Atrial Fibrillation Associated Genetic Variants and Left Atrial Histology: Evaluation for Molecular Sub-Phenotypes

Jason D. Roberts, Jingkun Yang, Rachel A. Gladstone, James Longoria, ISAAC R. Whitman, Thomas Dewland, Caroline Miller, Anatalia Robles, Annie Poon, Beverly Seiler, William A. Laframboise, Jeffrey E. Olgin, Pui Yan Kwok, Gregory M. Marcus

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Introduction: Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with atrial fibrillation (AF), but the mechanisms underlying these relationships have not yet been elucidated. Inflammation and fibrosis have been posited as important mechanisms responsible for AF. We sought to investigate the impact of SNP carrier status on inflammation and fibrosis in left atrial appendage tissue. Methods and Results: Carrier status of 10 AF-associated SNPs was evaluated on DNA extracted from left atrial appendage tissue in 176 individuals (120 with AF). The presence of inflammation was evaluated through visual quantification of leukocyte infiltration following hematoxylin and eosin staining, while fibrosis was quantified using picrosirius red with fast green staining. Unadjusted and adjusted linear and logistic regression models were utilized to evaluate for an association between SNP carrier status and inflammation and fibrosis. On adjusted logistic regression analysis, the rs7164883 SNP (intronic within HCN4) was associated with a reduced odds of inflammation (odds ratio: 0.42; 95% CI: 0.22–0.81, P = 0.01), and was not associated with fibrosis on adjusted linear regression analysis (β-coefficient: –0.31; 95% CI: –1.03–0.40, P = 0.40). None of the remaining SNPs exhibited significant associations with left atrial inflammation or fibrosis. Conclusions: Among 10 AF-associated SNPs, a single genetic variant was associated with reduced left atrial inflammation, while no histologic differences were observed in the remaining 9. The known AF-associated SNPs do not appear to predispose to the development of pro-inflammatory or pro-fibrotic AF sub-phenotypes.

Original languageEnglish (US)
Pages (from-to)1264-1270
Number of pages7
JournalJournal of Cardiovascular Electrophysiology
Volume27
Issue number11
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Fingerprint

Atrial Fibrillation
Single Nucleotide Polymorphism
Histology
Phenotype
Fibrosis
Inflammation
Atrial Appendage
Logistic Models
Linear Models
Regression Analysis
Staining and Labeling
Genome-Wide Association Study
Hematoxylin
Eosine Yellowish-(YS)
Leukocytes
Odds Ratio
DNA

Keywords

  • atrial fibrillation
  • fibrosis
  • genetics
  • inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Atrial Fibrillation Associated Genetic Variants and Left Atrial Histology : Evaluation for Molecular Sub-Phenotypes. / Roberts, Jason D.; Yang, Jingkun; Gladstone, Rachel A.; Longoria, James; Whitman, ISAAC R.; Dewland, Thomas; Miller, Caroline; Robles, Anatalia; Poon, Annie; Seiler, Beverly; Laframboise, William A.; Olgin, Jeffrey E.; Kwok, Pui Yan; Marcus, Gregory M.

In: Journal of Cardiovascular Electrophysiology, Vol. 27, No. 11, 01.11.2016, p. 1264-1270.

Research output: Contribution to journalArticle

Roberts, JD, Yang, J, Gladstone, RA, Longoria, J, Whitman, ISAACR, Dewland, T, Miller, C, Robles, A, Poon, A, Seiler, B, Laframboise, WA, Olgin, JE, Kwok, PY & Marcus, GM 2016, 'Atrial Fibrillation Associated Genetic Variants and Left Atrial Histology: Evaluation for Molecular Sub-Phenotypes', Journal of Cardiovascular Electrophysiology, vol. 27, no. 11, pp. 1264-1270. https://doi.org/10.1111/jce.13083
Roberts, Jason D. ; Yang, Jingkun ; Gladstone, Rachel A. ; Longoria, James ; Whitman, ISAAC R. ; Dewland, Thomas ; Miller, Caroline ; Robles, Anatalia ; Poon, Annie ; Seiler, Beverly ; Laframboise, William A. ; Olgin, Jeffrey E. ; Kwok, Pui Yan ; Marcus, Gregory M. / Atrial Fibrillation Associated Genetic Variants and Left Atrial Histology : Evaluation for Molecular Sub-Phenotypes. In: Journal of Cardiovascular Electrophysiology. 2016 ; Vol. 27, No. 11. pp. 1264-1270.
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T1 - Atrial Fibrillation Associated Genetic Variants and Left Atrial Histology

