Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: Support for the notion of a gene‐dose effect from the X chromosome

Scofield, R. Hal; Bruner, Gail R.; Namjou, Bahram; Kimberly, Robert P.; Ramsey‐Goldman, Rosalind; Petri, Michelle; Reveille, John D.; Alarcón, Graciela S.; Vilá, Luis M.; Reid, Jeff; Harris, Bryan; Li, Shibo; Kelly, Jennifer A.; Harley, John B.

doi:10.1002/art.23701

Cited by 338 publications

(269 citation statements)

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“…Indeed, data from Scofield et al suggest that men with Klinefelter's syndrome (47, XXY) have a similar risk to develop lupus as normal women (46, XX) and ~14 times higher risk to develop lupus compared to normal men (46,XY). 19,20 These data reinforce the idea of a gene-dose effect on the X-chromosome for the risk to develop lupus. This genedose effect may be achieved by hypomethylation of the X chromosome, making more than one X chromosome available for transcription.…”

Section: O N O T D I S T R I B U T Esupporting

confidence: 72%

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

et al. 2011

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Section: O N O T D I S T R I B U T Esupporting

confidence: 72%

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

et al. 2011

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“…Furthermore, many authors published one or more cases with association of both KS and SLE, and its various manifestations Recently, a large genotyping study in SLE patients revealed that of the 213 SLE men, five had KS (47, XXY) genotype. The risk of SLE in men with 47, XXY genotype has been calculated to be approximately 14-times higher than in men with 46, XY genotype, consistent with the notion that SLE susceptibility is partially explained by an X chromosome gene-dose effect (Scofield et al, 2008). Such effect could be mediated by abnormal inactivation of genes on the X chromosome, as has been demonstrated for CD40L, or by genetic polymorphism as has been demonstrated for Xq28.…”

Section: Ks and Systemic Lupus Erythematosus (Sle)supporting

confidence: 71%

Autoimmune rheumatic diseases and Klinefelter syndrome Autoimunitné reumatické choroby a Klinefelterov syndróm

Lazúrová

Rovenský

Imrich

et al. 2016

European Pharmaceutical Journal

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The article summarizes data on the association of Klinefelter syndrome (KS) with autoimmune rheumatic diseases, that is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), polymyositis/dermatomyositis, systemic sclerosis (SSc), mixed connective tissue diseases (MCTD), Sjogren’s syndrome and antiphospholipid syndrome (APS). Recently, a higher risk for RA, SLE and Sjogren’s syndrome in patients with KS has been clearly demonstrated. However, the association of other autoimmune rheumatic disorders such as dermatomyositis/polymyositis, SSc, MCTD and APS is reported only casually. Based on the hormonal changes in KS, there are suggestions that low androgen and higher estrogen levels might be a predisposing factor for the development of autoimmune diseases, but evidence for the association is poor. Epidemiologic studies on larger cohorts of patients are required.

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“…Male patients with SLE, although rare, tend to have more severe disease and poorer outcome (2), suggesting potential sex dimorphism in the disease development. Although the sex effect has often been attributed to sex hormones, the fact that XXY male subjects have approximately a 14-fold higher risk of developing SLE than 46 XY men indicates that X-linked genes may be risk factors for human SLE (3).…”

mentioning

confidence: 99%

Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus

Shen

Deng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that predominantly affects women. Previous findings that duplicated Toll-like receptor 7 (Tlr7) promotes lupus-like disease in male BXSB mice prompted us to evaluate TLR7 in human SLE. By using a candidate gene approach, we identified and replicated association of a TLR7 3′UTR SNP, rs3853839 (G/C), with SLE in 9,274 Eastern Asians (P combined = 6.5 × 10 −10 ), with a stronger effect in male than female subjects [odds ratio, male vs. female = 2.33 (95% CI = 1.64-3.30) vs. 1.24 (95% CI = 1.14-1.34); P = 4.1 × 10]. G-allele carriers had increased TLR7 transcripts and more pronounced IFN signature than C-allele carriers; heterozygotes had 2.7-fold higher transcripts of G-allele than C-allele. These data established a functional polymorphism in type I IFN pathway gene TLR7 predisposing to SLE, especially in Chinese and Japanese male subjects. functional polymorphism | disease susceptibility | autoimmunity | type I interferon S ystemic lupus erythematosus [SLE; Online Mendelian Inheritance in Man (OMIM) no. 152700] is a multisystem, autoimmune disease with strong genetic and environmental components (1). SLE predominantly affects women, with a female-to-male ratio of approximately 9:1. Male patients with SLE, although rare, tend to have more severe disease and poorer outcome (2), suggesting potential sex dimorphism in the disease development. Although the sex effect has often been attributed to sex hormones, the fact that XXY male subjects have approximately a 14-fold higher risk of developing SLE than 46 XY men indicates that X-linked genes may be risk factors for human SLE (3).Located at Xp22.2, Toll-like receptor 7 (TLR7; OMIM no. 300365) and its functionally related gene TLR8 (OMIM no. 300366) encode proteins that play critical roles in pathogen recognition and activation of innate immunity (4). They recognize endogenous RNA-containing autoantigens and induce the expression of type I IFN, a pivotal cytokine in the pathogenesis of SLE (5). In lupus-prone BXSB mice, the translocation of a segmental duplication of X chromosome to Y chromosome creates the Y-linked autoimmune accelerator (Yaa) locus, which was associated with autoreactive B cell responses to RNA-related antigens and exacerbation of glomerulonephritis in male mice (6). Although translocated X chromosome segment in Yaa may contain as many as 16 genes, the major gene for causation of the autoimmune phenotypes was identified to be TLR7 (7), making it a potential susceptibility gene for SLE. By using a candidate gene approach, we report herein that a functional polymorphism in 3′UTR of TLR7 is associated with SLE in Chinese and Japanese populations, with a stronger effect in male than female subjects. ResultsDiscovery and Replication of the Association of a TLR7 3′UTR SNP with SLE in Eastern Asian Population. We genotyped 27 SNPs from the TLR7-TLR8 region (12 in TLR7 and 15 in TLR8) in 1,434 SLE cases and 1,591 control subjects of Eastern Asian ancestry using the Beadstation Infinium II...

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Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: Support for the notion of a gene‐dose effect from the X chromosome

Cited by 338 publications

References 70 publications

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus

Autoimmune rheumatic diseases and Klinefelter syndrome Autoimunitné reumatické choroby a Klinefelterov syndróm

Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus

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