| Title |
A novel genetic marker of decreased inflammation and improved survival after acute myocardial infarction
|
|---|---|
| Published in |
Basic Research in Cardiology, August 2018
|
| DOI | 10.1007/s00395-018-0697-7 |
| Pubmed ID | |
| Authors |
Edward D. Coverstone, Richard G. Bach, LiShiun Chen, Laura J. Bierut, Allie Y. Li, Petra A. Lenzini, Heidi C. O’Neill, John A. Spertus, Carmen C. Sucharov, Jerry A. Stitzel, Joel D. Schilling, Sharon Cresci |
| Abstract |
The CHRNA5 gene encodes a neurotransmitter receptor subunit involved in multiple processes, including cholinergic autonomic nerve activity and inflammation. Common variants in CHRNA5 have been linked with atherosclerotic cardiovascular disease. Association of variation in CHRNA5 and specific haplotypes with cardiovascular outcomes has not been described. The aim of this study was to examine the association of CHRNA5 haplotypes with gene expression and mortality among patients with acute myocardial infarction (AMI) and explore potential mechanisms of this association. Patients (N = 2054) hospitalized with AMI were genotyped for two common variants in CHRNA5. Proportional hazard models were used to estimate independent association of CHRNA5 haplotype with 1-year mortality. Both individual variants were associated with mortality (p = 0.0096 and 0.0004, respectively) and were in tight LD (D' = 0.99). One haplotype, HAP3, was associated with decreased mortality one year after AMI (adjusted HR = 0.42, 95% CI 0.26, 0.68; p = 0.0004). This association was validated in an independent cohort (N = 637) of post-MI patients (adjusted HR = 0.23, 95% CI 0.07, 0.79; p = 0.019). Differences in CHRNA5 expression by haplotype were investigated in human heart samples (n = 28). Compared with non-carriers, HAP3 carriers had threefold lower cardiac CHRNA5 mRNA expression (p = 0.023). Circulating levels of the inflammatory marker hsCRP were significantly lower in HAP3 carriers versus non-carriers (3.43 ± 4.2 versus 3.91 ± 5.1; p = 0.0379). Activation of the inflammasome, an important inflammatory complex involved in cardiovascular disease that is necessary for release of the pro-inflammatory cytokine IL-1 β, was assessed in bone marrow-derived macrophages (BMDM) from CHRNA5 knockout mice and wild-type controls. In BMDM from CHRNA5 knockout mice, IL-1β secretion was reduced by 50% compared to wild-type controls (p = 0.004). Therefore, a common haplotype of CHRNA5 that results in reduced cardiac expression of CHRNA5 and attenuated macrophage inflammasome activation is associated with lower mortality after AMI. These results implicate CHRNA5 and the cholinergic anti-inflammatory pathway in survival following AMI. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 2 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 21 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 21 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Doctoral Student | 3 | 14% |
| Student > Bachelor | 3 | 14% |
| Professor > Associate Professor | 3 | 14% |
| Student > Master | 2 | 10% |
| Researcher | 2 | 10% |
| Other | 2 | 10% |
| Unknown | 6 | 29% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 6 | 29% |
| Neuroscience | 3 | 14% |
| Biochemistry, Genetics and Molecular Biology | 2 | 10% |
| Immunology and Microbiology | 1 | 5% |
| Pharmacology, Toxicology and Pharmaceutical Science | 1 | 5% |
| Other | 2 | 10% |
| Unknown | 6 | 29% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 13 August 2018.
All research outputs
#17,987,106
of 23,099,576 outputs
Outputs from Basic Research in Cardiology
#515
of 654 outputs
Outputs of similar age
#238,112
of 331,118 outputs
Outputs of similar age from Basic Research in Cardiology
#5
of 6 outputs
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