Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen.
Autoimmunity
Genetics
Interferon
Journal
Cytokine
ISSN: 1096-0023
Titre abrégé: Cytokine
Pays: England
ID NLM: 9005353
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
11
10
2018
revised:
20
12
2018
accepted:
24
12
2018
pubmed:
28
1
2019
medline:
22
9
2021
entrez:
28
1
2019
Statut:
ppublish
Résumé
High serum interferon alpha (IFN-α) is an important heritable phenotype in systemic lupus erythematosus (SLE) which is involved in primary disease pathogenesis. High vs. low levels of IFN-α are associated with disease severity and account for some of the biological heterogeneity between SLE patients. The aim of the study was to replicate and fine-map previously detected genetic associations with serum IFN-α in SLE. We previously undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci identified in this screen were selected for follow up in a large independent cohort of 1370 SLE patients (703 European-ancestry, 432 African ancestry, and 235 Amerindian ancestry). Each ancestral background was analyzed separately, and ancestry-informative markers were used to control for ancestry and admixture. We find a rare haplotype spanning the promoter region of EFNA5 that is strongly associated with serum IFN-α in both African-American and European-American SLE patients (OR = 3.0, p = 3.7 × 10 This study demonstrates the power of molecular sub-phenotypes to reveal genetic factors involved in complex autoimmune disease. The distinct associations observed in different ancestral backgrounds emphasize the heterogeneity of molecular pathogenesis in SLE.
Sections du résumé
BACKGROUND/PURPOSE
High serum interferon alpha (IFN-α) is an important heritable phenotype in systemic lupus erythematosus (SLE) which is involved in primary disease pathogenesis. High vs. low levels of IFN-α are associated with disease severity and account for some of the biological heterogeneity between SLE patients. The aim of the study was to replicate and fine-map previously detected genetic associations with serum IFN-α in SLE.
METHODS
We previously undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci identified in this screen were selected for follow up in a large independent cohort of 1370 SLE patients (703 European-ancestry, 432 African ancestry, and 235 Amerindian ancestry). Each ancestral background was analyzed separately, and ancestry-informative markers were used to control for ancestry and admixture.
RESULTS
We find a rare haplotype spanning the promoter region of EFNA5 that is strongly associated with serum IFN-α in both African-American and European-American SLE patients (OR = 3.0, p = 3.7 × 10
CONCLUSION
This study demonstrates the power of molecular sub-phenotypes to reveal genetic factors involved in complex autoimmune disease. The distinct associations observed in different ancestral backgrounds emphasize the heterogeneity of molecular pathogenesis in SLE.
Identifiants
pubmed: 30685201
pii: S1043-4666(19)30002-X
doi: 10.1016/j.cyto.2018.12.014
pmc: PMC7723062
mid: NIHMS1518392
pii:
doi:
Substances chimiques
Ephrin-A5
0
Interferon-alpha
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
154631Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR057781
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104938
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR053483
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI144292
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR065964
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR073750
Pays : United States
Organisme : NIAID NIH HHS
ID : L30 AI071651
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR060861
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI082714
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM103510
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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