Characteristics of HAPI Heart Study Participants.

<p>Abbreviations: BMI, body mass index; HAPI, Heredity and Phenotype Intervention; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation.</p><p>SI conversion factors: To convert HDL-cholesterol, LDL-cholesterol, and total cholesterol values to mmol/L, multiply by 0.0259; triglycerides to mmol/L, multiply by 0.0113.</p><p>^*Defined as systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg or taking prescription medication for previously diagnosed hypertension.</p><p>^†Logarithm-transformed for analysis and back-transformed for presentation.</p><p>^‡Defined as LDL-cholesterol greater than 160 mg/dl or taking prescription medication for previously diagnosed hypercholesterolemia.</p><p>^§Self-reported history of smoking cigarette, pipe, or cigar. Only men report smoking in the OOA community.</p><p>Characteristics of HAPI Heart Study Participants.</p

The Impact of <i>PEAR1</i> rs12041331 on Endothelial Cell Migration in Human Umbilical Vein Endothelial Cells (HUVECs).

<p>(A) Representative phase-contrast images of rs12041331-stratified HUVECs at 0 and 6 hours post-scratch generation during an <i>ex vivo</i> endothelial cell migration assay. Scale bar, 250 μm. (B) Quantitative depiction of mean HUVEC migration. Endothelial cell migration distance was calculated by dividing the area of the scratch by the height of the frame using ImageJ. Mean endothelial cell migration distance was calculated based on 72, 72, and 36 independent measurements for GG, GA, and AA genotypes, respectively, as described in the Materials and Methods section.</p

Predictors of Variance in Flow-Mediated Dilation in HAPI Study Participants.

<p>Abbreviations: BMI, body mass index; HAPI, Heredity and Phenotype Intervention; HDL, high-density lipoprotein; LDL, low-density lipoprotein.</p><p>^*Observed using a sex-stratified analysis to account for the OOA community’s male-only smoking cohort.</p><p>Predictors of Variance in Flow-Mediated Dilation in HAPI Study Participants.</p

<i>PEAR1</i> Genetic Network.

<p>Genes highly correlated with <i>PEAR1</i> (green nodes) were evaluated for protein-protein interactions (gray nodes) that were shared by at least 2 of the 30 genes analyzed. Green lines indicate a co-expression relationship; black lines indicate a physical protein-protein interaction. Genetic neighborhoods of similar pathway or function have been highlighted and labeled.</p

Exome-chip meta-analysis identifies association between variation in <i>ANKRD26</i> and platelet aggregation

<p>Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10^–7) between rare genetic variants in <i>ANKRD26</i> and ADP-induced platelet aggregation. One of the <i>ANKRD26</i> SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20–50% were observed in heterozygotes in all cohorts. Novel genetic signals in <i>ABCG1</i> and <i>HCP5</i> were also associated with platelet aggregation to ADP in meta-analyses, although only results for <i>HCP5</i> could be replicated. The SNV in <i>HCP5</i> intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.</p

GWAS + Replication, Validation and Overall <i>P</i>-values for susceptibility loci identified from the Overall meta-analysis (P<2.5×10⁻⁵).

<p>SNPs are ordered by chromosome and position (NCBI Build 36.1, hg18) with the major/minor alleles (positive strand) and corresponding gene (underlined) or nearest annotated genes (+/−500 kb). For each phase of the study, GWAS + Replication, Validation and Overall (GWAS+Replication+T2DM+IRAS+IRASFS) analyses, the minor allele frequency (MAF) in controls, additive <i>P</i>-value and odds ratio (OR) with associated 95% confidence interval (CI) with respect to the minor allele is listed.</p

Clinical Characteristics of Study Samples.

<p>Values are presented as trait mean and standard deviation.</p

Study Design.

<p>Study Design.</p

Genome-Wide Association Study Results.

<p>Results are adjusted for admixture using PC1 as a covariate in the analysis. <i>P</i>-values are shown under the additive model. The blue line at -log₁₀(<i>P</i>-value) = 3 represents an additive <i>P</i>-value = 0.001 and the red line at -log₁₀(<i>P</i>-value) = 5 represents a <i>P</i>-value = 1.0×10⁻⁵.</p