Regional association plots for retinal arteriolar caliber conditioned on retinal venular caliber for A) Chromosome 5 near <i>TMEM161B</i> and <i>MEF2C</i> and B) Chromosome 17 on <i>SFRS2</i>.

<p>All regional plots are centered on the index SNPs, with a 500 kb buffer on both sides of the index SNP.</p

A) QQ-plot of –log₁₀(observed <i>P</i>-values) against –log₁₀(expected <i>P</i>-values) and B) Manhattan plot of –log₁₀ transformed <i>P</i>-values of retinal arteriolar caliber against their physical position.

<p>A) QQ-plot of –log₁₀(observed <i>P</i>-values) against –log₁₀(expected <i>P</i>-values) and B) Manhattan plot of –log₁₀ transformed <i>P</i>-values of retinal arteriolar caliber against their physical position.</p

Results for retinal arteriolar caliber for discovery cohort meta-analysis and replication cohorts.

<p>SE: standard error, OR: odds ratio, MESA: Multi-Ethnic Study of Atherosclerosis.</p><p>The allele that decreases retinal arteriolar caliber is presented as the effective allele (refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065804#pone-0065804-t002" target="_blank">Table 2</a>).</p

Regional association plots at the two loci that exhibit genome-wide significance at discovery stage and one locus that showed suggestive evidence of association at <i>P</i>-value &lt;10⁻⁶.

<p>A) Chromosome 5 near <i>TMEM161B</i> and <i>MEF2C</i>, B) Chromosome 17 on <i>SFRS2</i> and C) Chromosome 13 on <i>FLT</i>. In each regional plot, the index SNP is represented by a purple circle for the meta-analysis of the five discovery studies and a purple diamond for meta-analysis of discovery and replication studies. The remaining SNPs are colour coded according to pairwise linkage disequilibrium (LD) with the index SNP on a scale of r² from 0 (blue) to 1 (red). Estimated recombination rates reflect the local LD structure in the 500 kb buffer around the index SNP and plotted based on values on Hapmap II CEU. Data for gene annotations are obtained from the RefSeq track of the UCSC Gene Browser (See LocusZoom <a href="http://csg.sph.umich.edu/locuszoom/" target="_blank">http://csg.sph.umich.edu/locuszoom/</a> more details).</p

Association of the three index SNPs with macrovascular diseases.

<p>SE: standard error, OR: odds ratio, N: number of incident events, HR: hazards ratio, WTCCC: Wellcome Trust Case Control Consortium, CAD: Coronary Artery Disease, HVH: Heart and Vascular Health Study, MI: Myocardial infarction, Global BPGen: Global Blood Pressure Genetics Consortium; HTN: hypertension, GoDARTS: Genetics of Diabetes Audit and Reseach Tayside Scotland.</p><p>The allele that decreases retinal arteriolar caliber is presented as the effective allele (refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065804#pone-0065804-t002" target="_blank">Table 2</a>).</p>*<p>excludes cardioembolic stroke.</p>‡<p>adjusted for age, gender, BMI, history of smoking and hypertension medication.</p>†<p>adjusted for age, gender, BMI, history of smoking, previous CAD events and previous ischaemic stroke events.</p

Association of index SNP with retinal arteriolar caliber at three top loci for each discovery cohort and meta-analysis.

<p>AGES: Age Gene/Environment Susceptibility – Reykjavik Study, ARIC: Atherosclerosis Risk in Communities Study, CHS: Cardiovascular Health Study, RS: Rotterdam Study, BMES: Blue Mountains Eye Study.</p><p>The allele that decreases retinal arteriolar caliber is presented as the effective allele.</p><p>(G/I): Indicates if the SNP is directly genotyped (G) or imputed (I). If the SNP is imputed, the imputation quality is included.</p

Effects of calcium, magnesium, and potassium concentrations on ventricular repolarization in unselected individuals.

Background: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.Objectives: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.Methods: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.Results: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.Conclusions: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.</p

<i>G6PC2</i> gene-based association with FG levels using SKAT and BURDEN test

<p><i>G6PC2</i> gene-based association with FG levels using SKAT and BURDEN test</p

Functional characterization of wild type and variant G6PC2 proteins.

<p>(A) Expression levels in HEK293 and (B) INS-1E cells were determined by western blot and densitometry analysis. The multiple bands on the western blot are likely to represent glycosylated G6PC2 protein products. Data are presented as mean ± standard error of the mean for at least three independent experiments. Significant differences are indicated as ** <i>P</i><0.01; *** <i>P</i><0.001; **** <i>P</i><0.0001. EV, empty vector; WT, wild type. (C) Expression levels in HEK293 and INS-1E cells in the presence of proteasomal inhibitor MG-132 or lysosomal inhibitor chloroquine were determined by western blot. (D) Cellular localization in HEK293 cells was assessed by immunofluorescence microscopy. Cells were double immunostained for FLAG tag (green) and calnexin (red), and merged images with a DNA stain (blue) are shown. Images were taken with laser settings that were optimized separately for each sample. Scale bar, 10µm.</p

Haplotypes of the lead non-coding GWAS SNP rs560887 and the three coding variants.

<p>rs138726309 (p.His177Tyr), rs2232323 (p.Tyr207Ser), and rs492594 (p.Val219Leu), obtained from 4,442 unrelated individuals from the Oxford Biobank. (A) Percentage minor allele frequency (MAF) and effect size estimates (<math><mi>β</mi><mo>^</mo></math>) of the four variants reported for the minor allele in mmol/L of FG after adjustment for age, sex, and BMI. (B) Haplotypes of the four associated variants in G6PC2 revealed that the glucose-lowering Leu219 allele was carried exclusively in cis with the glucose-raising allele at the GWAS SNP. Wild-type, glucose-raising alleles are circled in blue and the mutant, glucose-lowering alleles are circled in red. Diameter of the circle is proportional to the effect size estimates. Haplotype association was performed with FG derived residuals (after adjustment for age, sex, and BMI) using the most frequent haplotype as baseline.</p