Abstract 17004: Genome-Wide Significant Findings for Endotoxin-Evoked but not Basal Inflammation in Americans of European and African Ancestry
Objective: To assess variation in response to endotoxemia and investigate genome-wide SNP associations with inflammatory response in Americans of European and African ancestry.
Background: Inflammation is a key component in the pathophysiology of cardiometabolic disease. We utilize a model of evoked endotoxemia (LPS) to explore differences in evoked inflammation. We hypothesized that inflammatory responses would differ by race and gender, and would be influenced by genetic background.
Methods: The Genetics of Evoked-Responses to Niacin and Endotoxemia (GENE) Study recruited N=294 healthy volunteers (age 18-45, 52% Female, 35% African (Af) ancestry, 65% European (Eu) ancestry) to an inpatient endotoxin challenge (1ng/kg LPS). Anthropometric and clinical measurements were recorded; blood was collected for Affy 6.0 SNP genotyping, and measurement of cytokines, lipids, and insulin resistance.
Results: LPS induced a robust inflammatory response characterized by increased temperature, heart rate and blood pressure (P< 0.0001). Cytokines increased significantly (TNFα ~50-fold, IL-6 ~150-fold P< 0.0001) peaking 2 hours post-LPS. Peak cytokine response varied by race and gender: IL-6 was higher in females than males (191 vs 145 pg/ml, P=0.01), while TNFα was higher in Eu compared to Af (54 vs 41 pg/ml, P=0.02). Decreased insulin sensitivity post-LPS (Si 4.4 to 2.8, P<0.0001) was observed in Eu, but not Af. Strikingly, 11 SNPs in moderate to high LD (r2 0.5-0.9) in an intergenic region on 7p11 were strongly associated at genome-wide significance with the change in temperature in Eu (best P=1x10-11). Several SNPs were associated with the change in TNFα in Eu (best P=1.7x10-10). Interestingly, we observed significant associations with SNPs in the LPS receptor TLR4 gene and both TNFα and temperature response in Eu (best P=0.009, P=0.004) and Af (best P=0.002, P=0.007).
Conclusion: The degree of inflammatory response to LPS differs by gender and race, although individual response within groups is heterogeneous. We detected numerous genome-wide significant SNP associations with evoked inflammatory response, not detected at baseline, potentially representing novel genetic markers, of important relevance to inflammatory cardiometabolic disease.
- © 2011 by American Heart Association, Inc.