Genetically predicted lipoprotein(a) associates with coronary artery plaque severity independent of low-density lipoprotein cholesterol
Authors: Clarke Shoa L , Huang Rose D L , Hilliard Austin T , Levin Michael G , Sharma Disha , Thomson Blake , Lynch Julie , Tsao Philip S , Gaziano J Michael , Assimes Themistocles L ,   the VA Million Veteran Program, Muralidha Sumitra , Moser Jennifer , Deen Jennifer E , Tsao Philip S , Muralidhar Sumitra , Michael Gaziano J , Hauser Elizabeth , Kilbourne Amy , Luoh Shiuh-Wen , Matheny Michael , Oslin Dave , Michael Gaziano J , Tsao Philip S , Churby Lori , Whitbourne Stacey B , Brewer Jessica V , Shayan Shahpoor , Selva Luis E , Pyarajan Saiju , Cho Kelly , DuVall Scott L , Brophy Mary T , Tsao Philip S , Stephens Brady , Assimes Themistocles L , Hung Adriana , Kranzler Henry , Aguayo Samuel , Ahuja Sunil , Alexander Kathrina , Androulakis Xiao M , Balasubramanian Prakash , Ballas Zuhair , Beckham Jean , Bhushan Sujata , Boyko Edward , Cohen David , Dellitalia Louis , Christine Faulk L , Fayad Joseph , Fujii Daryl , Gappy Saib , Gesek Frank , Greco Jennifer , Godschalk Michael , Gress Todd W , Gupta Samir , Gutierrez Salvador , Harley John , Hammer Kimberly , Hamner Mark , Hung Adriana , Hurley Robin , Iruvanti Pran , Jacono Frank , Jhala Darshana , Kinlay Scott , Klein Jon , Landry Michael , Liang Peter , Liangpunsakul Suthat , Lichy Jack , Scott Mahan C , Marrache Ronnie , Mastorides Stephen , Mates Elisabeth , Mattocks Kristin , Meyer Paul , Moorman Jonathan , Morgan Timothy , Murdoch Maureen , Norton James , Okusaga Olaoluwa , Oursler Kris Ann , Palacio Ana , Poon Samuel , Potter Emily , Rauchman Michael , Servatius Richard , Sharma Satish , Smith River , Sriram Peruvemba , Strollo Patrick , Tandon Neeraj , Tsao Philip , Villareal Gerardo , Wallbom Agnes , Walsh Jessica , Wells John , Whittle Jeffrey , Whooley Mary , Williams Allison E , Wilson Peter , Xu Junzhe , Yeh Shing Shing 
Published: August 2024

Abstract

Aims
Elevated lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease, but the mechanisms of risk are debated. Studies have found inconsistent associations between Lp(a) and measurements of atherosclerosis. We aimed to assess the relationship between Lp(a), low-density lipoprotein cholesterol (LDL-C), and coronary artery plaque severity.

Methods and results
The study population consisted of participants of the Million Veteran Program who have undergone an invasive angiogram. The primary exposure was genetically predicted Lp(a) estimated by a polygenic score. Genetically predicted LDL-C was also assessed for comparison. The primary outcome was coronary artery plaque severity categorized as normal, non-obstructive disease, one-vessel disease, two-vessel disease, and three-vessel or left main disease. Among 18 927 adults of genetically inferred European ancestry and 4039 adults of genetically inferred African ancestry, we observed consistent associations between genetically predicted Lp(a) and obstructive coronary plaque, with effect sizes trending upward for increasingly severe categories of disease. Associations were independent of risk factors, clinically measured LDL-C and genetically predicted LDL-C. However, we did not find strong or consistent evidence for an association between genetically predicted Lp(a) and risk for non-obstructive plaque.

Conclusion
Genetically predicted Lp(a) is positively associated with coronary plaque severity independent of LDL-C, consistent with Lp(a) promoting atherogenesis. However, the effects of Lp(a) may be greater for progression of plaque to obstructive disease than for the initial development of non-obstructive plaque. A limitation of this study is that Lp(a) was estimated using genetic markers and could not be directly assayed nor could apo(a) isoform size.