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Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production

Chung, SA and Taylor, KE and Graham, RR and Nititham, J and Lee, AT and Ortmann, WA and Jacob, CO and Alarcón-Riquelme, ME and Tsao, BP and Harley, JB and Gaffney, PM and Moser, KL and Petri, M and Demirci, FY and Kamboh, MI and Manzi, S and Gregersen, PK and Langefeld, CD and Behrens, TW and Criswell, LA (2011) Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genetics, 7 (3). ISSN 1553-7390

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Abstract

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chung, SA
Taylor, KE
Graham, RR
Nititham, J
Lee, AT
Ortmann, WA
Jacob, CO
Alarcón-Riquelme, ME
Tsao, BP
Harley, JB
Gaffney, PM
Moser, KL
Petri, M
Demirci, FYfyd1@pitt.eduFYD1
Kamboh, MIkamboh@pitt.eduKAMBOH
Manzi, S
Gregersen, PK
Langefeld, CD
Behrens, TW
Criswell, LA
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
UNSPECIFIEDAlarcón-Riquelme, Marta EUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
UNSPECIFIEDCriswell, Lindsey AUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
UNSPECIFIEDHarley, John BUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
UNSPECIFIEDJacob, Chaim OUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
UNSPECIFIEDKimberly, Robert PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
UNSPECIFIEDLangefeld, Carl DUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
UNSPECIFIEDMoser, Kathy LUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
UNSPECIFIEDTsao, Betty PUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
UNSPECIFIEDVyse, Timothy JUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 March 2011
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 7
Number: 3
DOI or Unique Handle: 10.1371/journal.pgen.1001323
Schools and Programs: School of Public Health > Human Genetics
Refereed: Yes
ISSN: 1553-7390
MeSH Headings: Antigens, CD11b--genetics; Autoantibodies--genetics; Autoantibodies--immunology; Case-Control Studies; DNA--immunology; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Interferon Regulatory Factors--genetics; Lupus Erythematosus, Systemic--genetics; Lupus Erythematosus, Systemic--immunology; Major Histocompatibility Complex--genetics; Polymorphism, Single Nucleotide; STAT4 Transcription Factor--genetics
Other ID: NLM PMC3048371
PubMed Central ID: PMC3048371
PubMed ID: 21408207
Date Deposited: 07 Aug 2012 15:50
Last Modified: 22 Jun 2021 11:55
URI: http://d-scholarship.pitt.edu/id/eprint/13426

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