Proteomics Analysis of Genetic Liability of Abdominal Aortic Aneurysm Identifies Plasma Neogenin and Kit Ligand: The ARIC Study

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Background: Genome-wide association studies have reported 23 gene loci related to abdominal aortic aneurysm (AAA) - a potentially lethal condition characterized by a weakened dilated vessel wall. This study aimed to identify proteomic signatures and pathways related to these risk loci to better characterize AAA genetic susceptibility. Methods: Plasma concentrations of 4870 proteins were determined using a DNA aptamer-based array. Linear regression analysis estimated the associations between the 23 risk alleles and plasma protein levels with adjustments for potential confounders in a race-stratified analysis of 1671 Black and 7241 White participants. Significant proteins were then evaluated for their prediction of clinical AAA (454 AAA events in 11 064 individuals), and those significantly associated with AAA were further interrogated using Mendelian randomization analysis. Results: Risk variants proximal to PSRC1-CELSR2-SORT1, PCIF1-ZNF335-MMP9, RP11-136O12.2/TRIB1, ZNF259/APOA5, IL6R, PCSK9, LPA, and APOE were associated with 118 plasma proteins in Whites and 59 were replicated in Black participants. Novel associations with clinical AAA incidence were observed for kit ligand (HR, 0.59 [95% CI, 0.42-0.82] for top versus first quintiles) and neogenin (HR, 0.64 [95% CI, 0.46-0.88]) over a median 21.2-year follow-up; neogenin was also associated with ultrasound-detected asymptomatic AAA (N=4295; 57 asymptomatic AAA cases). Mendelian randomization inverse variance weighted estimates suggested that AAA risk is promoted by lower levels of kit ligand (OR per SD=0.67; P=1.4×10-5) and neogenin (OR per SD=0.50; P=0.03). Conclusions: Low levels of neogenin and kit ligand may be novel risk factors for AAA development in potentially causal pathways. These findings provide insights and potential targets to reduce AAA susceptibility.

Original languageEnglish (US)
Pages (from-to)367-378
Number of pages12
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number2
StatePublished - Feb 1 2023

Bibliographical note

Funding Information:
This work was supported by (grant number 2T32HL007779-26) from the National Heart, Lung, and Blood Institute and by an award from the Hawley Foundation to (Dr Steffen). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (grant numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HSN268201700005I, R01HL087641, R01HL059367, and R01HL086694). Funding was also supported by R01HL103695, R01HL155209, R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. SomaLogic, Inc conducted the SomaScan assays in exchange for use of ARIC data. This work was supported in part by NIH/NHLBI grant R01 HL134320. Dr Lutsey was supported by NHLBI K24 HL159246.

Publisher Copyright:
© 2022 American Heart Association, Inc.


  • abdominal aortic aneurysm
  • genetics
  • proteomics
  • risk factors

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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