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Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.

ABSTRACT: OBJECTIVES:Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. METHODS:A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. RESULTS:A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10-8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. CONCLUSIONS:The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

SUBMITTER: Hughes T

PROVIDER: S-EPMC3324666 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.

Hughes Travis T Adler Adam A Merrill Joan T JT Kelly Jennifer A JA Kaufman Kenneth M KM Williams Adrienne A Langefeld Carl D CD Gilkeson Gary S GS Sanchez Elena E Martin Javier J Boackle Susan A SA Stevens Anne M AM Alarcón Graciela S GS Niewold Timothy B TB Brown Elizabeth E EE Kimberly Robert P RP Edberg Jeffrey C JC Ramsey-Goldman Rosalind R Petri Michelle M Reveille John D JD Criswell Lindsey A LA Vilá Luis M LM Jacob Chaim O CO Gaffney Patrick M PM Moser Kathy L KL Vyse Timothy J TJ Alarcón-Riquelme Marta E ME James Judith A JA Tsao Betty P BP Scofield R Hal RH Harley John B JB Richardson Bruce C BC Sawalha Amr H AH

Annals of the rheumatic diseases 20111121 5

<h4>Objectives</h4>Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci.<h4>Methods</h4>A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European ...[more]

PMID: 22110124

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Project description:Background: Systemic lupus erythematosus (SLE) is a potentially fatal complex autoimmune disease, that is characterized by widespread inflammation manifesting tissue damage and comorbidities across the human body including heart, blood vessels, joints, skin, liver, kidneys, and periodontal tissues. The etiology of SLE is partially attributed to a deregulated inflammatory response to microbial dysbiosis and environmental changes. In the mouth, periodontal environment provides an optimal niche for local and systemic inflammation. Our aim was to evaluate the reciprocal impact of periodontal subgingival microbiome on SLE systemic inflammation. Methods: Ninety-one female subjects were recruited, including healthy (n = 31), SLE-inactive (n = 29), and SLE-active (n = 31). Patients were screened for probing depth, bleeding on probing, clinical attachment level, and classified according to CDC/AAP criteria with or without periodontal dysbiosis. Serum inflammatory cytokines were measured by human cytokine panel and a targeted pathogenic subgingival biofilm panel was examined by DNA-DNA checkerboard from subgingival plaque samples. Results: The results showed significant upregulation of serum proinflammatory cytokines in individuals with SLE when compared to controls. Stratification of subject's into SLE-inactive (I) and SLE-active (A) phenotypes or periodontitis and non-periodontitis groups provided new insights into SLE pathophysiology. Ten proinflammatory cytokines were upregulated in serum of SLE-I only and one in SLE-A only. Four molecules overlapped in SLE-A and SLE-I. Anti-inflammatory cytokines included IL-4 IL-10, which were upregulated in SLE-I sera (but not SLE-A), controlling clinical phenotypes. Out of 24 significant differential oral microbial abundances found in SLE, 14 unique subgingival bacteria profiles were found to be elevated in SLE. The most severe oral pathogens (Treponema denticola and Tannerella forsythia) showed increase abundances on SLE-A periodontal sites when compared to SLE-I and healthy controls. Inflammation as measured by cytokine-microbial correlations showed that periodontal pathogens dominating the environment increased proinflammatory cytokines systemically. Conclusions: Altogether, low-grade systemic inflammation that influenced SLE disease activity and severity was correlated to dysbiotic changes of the oral microbiota present in periodontal diseases.

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Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.

Publications

Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.

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