Abstract 2533: CXCL5 Polymorphisms Are Associated With Variable Blood Pressure In Cardiovascular Disease-Free Adults
Objectives: Leukocyte count has been associated with hypertension and hypertensive complications. Leukocytosis may be a surrogate for underlying chemokine activity that contributes to blood pressure elevations. We therefore hypothesized that polymorphisms in the CXCL5 gene, which encodes the neutrophilic chemokine ENA-78, are associated with blood pressure in cardiovascular disease (CVD)-free adults, and that these polymorphisms are functional.
Methods: SBP and DBP were compared among 192 enrollees from two sites in the United States without known CVD and not taking anti- hypertensive or inflammatory medication. CXCL5 genotypes (-156G>C and 398G>A) were investigated. Multiple regression analyses were performed using covariates with a P<0.1 in univariate analyses. Allele-expression imbalance was quantified using the exonic 398A:G ratios from leukocyte DNA and RNA from 18 heterozygotes. P<0.05 was considered significant.
Results: Subjects (77% white; 65% female) were on average 39±12 years old with a BP of 126/75±15/11 mmHg. The polymorphisms were in linkage disequilibrium with identical variant allele frequencies (15%) and yielded similar BP results between variant -156C and 398A carriers in univariate analyses. Variant -156C carriers had higher SBP and DBP than wild-type homozygotes (131±17 vs. 124±14 mmHg, P=0.008; and 78±11 vs. 74±11 mmHg, P=0.013; respectively). Univariate predictors of both SBP and DBP were age, sex, BMI, and WBC (P≤0.001, 0.008, 0.002, and 0.10 respectively). Smoking status, CRP and ENA-78 levels were also associated with SBP (P<0.038, 0.005, and 0.033 respectively). In multivariate analyses significant predictors were age, sex, BMI, and -156C carrier status for SBP; and age, sex, WBC, and -156C carrier status for DBP. These models explained 32.5% and 16.8% of variability for SBP and DBP respectively (P<0.001). Allelic discrimination showed an over-expression of 398A variant mRNA levels by 2.9 fold (P=7.4E-15) supporting a functional role for this SNP and/or the highly concordant -156G>C SNP.
Conclusions: CXCL5 gene polymorphisms are functional and associated with variable blood pressure in CVD-free individuals. The role of CXCL5 as a hypertension- and CVD-susceptibility gene should be further explored.