title: 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.
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.
authors.affiliation: 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.
authors.forename: Nisa M
authors.initials: NM
authors.lastname: Maruthur
authors.affiliation: Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.affiliation: 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.
authors.forename: Brad C
authors.initials: BC
authors.lastname: Astor
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Division of Epidemiology, University of Texas at Houston School of Public Health, Houston, Texas, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: 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.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: 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.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Selvin
authors.affiliation: 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.
authors.forename: Wen Hong Linda
authors.initials: WH
authors.lastname: Kao
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D056186:Metagenomics; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood / Q000235:genetics*; D012307:Risk Factors; D016019:Survival Analysis; D044465:White People / Q000235:genetics
chemical_list: D000067759:Receptor for Advanced Glycation End Products