Abstract 18399: Higher Plasma Cxcl12 Levels Are Causally Associated With Increased Risk of Coronary Heart Disease
Introduction: Although CXCL12 (10q11) is one of the early coronary heart disease (CHD) loci discovered in genome-wide association studies, the directional impact of the CXCL12 pathway on CHD remains unknown. We used plasma CXCL12 as a surrogate to investigate the directional impact of the CXCL12 pathway on CHD risk.
Methods: We conducted measurements for plasma CXCL12 using an ELISA in 12,657 participants enrolled in the EPIC-Norfolk cohort (n = 3651) and the PROMIS study (n = 9006). We first examined the association of plasma CXCL12 with incident CHD events in the EPIC-Norfolk cohort (1312 incident cases and 2339 controls). Second, using genome-wide genotypes available in the two studies, we conducted discovery analyses in relation to plasma CXCL12. We conducted analyses to identify variants which were specifically associated with plasma CXCL12 but not with other traits. Using genetic data on a further 60,801 CHD cases and 123,504 controls, we compared the odds Ratio (OR) for incident CHD risk conferred by observed increases in plasma CXCL12 with equivalent differences caused by genetic variation specifically associated with plasma CXCL12.
Results: Per standard deviation (SD) increase in plasma CXCL12 was associated with increased CHD risk in the EPIC-Norfolk cohort independent of age, sex, T2D, hypertension, tobacco use and major lipids (OR: 1.10; P = 10-3). Using genome-wide analyses, we found several variants at the CXCL12 locus associated with plasma CXCL12 (P < 5 x 10-8). Conditional analyses at the CXCL12 locus identified four independent variants associated with plasma CXCL12; one of which was associated with increased expression of CXCL12 gene (P = 8 x 10-4) in the adipose, increased plasma CXCL12 (P = 3 x 10-8), and increased CHD risk (5 x 10-9). This variant was found exclusively associated with plasma CXCL12 in a phenome-scan involving 89 traits related to lipid, inflammatory, metabolic and other traits. Per-SD increase in plasma CXCL12 by this variant was found to be associated with increased CHD risk (OR: 1.15: P-value 5x10-9) which was directionally consistent with the OR observed in association with incident CHD risk.
Conclusions: Higher plasma CXCL12 may have a causal--but modest--effect on increasing the risk of CHD.
Author Disclosures: W. Zhao: None. J. Zhao: None. A. Rasheed: None. M. Reilly: None. R. Luben: None. A. Malarstig: Employment; Significant; Pfizer. K. Khaw: None. J. Danesh: None. N. Wareham: None. D. Rader: Research Grant; Significant; Pfizer. R. Luben: None. D. Saleheen: Research Grant; Significant; Pfizer.
- © 2016 by American Heart Association, Inc.