The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region

Abstract Background Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression. Methods We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study. Results We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved. Conclusion These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.http://deepblue.lib.umich.edu/bitstream/2027.42/111638/1/12920_2015_Article_94.pd

Hypertension during Pregnancy is Associated with Coronary Artery Calcium Independent of Renal Function

Abstract Background: Hypertension during pregnancy (HDP) increases the risk of future coronary heart disease (CHD), but it is unknown whether this association is mediated by renal injury. Reduced renal function is both a complication of HDP and a risk factor for CHD. Methods: Logistic regression models were fit to examine the association between a history of HDP and the presence and extent of coronary artery calcification (CAC), a measure of subclinical coronary artery atherosclerosis, in 498 women from the Epidemiology of Coronary Artery Calcification Study (mean age 63.3+/-9.3 years). Results: Fifty-two (10.4%) women reported a history of HDP. After adjusting for age at time of study participation, HDP was associated with increased serum creatinine later in life (p=0.014). HDP was positively associated with the presence of CAC after adjusting for age at time of study participation (OR=2.7, 95% CI 1.4-5.4). This association was slightly attenuated with adjustment for body size and blood pressure (OR=2.4, 95% CI 1.2-4.9) but was not further attenuated with adjustment for serum creatinine and urinary albumin/creatinine ratio (OR=2.6, 95% CI 1.3-5.3). Results were similar for CAC extent. Conclusions: HDP may increase a woman's risk of future CHD beyond traditional risk factors and renal function. Women with a history of HDP should be monitored for potential increased risk of CHD as they age.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78144/1/jwh.2008.1285.pd

Experimental Investigation of the Classical Rayleigh-Taylor Instability

The evolution of the Rayleigh-Taylor (RT) instability in a compressible medium has been investigated at an accelerating embedded interface and at the ablation front in a series of experiments on the Nova laser. The x-ray drive generated in a gold hohlraum ablatively accelerated a planar target consisting of a doped plastic pusher backed by a higher density titanium payload with perturbations placed at the plastic-Ti interface. The targets were diagnosed by face-on and side-on radiography. In previous work focusing on single mode perturbations, wavelengths as short as 10 m have been observed to grow strongly at the embedded interface. Here multimode perturbations consisting of either 2, 10 or 20 modes superposed in phase have been investigated

Review of experiments and calculations of the compressible richtmyer-meshkov instability from a single-mode, nonlinear initial perturbation

We review experiments and calculations of the compressible Richtmyer-Meshkov instability from a single-mode, nonlinear initial perturbation. These experiments were performed using the Nova laser. Measurements of the time-evolution of the mixing region were reported previously. We compared the experimental measurements with numerical simulations [1,2]. We found both experiment and simulation to be in good agreement with recent theories for the nonlinear evolution of the instability [3,4]. Experimental results beyond those previously presented provide additional support for the use of two phase flow models to describe the flow in the nonlinear regime. These experiments include measurement of the mixing region at additional times, including times earlier in the evolution of the instability than previously reported. We have also carried out experiments to examine the difference in the evolution of the instability from initial perturbations consisting of circular sawtooth grooves as well as rectilinear sawteeth. Our previous two-dimensional numerical simulations approximated the experimental linear grooves as circular grooves. We reasoned that the difference between the two cases would be small, based on scaling arguments, and limited to a very small region near the centerline. New experimental and numerical results confirm this. Finally, we discuss some additional issues in the derivation of the two-phase flow model used previously in describing the growth of the Richtmyer-Meshkov instability in the nonlinear phase relevant to other work presented at this meeting [5,6]

Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.Peer reviewe