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European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus.

ABSTRACT: To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease.SLE patients of European descent (n=1,754) from 8 case collections were genotyped for >1,400 ancestry informative markers that define a north-south gradient of European substructure. Using the Structure program, each SLE patient was characterized in terms of percent Northern (versus percent Southern) European ancestry based on these genetic markers. Nonparametric methods, including tests for trend, were used to identify associations between Northern European ancestry and specific SLE manifestations.In multivariate analyses, increasing levels of Northern European ancestry were significantly associated with photosensitivity (Ptrend=0.0021, odds ratio for highest quartile of Northern European ancestry versus lowest quartile [ORhigh-low] 1.64, 95% confidence interval [95% CI] 1.13-2.35) and discoid rash (Ptrend=0.014, ORhigh-low 1.93, 95% CI 0.98-3.83). In contrast, increasing levels of Northern European ancestry had a protective effect against the production of anticardiolipin autoantibodies (Ptrend=1.6x10(-4), ORhigh-low 0.46, 95% CI 0.30-0.69) and anti-double-stranded DNA autoantibodies (Ptrend=0.017, ORhigh-low 0.67, 95% CI 0.46-0.96).This study demonstrates that specific SLE manifestations vary according to Northern versus Southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure based on genetic ancestry.

SUBMITTER: Chung SA

PROVIDER: S-EPMC2739103 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus.

Chung Sharon A SA Tian Chao C Taylor Kimberly E KE Lee Annette T AT Ortmann Ward A WA Hom Geoffrey G Graham Robert R RR Nititham Joanne J Kelly Jennifer A JA Morrisey Jean J Wu Hui H Yin Hong H Alarcón-Riquelme Marta E ME Tsao Betty P BP Harley John B JB Gaffney Patrick M PM Moser Kathy L KL Manzi Susan S Petri Michelle M Gregersen Peter K PK Langefeld Carl D CD Behrens Timothy W TW Seldin Michael F MF Criswell Lindsey A LA

Arthritis and rheumatism 20090801 8

<h4>Objective</h4>To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease.<h4>Methods</h4>SLE patients of European descent (n=1,754) from 8 case collections were genotyped for >1,400 ancestry informative markers that define a north-south gradient of European substructure. Using the Structure program, each SLE patient wa ...[more]

PMID: 19644962

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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.

Project description:Systemic lupus erythematosus is a chronic autoimmune disease of complex clinical presentation and etiology and is likely influenced by numerous genetic and environmental factors. While a large number of susceptibility genes have been identified, the production of antibodies against a distinct subset of nuclear proteins remains a primary distinguishing characteristic in disease diagnosis. However, the utility of autoantibody biomarkers for disease sub-classification and grouping remains elusive, in part, because of the difficulty in large scale profiling using a uniform, quantitative platform. In the present study serological profiles of several known SLE antigens, including Sm-D3, RNP-A, RNP-70k, Ro52, Ro60, and La, as well as other cytokine and neuronal antigens were obtained using the luciferase immunoprecipitation systems (LIPS) approach. The resulting autoantibody profiles revealed that 88% of a pilot cohort and 98% of a second independent cohort segregated into one of two distinct clusters defined by autoantibodies against Sm/anti-RNP or Ro/La autoantigens, proteins often involved in RNA binding activities. The Sm/RNP cluster was associated with a higher prevalence of serositis in comparison to the Ro/La cluster (P?=?0.0022). However, from the available clinical information, no other clinical characteristics were associated with either cluster. In contrast, evaluation of autoantibodies on an individual basis revealed an association between anti-Sm (P?=?0.006), RNP-A (P?=?0.018) and RNP-70k (P?=?0.010) autoantibodies and mucocutaneous symptoms and between anti-RNP-70k and musculoskeletal manifestations (P?=?0.059). Serologically active, but clinically quiescent disease also had a higher prevalence of anti-IFN-? autoantibodies. Based on our findings that most SLE patients belong to either a Sm/RNP or Ro/La autoantigen cluster, these results suggest the possibility that alterations in RNA-RNA-binding protein interactions may play a critical role in triggering and/or the pathogenesis of SLE.

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European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus.

Publications

European population substructure is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus.

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