A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy.
Depending on the epidemiological setting, a variable proportion of leprosy patients will suffer from excessive pro-inflammatory responses, termed type-1 reactions (T1R). The LRRK2 gene encodes a multi-functional protein that has been shown to modulate pro-inflammatory responses. Variants near the LR...
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ftdoajarticles:oai:doaj.org/article:2d0ef309b71846b79607e3d14d753f3f 2023-05-15T15:16:48+02:00 A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy. Vinicius M Fava Jérémy Manry Aurélie Cobat Marianna Orlova Nguyen Van Thuc Nguyen Ngoc Ba Vu Hong Thai Laurent Abel Alexandre Alcaïs Erwin Schurr Canadian Lrrk2 in Inflammation Team (CLINT) 2016-02-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004412 https://doaj.org/article/2d0ef309b71846b79607e3d14d753f3f EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4742274?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004412 https://doaj.org/article/2d0ef309b71846b79607e3d14d753f3f PLoS Neglected Tropical Diseases, Vol 10, Iss 2, p e0004412 (2016) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2016 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004412 2022-12-31T02:26:57Z Depending on the epidemiological setting, a variable proportion of leprosy patients will suffer from excessive pro-inflammatory responses, termed type-1 reactions (T1R). The LRRK2 gene encodes a multi-functional protein that has been shown to modulate pro-inflammatory responses. Variants near the LRRK2 gene have been associated with leprosy in some but not in other studies. We hypothesized that LRRK2 was a T1R susceptibility gene and that inconsistent association results might reflect different proportions of patients with T1R in the different sample settings. Hence, we evaluated the association of LRRK2 variants with T1R susceptibility.An association scan of the LRRK2 locus was performed using 156 single-nucleotide polymorphisms (SNPs). Evidence of association was evaluated in two family-based samples: A set of T1R-affected and a second set of T1R-free families. Only SNPs significant for T1R-affected families with significant evidence of heterogeneity relative to T1R-free families were considered T1R-specific. An expression quantitative trait locus (eQTL) analysis was applied to evaluate the impact of T1R-specific SNPs on LRRK2 gene transcriptional levels.A total of 18 T1R-specific variants organized in four bins were detected. The core SNP capturing the T1R association was the LRRK2 missense variant M2397T (rs3761863) that affects LRRK2 protein turnover. Additionally, a bin of nine SNPs associated with T1R were eQTLs for LRRK2 in unstimulated whole blood cells but not after exposure to Mycobacterium leprae antigen.The results support a preferential association of LRRK2 variants with T1R. LRRK2 involvement in T1R is likely due to a pathological pro-inflammatory loop modulated by LRRK2 availability. Interestingly, the M2397T variant was reported in association with Crohn's disease with the same risk allele as in T1R suggesting common inflammatory mechanism in these two distinct diseases. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 10 2 e0004412 |
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Directory of Open Access Journals: DOAJ Articles |
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language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Vinicius M Fava Jérémy Manry Aurélie Cobat Marianna Orlova Nguyen Van Thuc Nguyen Ngoc Ba Vu Hong Thai Laurent Abel Alexandre Alcaïs Erwin Schurr Canadian Lrrk2 in Inflammation Team (CLINT) A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Depending on the epidemiological setting, a variable proportion of leprosy patients will suffer from excessive pro-inflammatory responses, termed type-1 reactions (T1R). The LRRK2 gene encodes a multi-functional protein that has been shown to modulate pro-inflammatory responses. Variants near the LRRK2 gene have been associated with leprosy in some but not in other studies. We hypothesized that LRRK2 was a T1R susceptibility gene and that inconsistent association results might reflect different proportions of patients with T1R in the different sample settings. Hence, we evaluated the association of LRRK2 variants with T1R susceptibility.An association scan of the LRRK2 locus was performed using 156 single-nucleotide polymorphisms (SNPs). Evidence of association was evaluated in two family-based samples: A set of T1R-affected and a second set of T1R-free families. Only SNPs significant for T1R-affected families with significant evidence of heterogeneity relative to T1R-free families were considered T1R-specific. An expression quantitative trait locus (eQTL) analysis was applied to evaluate the impact of T1R-specific SNPs on LRRK2 gene transcriptional levels.A total of 18 T1R-specific variants organized in four bins were detected. The core SNP capturing the T1R association was the LRRK2 missense variant M2397T (rs3761863) that affects LRRK2 protein turnover. Additionally, a bin of nine SNPs associated with T1R were eQTLs for LRRK2 in unstimulated whole blood cells but not after exposure to Mycobacterium leprae antigen.The results support a preferential association of LRRK2 variants with T1R. LRRK2 involvement in T1R is likely due to a pathological pro-inflammatory loop modulated by LRRK2 availability. Interestingly, the M2397T variant was reported in association with Crohn's disease with the same risk allele as in T1R suggesting common inflammatory mechanism in these two distinct diseases. |
format |
Article in Journal/Newspaper |
author |
Vinicius M Fava Jérémy Manry Aurélie Cobat Marianna Orlova Nguyen Van Thuc Nguyen Ngoc Ba Vu Hong Thai Laurent Abel Alexandre Alcaïs Erwin Schurr Canadian Lrrk2 in Inflammation Team (CLINT) |
author_facet |
Vinicius M Fava Jérémy Manry Aurélie Cobat Marianna Orlova Nguyen Van Thuc Nguyen Ngoc Ba Vu Hong Thai Laurent Abel Alexandre Alcaïs Erwin Schurr Canadian Lrrk2 in Inflammation Team (CLINT) |
author_sort |
Vinicius M Fava |
title |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy. |
title_short |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy. |
title_full |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy. |
title_fullStr |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy. |
title_full_unstemmed |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy. |
title_sort |
missense lrrk2 variant is a risk factor for excessive inflammatory responses in leprosy. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2016 |
url |
https://doi.org/10.1371/journal.pntd.0004412 https://doaj.org/article/2d0ef309b71846b79607e3d14d753f3f |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 10, Iss 2, p e0004412 (2016) |
op_relation |
http://europepmc.org/articles/PMC4742274?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004412 https://doaj.org/article/2d0ef309b71846b79607e3d14d753f3f |
op_doi |
https://doi.org/10.1371/journal.pntd.0004412 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
10 |
container_issue |
2 |
container_start_page |
e0004412 |
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1766347091198607360 |