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Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese

Autophagy is associated with various immune diseases, including systemic lupus erythematosus (SLE). Seven variants within autophagy-related genes previously reported to show top association signals by genome-wide association studies in immune diseases were selected for analysis. Initially, 510 SLE p...

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Autores principales: Zhang, Yue-miao, Zhou, Xu-jie, Cheng, Fa-juan, Qi, Yuan-yuan, Hou, Ping, Zhao, Ming-hui, Zhang, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355135/
https://www.ncbi.nlm.nih.gov/pubmed/28099919
http://dx.doi.org/10.18632/oncotarget.14631
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author Zhang, Yue-miao
Zhou, Xu-jie
Cheng, Fa-juan
Qi, Yuan-yuan
Hou, Ping
Zhao, Ming-hui
Zhang, Hong
author_facet Zhang, Yue-miao
Zhou, Xu-jie
Cheng, Fa-juan
Qi, Yuan-yuan
Hou, Ping
Zhao, Ming-hui
Zhang, Hong
author_sort Zhang, Yue-miao
collection PubMed
description Autophagy is associated with various immune diseases, including systemic lupus erythematosus (SLE). Seven variants within autophagy-related genes previously reported to show top association signals by genome-wide association studies in immune diseases were selected for analysis. Initially, 510 SLE patients (631 controls) were enrolled in the study. An additional independent cohort of 511 SLE patients (687 controls) was included for replication. Polymorphism rs2638272 in LRRK2 gene showed significant association with susceptibility to SLE (P = 1.14 × 10(−2)) within the initial patient population. This was independently replicated (second patient cohort), and was reinforced with combination (P = 2.82 × 10(−3)). By combining multiple layers of regulatory effects, rs1491941 in high linkage disequilibrium with rs2638272 (r(2) = 0.99) was regarded to have the strongest function in LRRK2. The rs1491941 protective A-allele exhibited an increase of nuclear protein binding, and an increase in LRRK2 transcription compared with G-allele. Furthermore, we observed increased transcription levels of LRRK2 in peripheral blood mononuclear cells from SLE patients compared with controls. In conclusion, we have identified a novel genetic association between the autophagy-related LRRK2 gene and susceptibility to SLE. By integrating layers of functional data, we derived the beneficial effect of autophagy on the pathogenesis of SLE.
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spelling pubmed-53551352017-04-15 Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese Zhang, Yue-miao Zhou, Xu-jie Cheng, Fa-juan Qi, Yuan-yuan Hou, Ping Zhao, Ming-hui Zhang, Hong Oncotarget Research Paper Autophagy is associated with various immune diseases, including systemic lupus erythematosus (SLE). Seven variants within autophagy-related genes previously reported to show top association signals by genome-wide association studies in immune diseases were selected for analysis. Initially, 510 SLE patients (631 controls) were enrolled in the study. An additional independent cohort of 511 SLE patients (687 controls) was included for replication. Polymorphism rs2638272 in LRRK2 gene showed significant association with susceptibility to SLE (P = 1.14 × 10(−2)) within the initial patient population. This was independently replicated (second patient cohort), and was reinforced with combination (P = 2.82 × 10(−3)). By combining multiple layers of regulatory effects, rs1491941 in high linkage disequilibrium with rs2638272 (r(2) = 0.99) was regarded to have the strongest function in LRRK2. The rs1491941 protective A-allele exhibited an increase of nuclear protein binding, and an increase in LRRK2 transcription compared with G-allele. Furthermore, we observed increased transcription levels of LRRK2 in peripheral blood mononuclear cells from SLE patients compared with controls. In conclusion, we have identified a novel genetic association between the autophagy-related LRRK2 gene and susceptibility to SLE. By integrating layers of functional data, we derived the beneficial effect of autophagy on the pathogenesis of SLE. Impact Journals LLC 2017-01-13 /pmc/articles/PMC5355135/ /pubmed/28099919 http://dx.doi.org/10.18632/oncotarget.14631 Text en Copyright: © 2017 Zhang et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zhang, Yue-miao
Zhou, Xu-jie
Cheng, Fa-juan
Qi, Yuan-yuan
Hou, Ping
Zhao, Ming-hui
Zhang, Hong
Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese
title Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese
title_full Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese
title_fullStr Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese
title_full_unstemmed Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese
title_short Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese
title_sort autophagy-related gene lrrk2 is likely a susceptibility gene for systemic lupus erythematosus in northern han chinese
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355135/
https://www.ncbi.nlm.nih.gov/pubmed/28099919
http://dx.doi.org/10.18632/oncotarget.14631
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