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Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis

Rheumatoid arthritis (RA) is a risk factor for atherosclerotic cardiovascular diseases (CVD). Given the critical roles of the immune system and inflammatory signals in the pathogenesis of CVD, we hypothesized that interrogation of CVD-related proteins using integrative genomics might provide new ins...

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Autores principales: Lee, Gha Young, Yao, Chen, Hwang, Shih-Jen, Ma, Jiantao, Joehanes, Roby, Lee, Dong Heon, Ellison, R. Curtis, Moore, Lynn L., Liu, Chunyu, Levy, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192300/
https://www.ncbi.nlm.nih.gov/pubmed/37198231
http://dx.doi.org/10.1038/s41598-023-35098-4
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author Lee, Gha Young
Yao, Chen
Hwang, Shih-Jen
Ma, Jiantao
Joehanes, Roby
Lee, Dong Heon
Ellison, R. Curtis
Moore, Lynn L.
Liu, Chunyu
Levy, Daniel
author_facet Lee, Gha Young
Yao, Chen
Hwang, Shih-Jen
Ma, Jiantao
Joehanes, Roby
Lee, Dong Heon
Ellison, R. Curtis
Moore, Lynn L.
Liu, Chunyu
Levy, Daniel
author_sort Lee, Gha Young
collection PubMed
description Rheumatoid arthritis (RA) is a risk factor for atherosclerotic cardiovascular diseases (CVD). Given the critical roles of the immune system and inflammatory signals in the pathogenesis of CVD, we hypothesized that interrogation of CVD-related proteins using integrative genomics might provide new insights into the pathophysiology of RA. We utilized two-sample Mendelian randomization (MR) for causal inference between circulating protein levels and RA by incorporating genetic variants, followed by colocalization to characterize the causal associations. Genetic variants from three sources were obtained: those associated with 71 CVD-related proteins measured in nearly 7000 Framingham Heart Study participants, a published genome-wide association study (GWAS) of RA (19 234 cases, 61 565 controls), and GWAS of rheumatoid factor (RF) levels from the UK Biobank (n = 30 565). We identified the soluble receptor for advanced glycation end products (sRAGE), a critical inflammatory pathway protein, as putatively causal and protective for both RA (odds ratio per 1-standard deviation increment in inverse-rank normalized sRAGE level = 0.364; 95% confidence interval 0.342–0.385; P = 6.40 × 10(–241)) and RF levels (β [change in RF level per sRAGE increment] = − 1.318; SE = 0.434; P = 0.002). Using an integrative genomic approach, we highlight the AGER/RAGE axis as a putatively causal and promising therapeutic target for RA.
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spelling pubmed-101923002023-05-19 Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis Lee, Gha Young Yao, Chen Hwang, Shih-Jen Ma, Jiantao Joehanes, Roby Lee, Dong Heon Ellison, R. Curtis Moore, Lynn L. Liu, Chunyu Levy, Daniel Sci Rep Article Rheumatoid arthritis (RA) is a risk factor for atherosclerotic cardiovascular diseases (CVD). Given the critical roles of the immune system and inflammatory signals in the pathogenesis of CVD, we hypothesized that interrogation of CVD-related proteins using integrative genomics might provide new insights into the pathophysiology of RA. We utilized two-sample Mendelian randomization (MR) for causal inference between circulating protein levels and RA by incorporating genetic variants, followed by colocalization to characterize the causal associations. Genetic variants from three sources were obtained: those associated with 71 CVD-related proteins measured in nearly 7000 Framingham Heart Study participants, a published genome-wide association study (GWAS) of RA (19 234 cases, 61 565 controls), and GWAS of rheumatoid factor (RF) levels from the UK Biobank (n = 30 565). We identified the soluble receptor for advanced glycation end products (sRAGE), a critical inflammatory pathway protein, as putatively causal and protective for both RA (odds ratio per 1-standard deviation increment in inverse-rank normalized sRAGE level = 0.364; 95% confidence interval 0.342–0.385; P = 6.40 × 10(–241)) and RF levels (β [change in RF level per sRAGE increment] = − 1.318; SE = 0.434; P = 0.002). Using an integrative genomic approach, we highlight the AGER/RAGE axis as a putatively causal and promising therapeutic target for RA. Nature Publishing Group UK 2023-05-17 /pmc/articles/PMC10192300/ /pubmed/37198231 http://dx.doi.org/10.1038/s41598-023-35098-4 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lee, Gha Young
Yao, Chen
Hwang, Shih-Jen
Ma, Jiantao
Joehanes, Roby
Lee, Dong Heon
Ellison, R. Curtis
Moore, Lynn L.
Liu, Chunyu
Levy, Daniel
Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis
title Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis
title_full Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis
title_fullStr Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis
title_full_unstemmed Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis
title_short Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis
title_sort integrative mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192300/
https://www.ncbi.nlm.nih.gov/pubmed/37198231
http://dx.doi.org/10.1038/s41598-023-35098-4
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