TY - JOUR
T1 - Proteomics Analysis of Genetic Liability of Abdominal Aortic Aneurysm Identifies Plasma Neogenin and Kit Ligand
T2 - The ARIC Study
AU - Steffen, Brian T.
AU - Pankow, James S.
AU - Norby, Faye L.
AU - Lutsey, Pamela L.
AU - Demmer, Ryan T.
AU - Guan, Weihua
AU - Pankratz, Nathan
AU - Li, Aixin
AU - Liu, Guning
AU - Matsushita, Kunihiro
AU - Tin, Adrienne
AU - Tang, Weihong
N1 - Publisher Copyright:
© 2022 American Heart Association, Inc.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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.
AB - 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.
KW - abdominal aortic aneurysm
KW - genetics
KW - proteomics
KW - risk factors
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U2 - 10.1161/ATVBAHA.122.317984
DO - 10.1161/ATVBAHA.122.317984
M3 - Article
C2 - 36579647
AN - SCOPUS:85146860064
SN - 1079-5642
VL - 43
SP - 367
EP - 378
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 2
ER -