Publications

BACKGROUND

Previous studies suggest that markers of inflammation are elevated in patients with atrial fibrillation (AF). However, because inflammation has been implicated in contributing to risk of both AF and coronary artery disease (CAD), which are often present in the same populations, it is important to control for confounding by the presence of CAD. We therefore examined several biomarkers of inflammation and ultimately genotyped IL-6 polymorphisms in patients with AF in a cohort of subjects with known CAD.

METHODS

We performed a cross-sectional analysis of 971 participants in the Heart and Soul Study, 46 of whom had AF. Interleukin-6, C-reactive protein, tumor necrosis factor-alpha, CD-40 ligand, monocyte chemoattractant protein-1, and fibrinogen levels were measured.

RESULTS

In both unadjusted and adjusted analyses, IL-6 was the only biomarker significantly associated with AF (median IL-6 3.76 and 2.52 pg/mL in those with and without AF, respectively, P = .0005; adjusted odds ratio 1.77, P = .032). The IL-6-174CC genotype was significantly associated with the presence of AF in the adjusted analysis (odds ratio 2.34, P = .04) and with higher IL-6 levels (P = .002).

CONCLUSIONS

In this cohort of subjects with CAD, AF was significantly associated with elevated IL-6 levels and the IL-6-174CC genotype. No associations were found with other biomarkers, including C-reactive protein. This suggests that IL-6 is a uniquely important mediator in the pathophysiology of AF.

Human immunodeficiency virus (HIV) immunopathogenesis in children remains poorly understood. We assessed T cell immune activation in antiretroviral therapy-naive children in Uganda (n=154). Increased CD4+ and CD8+ T cell activation strongly correlated with decreased CD4+ T cell percentage. Interestingly, no correlation between plasma HIV RNA level and T cell activation was observed after controlling for CD4+ T cell count. In addition, the presence of Gag-specific CD4+ T helper responses was associated with increased HIV-specific CD8+ T cells. Understanding the balance between immune activation and T cell immunity in HIV-infected children may provide further insights into the mechanisms leading to effective immune control.

Increased plasma triglyceride concentrations are an independent risk factor for cardiovascular disease. Numerous studies support a reproducible genetic association between two minor haplotypes in the human apolipoprotein A5 gene (APOA5) and increased plasma triglyceride concentrations. We thus sought to investigate the effects of these minor haplotypes (APOA5*2 and APOA5*3) on ApoAV plasma levels through the precise insertion of single-copy APOA5 haplotypes at a targeted location (Hprt) in the mouse genome. While we found no difference in the amount of human plasma ApoAV in mice containing the common APOA5*1 or minor APOA5*2 haplotype, the introduction of the single APOA5*3-defining allele (19W) resulted in three fold lower ApoAV plasma levels, consistent with existing genetic association studies. These results indicate that the S19W polymorphism is likely to be functional and explain the strong association of this variant with plasma triglycerides, supporting the value of sensitive in vivo assays to define the functional nature of human haplotypes.