Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study

INTRODUCTION:Subclinical atherosclerosis (SCA) measures in multiple arterial beds are heritable phenotypes that are associated with increased incidence of cardiovascular disease. We conducted a genome-wide association study (GWAS) for SCA measurements in the community-based Framingham Heart Study.METHODS:Over 100,000 single nucleotide polymorphisms (SNPs) were genotyped (Human 100K GeneChip, Affymetrix) in 1345 subjects from 310 families. We calculated sex-specific age-adjusted and multivariable-adjusted residuals in subjects tested for quantitative SCA phenotypes, including ankle-brachial index, coronary artery calcification and abdominal aortic calcification using multi-detector computed tomography, and carotid intimal medial thickness (IMT) using carotid ultrasonography. We evaluated associations of these phenotypes with 70,987 autosomal SNPs with minor allele frequency [greater than or equal to] 0.10, call rate [greater than or equal to] 80%, and Hardy-Weinberg p-value [greater than or equal to] 0.001 in samples ranging from 673 to 984 subjects, using linear regression with generalized estimating equations (GEE) methodology and family-based association testing (FBAT). Variance components LOD scores were also calculated.RESULTS:There was no association result meeting criteria for genome-wide significance, but our methods identified 11 SNPs with p < 10-5 by GEE and five SNPs with p < 10-5 by FBAT for multivariable-adjusted phenotypes. Among the associated variants were SNPs in or near genes that may be considered candidates for further study, such as rs1376877 (GEE p < 0.000001, located in ABI2) for maximum internal carotid artery IMT and rs4814615 (FBAT p = 0.000003, located in PCSK2) for maximum common carotid artery IMT. Modest significant associations were noted with various SCA phenotypes for variants in previously reported atherosclerosis candidate genes, including NOS3 and ESR1. Associations were also noted of a region on chromosome 9p21 with CAC phenotypes that confirm associations with coronary heart disease and CAC in two recently reported genome-wide association studies. In linkage analyses, several regions of genome-wide linkage were noted, confirming previously reported linkage of internal carotid artery IMT on chromosome 12. All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:The results from this GWAS generate hypotheses regarding several SNPs that may be associated with SCA phenotypes in multiple arterial beds. Given the number of tests conducted, subsequent independent replication in a staged approach is essential to identify genetic variants that may be implicated in atherosclerosis.

A FLOW-THROUGH ACOUSTIC WAVEGUIDE FOR TWO-PHASE BUBBLY FLOW VOID FRACTION MEASUREMENT

In the Spallation Neutron Source (SNS) facility at Oak Ridge National Laboratory (ORNL), the deposition of a high-energy proton beam into the liquid mercury target forms bubbles whose asymmetric collapse cause Cavitation Damage Erosion (CDE) to the container walls, thereby reducing its usable lifetime. One proposed solution for mitigation of this damage is to inject a population of microbubbles into the mercury, yielding a compliant and attenuative medium that will reduce the resulting cavitation damage. This potential solution presents the task of creating a diagnostic tool to monitor bubble population in the mercury flow in order to correlate void fraction and damage. Details of an acoustic waveguide for the eventual measurement of two-phase mercury-helium flow void fraction are discussed. The assembly’s waveguide is a vertically oriented stainless steel cylinder with 5.08cm ID, 1.27cm wall thickness and 40cm length. For water experiments, a 2.54cm thick stainless steel plate at the bottom supports the fluid, provides an acoustically rigid boundary condition, and is the mounting point for a hydrophone. A port near the bottom is the inlet for the fluid of interest. A spillover reservoir welded to the upper portion of the main tube allows for a flow-through design, yielding a pressure release top boundary condition for the waveguide. A cover on the reservoir supports an electrodynamic shaker that is driven by linear frequency sweeps to excite the tube. The hydrophone captures the frequency response of the waveguide. The sound speed of the flowing medium is calculated, assuming a linear dependence of axial mode number on modal frequency (plane wave). Assuming that the medium has an effective-mixture sound speed, and that it contains bubbles which are much smaller than the resonance radii at the highest frequency of interest (Wood’s limit), the void fraction of the flow is calculated. Results for water and bubbly water of varying void fraction are presented, and serve to demonstrate the accuracy and precision of the apparatus.