Global priority scores of objectives.

<p>Global priority scores of objectives.</p

Relative differences in importance between objectives at lowest level of hierarchy.^*

<p>*Relative difference is calculated as ratio of global priority scores shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126625#pone.0126625.t001" target="_blank">Table 1</a> (e.g., relative difference for minimizing severe hypoglycemia versus minimizing fracture risk is 14.0/2.57 = 5.45)</p><p>Relative differences in importance between objectives at lowest level of hierarchy.^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126625#t002fn001" target="_blank">*</a>}</p

Overall relative differences between treatment alternatives.^*

<p>*Relative difference is calculated as ratio of global priority scores shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126625#pone.0126625.t001" target="_blank">Table 1</a> (e.g., relative difference for minimizing severe hypoglycemia versus minimizing fracture risk is 14.0/2.57 = 5.45)</p><p>Overall relative differences between treatment alternatives.^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126625#t003fn001" target="_blank">*</a>}</p

Genetics of Plasma Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Outcomes in a Community-based Population: Results from the Atherosclerosis Risk in Communities Study

<div><p>Plasma soluble Receptor for Advanced Glycation End-products (sRAGE) is a strong marker of vascular outcomes although evidence on the direction of association is mixed. Compared to whites, blacks have lower levels of sRAGE. We hypothesized that genetic determinants of sRAGE would help clarify the causal role of sRAGE and the black-white difference in sRAGE levels. We conducted a genome-wide analysis of sRAGE in whites and blacks from the Atherosclerosis Risk in Communities Study. Median plasma sRAGE levels were lower in blacks than whites (728 vs. 1067 pg/ml; P<0.0001). The T (vs. C) allele of rs2070600, a missense variant in <i>AGER</i>, the gene encoding RAGE, was associated with approximately 50% lower sRAGE levels in both whites (N = 1,737; P = 7.26x10^-16; minor allele frequency (MAF) = 0.04) and blacks (N = 581; P = 0.02; MAF = 0.01). In blacks, the T (vs. C) allele of rs2071288, intronic to <i>AGER</i>, was associated with 43% lower sRAGE levels (P = 2.22x10^-8; MAF = 0.10) and was nearly absent in whites. These <i>AGER</i> SNPs explained 21.5% and 26% of the variation in sRAGE in blacks and whites, respectively, but did not explain the black-white difference in sRAGE. These SNPs were not significantly associated with incident death, coronary heart disease, diabetes, heart failure, or chronic kidney disease in whites (N = 8,130–9,017) or blacks (N = 2,293–2,871) (median follow up ~20 years). We identified strong genetic determinants of sRAGE that did not explain the large black-white difference in sRAGE levels or clearly influence risk of clinical outcomes, suggesting that sRAGE may not be a causal factor in development of these outcomes.</p></div

Manhattan plot for genome-wide association for ln(sRAGE) in blacks (N = 581).

<p>Manhattan plot for genome-wide association for ln(sRAGE) in blacks (N = 581).</p

<i>AGER</i> SNPs and risk of death, incident coronary heart disease, heart failure, diabetes, and chronic kidney disease by race.

<p>Abbreviations: CHD, coronary heart disease; CKD, chronic kidney disease. Hazard ratio for T vs. C allele adjusted for age, sex, and center. Median follow up in years displayed.</p

Manhattan plot for genome-wide association for ln(sRAGE) in whites (N = 1,737).

<p>Manhattan plot for genome-wide association for ln(sRAGE) in whites (N = 1,737).</p

Genetic variants and the black-white difference in ln(sRAGE).

<p>Model 1: age + race + gender + center</p><p>Model 2: Model 1 + rs2070600 + rs2071288</p><p>Model 3: Model 2 + education</p><p>Model 4: Model 3 + BMI, eGFR, fasting glucose, prevalent CHD</p><p>^aBeta for difference in ln(sRAGE) for T vs. C allele</p><p>Genetic variants and the black-white difference in ln(sRAGE).</p

Characteristics of black and white participants with sRAGE levels (N = 2,329).^a^,^b^,^c^,^d

<p>^a Continuous variables reported as means (SD) and categorical variables as n (%). Median (p25, p75) provided for sRAGE.</p><p>^b Education, n = 1739 for whites and 588 for blacks; prevalent CHD, n = 1707 for whites and n = 577 for blacks; eGFR, n = 568 for blacks; fasting glucose, n = 1726 for whites and n = 586 for blacks</p><p>^c P<0.05 for differences between race groups for all characteristics</p><p>^d Abbreviations: sRAGE, soluble receptor for advanced glycation end-products; BMI, body mass index; CHD, coronary heart disease; eGFR, estimated glomerular filtration rate</p><p>Characteristics of black and white participants with sRAGE levels (N = 2,329).<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128452#t001fn001" target="_blank">^a</a>^,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128452#t001fn002" target="_blank">^b</a>^,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128452#t001fn003" target="_blank">^c</a>^,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128452#t001fn004" target="_blank">^d</a></p

Regional association plot for genome-wide significant locus (<i>AGER</i>) in blacks.

<p>Regional association plot for genome-wide significant locus (<i>AGER</i>) in blacks.</p