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PLoS One. 2015 Jun 17;10(6):e0128452. doi: 10.1371/journal.pone.0128452. eCollection 2015.

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.

Author information

1
Department of Medicine, Division of General Internal Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; The Welch Center for Prevention, Epidemiology, and Clinical Research, The Johns Hopkins University, Baltimore, Maryland, United States of America; Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
2
Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
3
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
4
Department of Medicine, The University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America; Department of Population Health Sciences, The University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
5
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
6
Division of Epidemiology, University of Texas at Houston School of Public Health, Houston, Texas, United States of America.

Abstract

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 AGER, 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 AGER, was associated with 43% lower sRAGE levels (P = 2.22x10-8; MAF = 0.10) and was nearly absent in whites. These AGER 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.

PMID:
26083729
PMCID:
PMC4471120
DOI:
10.1371/journal.pone.0128452
[Indexed for MEDLINE]
Free PMC Article

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