>A are associated with a significantly lower hazard ratio for CAD (0.91 [0.89-0.93], p<0.001 and 0.88 [0.84-0.93], p<0.001).

Conclusions

Hidden functional LPA variants profoundly modulate Lp(a) concentrations and CAD risk. Furthermore, the 4733G>A variant is a novel instrument to dissect the effect of Lp(a) concentrations and apolipoprotein(a) isoforms.

Hide