Understanding The Metabolic Pathways of Lipoprotein(a) Through Genetic Recall
Description: Lipoprotein(a) [Lp(a)] is an atherogenic, prothrombotic and, proatherogenic cardiovascular risk factor for which there is no current targeted treatment. Lp(a) levels are higher in Blacks and Hispanics compare to White populations and recent data from the UK Biobank suggest increased risk in these populations. Lp(a) levels are strongly regulated by the LPA gene. Genomic analyses examining Lp(a) levels, confirm causality with cardiovascular disease (CVD). The LPA gene controls 90% of the variance of Lp(a) levels. The Kringle IV type 2 (KIV-2) region within the LPA gene, which can be present as 3 to 40 repeats, determines the size of the express isoforms, providing high variability to these liver secreted protein particles. The levels are determined mainly by production, but clearance pathways have been also implicated. Our knowledge of the genetic regulation of the Lp(a) protein production is still limited. Additionally, it is not clear why Blacks have higher levels of Lp(a) compared to Whites, even when they express similar isoform sizes. Genetic variants in LPA , linked to Lp(a) plasma levels, have been identified both outside and recently within the KIV-2 region. However, these studies have low numbers of Blacks and Hispanics compare to Whites and have never been linked to the pathways regulating Lp(a) plasma levels. The PI is an expert in examining these pathways in humans. We propose to identify known and unknown SNPS within the LPA gene in the multiethnic Washington Heights–Inwood Columbia Aging Project (WHICAP). The proposal capitalizes on the availability of this diversity rich genetic cohort, to perform the following goal and objectives: Identify rare and common variants within the KIV-2 repeat region of the LPA gene to: (a) describe the ethnic-specific frequencies for genetic variants linked to Lp(a) levels, (b) link these variants to function by studying proteomic and lipidomic phenotypes of the isolated Lp(a) particle, and (c) describe the relationship of extracellular vesicles with apolipoprotein(a) in the presence of these variants. Our long-term research goal is to understand Lp(a) biology, physiology and impact on cardiometabolic risk. This proposal supports the AHA mission to prolong life in individuals of ALL backgrounds by studying areas that increase cardiovascular risk in these populations.
Funder: American Heart Association
Amount: $200,000
Funding type: research
Funder scheme: Innovative Project Award
Start date: 2023-07-01
End date: 2025-06-30
Investigators: Gissette Soffer, Gissette Soffer
Institution: The Trustees of Columbia University in the City of New York
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 23IPA1054039
OpenAlex ID: G2225265173