T2 - Evaluation for Molecular Sub-Phenotypes

AU - Roberts, Jason D.

AU - Yang, Jingkun

AU - Gladstone, Rachel A.

AU - Longoria, James

AU - Whitman, ISAAC R.

AU - Dewland, Thomas

AU - Miller, Caroline

AU - Robles, Anatalia

AU - Poon, Annie

AU - Seiler, Beverly

AU - Laframboise, William A.

AU - Olgin, Jeffrey E.

AU - Kwok, Pui Yan

AU - Marcus, Gregory M.

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N2 - Introduction: Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with atrial fibrillation (AF), but the mechanisms underlying these relationships have not yet been elucidated. Inflammation and fibrosis have been posited as important mechanisms responsible for AF. We sought to investigate the impact of SNP carrier status on inflammation and fibrosis in left atrial appendage tissue. Methods and Results: Carrier status of 10 AF-associated SNPs was evaluated on DNA extracted from left atrial appendage tissue in 176 individuals (120 with AF). The presence of inflammation was evaluated through visual quantification of leukocyte infiltration following hematoxylin and eosin staining, while fibrosis was quantified using picrosirius red with fast green staining. Unadjusted and adjusted linear and logistic regression models were utilized to evaluate for an association between SNP carrier status and inflammation and fibrosis. On adjusted logistic regression analysis, the rs7164883 SNP (intronic within HCN4) was associated with a reduced odds of inflammation (odds ratio: 0.42; 95% CI: 0.22–0.81, P = 0.01), and was not associated with fibrosis on adjusted linear regression analysis (β-coefficient: –0.31; 95% CI: –1.03–0.40, P = 0.40). None of the remaining SNPs exhibited significant associations with left atrial inflammation or fibrosis. Conclusions: Among 10 AF-associated SNPs, a single genetic variant was associated with reduced left atrial inflammation, while no histologic differences were observed in the remaining 9. The known AF-associated SNPs do not appear to predispose to the development of pro-inflammatory or pro-fibrotic AF sub-phenotypes.

AB - Introduction: Genome wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with atrial fibrillation (AF), but the mechanisms underlying these relationships have not yet been elucidated. Inflammation and fibrosis have been posited as important mechanisms responsible for AF. We sought to investigate the impact of SNP carrier status on inflammation and fibrosis in left atrial appendage tissue. Methods and Results: Carrier status of 10 AF-associated SNPs was evaluated on DNA extracted from left atrial appendage tissue in 176 individuals (120 with AF). The presence of inflammation was evaluated through visual quantification of leukocyte infiltration following hematoxylin and eosin staining, while fibrosis was quantified using picrosirius red with fast green staining. Unadjusted and adjusted linear and logistic regression models were utilized to evaluate for an association between SNP carrier status and inflammation and fibrosis. On adjusted logistic regression analysis, the rs7164883 SNP (intronic within HCN4) was associated with a reduced odds of inflammation (odds ratio: 0.42; 95% CI: 0.22–0.81, P = 0.01), and was not associated with fibrosis on adjusted linear regression analysis (β-coefficient: –0.31; 95% CI: –1.03–0.40, P = 0.40). None of the remaining SNPs exhibited significant associations with left atrial inflammation or fibrosis. Conclusions: Among 10 AF-associated SNPs, a single genetic variant was associated with reduced left atrial inflammation, while no histologic differences were observed in the remaining 9. The known AF-associated SNPs do not appear to predispose to the development of pro-inflammatory or pro-fibrotic AF sub-phenotypes.

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