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The Gly82Ser polymorphism in the receptor for advanced glycation endproducts increases the risk for coronary events in the general population

Grauen Larsen, Helena LU ; Sun, Jiangming LU orcid ; Sjögren, Marketa LU ; Borné, Yan LU ; Engström, Gunnar LU ; Nilsson, Peter LU ; Orho-Melander, Marju LU ; Goncalves, Isabel LU orcid ; Nilsson, Jan LU and Melander, Olle LU orcid , et al. (2024) In Scientific Reports 14(1).
Abstract

The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600,... (More)

The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02–1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
14
issue
1
article number
11567
publisher
Nature Publishing Group
external identifiers
  • scopus:85194020956
  • pmid:38773223
ISSN
2045-2322
DOI
10.1038/s41598-024-62385-5
language
English
LU publication?
yes
id
34a34779-360f-4604-b50c-38413ef436f8
date added to LUP
2024-06-13 14:42:28
date last changed
2024-11-15 07:48:59
@article{34a34779-360f-4604-b50c-38413ef436f8,
  abstract     = {{<p>The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02–1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship.</p>}},
  author       = {{Grauen Larsen, Helena and Sun, Jiangming and Sjögren, Marketa and Borné, Yan and Engström, Gunnar and Nilsson, Peter and Orho-Melander, Marju and Goncalves, Isabel and Nilsson, Jan and Melander, Olle and Schiopu, Alexandru}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{The Gly82Ser polymorphism in the receptor for advanced glycation endproducts increases the risk for coronary events in the general population}},
  url          = {{http://dx.doi.org/10.1038/s41598-024-62385-5}},
  doi          = {{10.1038/s41598-024-62385-5}},
  volume       = {{14}},
  year         = {{2024}},
}