Replication of Newly Identified Genetic Associations Between Abdominal Aortic Aneurysm and SMYD2, LINC00540, PCIF1/MMP9/ZNF335, and ERG

Weihong Tang, Athanasios Saratzis, Jack Pattee, Jacqueline Smith, Nathan Pankratz, Olivia C. Leavy, Weihua Guan, Frank Dudbridge, James S. Pankow, George D. Kitas, Pamela L. Lutsey, Matthew J. Bown

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: A recently published genome wide association study of abdominal aortic aneurysms (AAA), based on pooled case control data of European ancestry, identified four new loci for AAA: SMYD2 (top single nucleotide polymorphism [SNP] rs1795061), LINC00540 (rs9316871), PCIF1/MMP9/ZNF335 (rs3827066), and ERG (rs2836411). Of the four, rs1795061 and rs2836411 showed significant heterogeneity across studies and the p value for rs9316871 did not reach the genome wide significance threshold until discovery and replication data were pooled together in that study. The objective of this study was to replicate these newly identified genetic associations for AAA in a US based prospective cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, and a Greece based case control study. Methods: ARIC identified 408 clinically diagnosed AAAs among 8 962 individuals of European ancestry during a median of 22 years of follow up. The Greek case control study included 341 AAAs of European ancestry recruited in a tertiary referral centre and 292 geographically and ethnically matched controls recruited from the same institution. A Cox proportional hazards model was used to analyse the ARIC data and logistic regression to analyse the Greek data. Results: In ARIC, rs9316871 and rs3827066 were significantly associated with AAA risk (HR [p] was 0.77 [.004] and 1.22 [.03], respectively), rs2836411 was associated at borderline significance (1.13 [.08]), whereas rs1795061 was not associated (p = .55). In the Greek case control study, rs1795061 and rs2836411 were significantly associated with AAA (OR [p] was 1.66 [< .001] and 1.29 [.04], respectively), whereas rs9316871 was not (p = .81). Genotyping of rs3827066 did not succeed. In the meta-analysis of the two studies, the association for rs9316871and rs2836411 was statistically significant and consistent between the two studies: p = .02 and .007, respectively. Conclusions: Associations between rs9316871and rs2836411 and AAA risk were replicated in the meta-analysis of the two independent cohorts, providing further support for the importance of these loci in the aetiology of AAA.

Original languageEnglish (US)
Pages (from-to)92-97
Number of pages6
JournalEuropean Journal of Vascular and Endovascular Surgery
Volume59
Issue number1
DOIs
StatePublished - Jan 2020

Bibliographical note

Funding Information:
This ARIC AAA Study was supported by the National Heart, Lung, and Blood Institute through grant R01HL103695 . The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, 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. Funding for the Greek case control study was provided via a fellowship grant awarded to Mr. A. Saratzis by ElectroMedical S.A. (Reference: ANS2013); Mr. Saratzis is currently funded by the National Institute for Health Research (NIHR; no reference number is applicable in this case).

Funding Information:
This ARIC AAA Study was supported by the National Heart, Lung, and Blood Institute through grant R01HL103695. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, 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. Funding for the Greek case control study was provided via a fellowship grant awarded to Mr. A. Saratzis by ElectroMedical S.A. (Reference: ANS2013); Mr. Saratzis is currently funded by the National Institute for Health Research (NIHR; no reference number is applicable in this case).

Publisher Copyright:
© 2019 European Society for Vascular Surgery

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Abdominal aortic aneurysm
  • Association
  • Genetic
  • Replication

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