Abstract 15225: A New Genetic BiomMarker for Coronary Artery Disease: Nicotinamide Phosphoribosyltransferase
Background: Our lab previously reported that 2 of 11 SNPs in the promoter of human nicotinamide phophoribosyltranssferase (NAMPT) gene altered the transcription rate and were associated with acute respiratory distress syndrome. This study aimed to determine whether these SNPs are associated with the susceptibility, severity and outcome of CAD and the role of NAMPT in mouse myocardial ischemia/ reperfusion injury.
Methods: Four NAMPT SNPs (G-1535A, A-1001C, C-948A, T-423C) were genotyped using the Taqman Assay in a well phenotyped CAD population (n = 2981) from the TRIUMPH Registry (P50HL077113, NHLBI) and compared to healthy controls (n = 1092) from the 1000 Human Genomes Project. Haplotype analysis was performed using both HPlus and Haplo.stats. In the animal study, male C57BL/6J Nampt overexpression (NamptOE)-, wild type (Nampt+/+)-, and heart specific Nampt deficient type (NamptH+/-)-mice, 10 weeks-old, were subjected to either sham or myocardial ischemia by a 40 min occlusion of the left anterior descending coronary artery followed by 3h reperfusion. Mouse hearts and sera were harvested for assessing infarct size and area at risk, apoptosis and serum troponin I.
Results: In the human study, carriers of the ‘susceptible haplotype’ of GCCT and GACC had a 32.82 and 5.95-fold higher risk of CAD, respectively (95% CI, 12.21-88.21 and 3.76-9.41, p<0.01). Carriers of the ‘protective haplotype’ of AACT and GCCC had significantly lower risks of CAD (OR=0.54 and 0.39; 95% CI, 0.46-0.63 and 0.30-0.50, p<0.01). The haplotype AACT was also associated with the number of diseased vessels in the heart (OR=1.18, 95% CI, 1.01-1.39, p=0.04). The haplotype GACC predicted 24-month mortality of patients with CAD (p=0.02). In the animal study, the ratio of MI/area at risk was from the least to the highest in NamptOE, Nampt+/+, NamptH+/- mice (15.10 %, 34.32%, 46.39%, n≥ 7/per group, p<0.01). TUNEL and serum troponin I assays indicated the least myocardial apoptosis and injury in NamptOE mice.
Conclusion: NAMPT haplotypes are associated with the susceptibility, severity and outcome of CAD. NAMPT can protect against mouse heart ischemic/reperfusion injury. These results suggest that NAMPT may be an important genetic biomarker and therapeutic target for CAD.
- © 2013 by American Heart Association, Inc.