Dataset Information

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

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 p(heterogeneity)<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.

SUBMITTER: Chung SA

PROVIDER: S-EPMC3048371 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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

Chung Sharon A SA Taylor Kimberly E KE Graham Robert R RR Nititham Joanne J Lee Annette T AT Ortmann Ward A WA Jacob Chaim O CO Alarcón-Riquelme Marta E ME Tsao Betty P BP Harley John B JB Gaffney Patrick M PM Moser Kathy L KL Petri Michelle M Demirci F Yesim FY Kamboh M Ilyas MI Manzi Susan S Gregersen Peter K PK Langefeld Carl D CD Behrens Timothy W TW Criswell Lindsey A LA

PLoS genetics 20110303 3

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 (SNP ...[more]

PMID: 21408207

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Project description:Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies associated with specific clinical manifestations. Previous studies have shown an association between differential DNA methylation and SLE susceptibility, but have not investigated SLE-related autoantibodies. Our goal was to determine whether DNA methylation is associated with production of clinically relevant SLE-related autoantibodies, with an emphasis on the anti-dsDNA autoantibody. In this study, we characterized the methylation status of 467,314 CpG sites in 326 women with SLE. Using a discovery and replication study design, we identified and replicated significant associations between anti-dsDNA autoantibody production and the methylation status of 16 CpG sites (pdiscovery<1.07E-07 and preplication<0.0029) in 11 genes. Associations were further investigated using multivariable regression to adjust for estimated leukocyte cell proportions and population substructure. The adjusted mean DNA methylation difference between anti-dsDNA positive and negative cases ranged from 1.2% to 19%, and the adjusted odds ratio for anti-dsDNA autoantibody production comparing the lowest and highest methylation tertiles ranged from 6.8 to 18.2. Differential methylation for these CpG sites was also associated with anti-SSA, anti-Sm, and anti-RNP autoantibody production. Overall, associated CpG sites were hypomethylated in autoantibody positive compared to autoantibody negative cases. Differential methylation of CpG sites within the major histocompatibility region was not strongly associated with autoantibody production. Genes with differentially methylated CpG sites represent multiple biologic pathways, and have not been associated with autoantibody production in genetic association studies. In conclusion, hypomethylation of CpG sites within genes from different pathways is associated with anti-dsDNA, anti-SSA, anti-Sm, and anti-RNP production in SLE, and these associations are not explained by genetic variation. Thus, studies of epigenetic mechanisms such as DNA methylation represent a complementary method to genetic association studies to identify biologic pathways that may contribute to the clinical heterogeneity of autoimmune diseases.

Project description:Autoantibody and inflammatory cytokines play crucial roles in the development of systemic lupus erythematosus (SLE); however, the regulation of their production warrants further investigation. This study aimed to investigate the role of basophil activation in the development of SLE based on studies in patients with SLE and spontaneous lupus-prone MRL-lpr/lpr mice.The phenotypes of peripheral basophils and the production of autoantibody and interleukin (IL)-17 in patients with SLE were determined by flow cytometry and enzyme-linked immunosorbent assay, and also their correlations were investigated by statistical analysis. Thereafter, the effect of basophils on autoantibody production by B cells and Th17 differentiation in SLE were evaluated in vitro. Finally, the effect of basophil depletion on the development of autoimmune disorders in spontaneous lupus-prone MRL-lpr/lpr mice was examined.The decreased numbers and an increased activation of peripheral basophils were found to be correlated with increased autoantibody production and disease activity in patients with SLE. Correspondingly, in vitro coculture studies showed that basophils obtained from patients with SLE promoted autoantibody production by SLE B cells and promoted Th17 differentiation from SLE naïve CD4+ T cells. The decrease of peripheral basophils in patients with SLE might be due to their migration to lymph nodes post their activation mediated by (autoreactive) IgE as supported by their increased CD62L and CCR7 expressions and accumulation in the lymph nodes of MRL-lpr/lpr mice. Furthermore, an increased activation of peripheral basophils was identified in MRL-lpr/lpr mice. Importantly, basophil-depleted MRL-lpr/lpr mice exhibited an extended life span, improved renal function, and lower serum levels of autoantibodies and IL-17, while basophil-adoptive-transferred mice exhibited the opposite results.These finding suggest that basophil activation-dependent autoantibody and IL-17 production may constitute a critical pathogenic mechanism in SLE.

Dataset Information

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

Publications

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

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