Androgen receptor (CAG)n polymorphism and androgen levels in women with systemic lupus erythematosus and healthy controls

Robeva, Ralitsa; Tanev, Dobromir; Andonova, Silvia; Кirilov, Georgi; Savov, Alexey; Stoycheva, Milena; Tomova, Analia; Kumanov, Philip; Rashkov, Rasho; Kolarov, Zlatimir

doi:10.1007/s00296-013-2687-2

Cited by 17 publications

(15 citation statements)

References 29 publications

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“…Conversely, females with lupus who had shorter AR exon 1 CAG repeats (which are associated with relatively amplified hormonal action) were found to have greater disease activity and more robust humoral autoimmune responses. Our current data are also similar to the observations in women with rheumatoid arthritis – in whom a shorter AR CAG repeat length was noted to be associated with earlier onset and more aggressive disease course (24) – and to a recent study of women with SLE in which the AR CAG repeat length was inversely correlated with the SLICC/ACR index of disease damage (25). Differences in androgen sensitivity conferred by AR CAG repeat variation in women do not appear to be compensated by alterations in circulating hormone levels.…”

Section: Discussionsupporting

confidence: 90%

“…In humans, such variation in AR CAG repeat lengths has been found to be associated with phenotypic features of men with Klinefelter's syndrome (18), as well as with normal variation in facial and body hair (19), in body composition (20), in HDL levels (21), and in response to treatment with exogenous androgens (22). In a previous study, we found that longer AR CAG repeats were associated with more exuberant expression of IgG autoantibodies in males with lupus (23), while two recent reports have now identified inverse correlations between AR CAG repeat length and disease activity in women with rheumatoid arthritis (24) and lupus (25).…”

Section: Introductionmentioning

confidence: 88%

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Variation in the androgen receptor gene exon 1 CAG repeat correlates with manifestations of autoimmunity in women with lupus

Olsen

Benko

Kovacs

2014

Endocrine Connections

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Clinical and experimental evidence support a role for gonadal steroids in modulating the expression and course of autoimmune diseases such as lupus. Whether or not inherited variation in sensitivity to circulating androgenic hormones could influence the manifestations of such disease is, however, unknown. We sought to determine whether differences in androgen sensitivity conferred by variation in the exon 1 CAG repeat region of the androgen receptor (AR) gene were associated with differences in the clinical or humoral immune manifestations of lupus in a cohort of female subjects. We found that shorter AR CAG repeat lengths in lupus subjects correlated with a higher Systemic Lupus Erythematosus Disease Activity Index score, higher ANA levels, and expression of a broader array of IgG autoantibodies. Our findings of more severe clinical manifestations and more exuberant humoral autoimmunity in women with a shorter AR exon 1 CAG repeat length suggest a role for genetically determined sensitivity to androgens as a modulator of autoimmune processes.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 88%

Variation in the androgen receptor gene exon 1 CAG repeat correlates with manifestations of autoimmunity in women with lupus

Olsen

Benko

Kovacs

2014

Endocrine Connections

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“…The minor allele A will significantly reduce the binding activity of the androgen receptor and then may result in the development of SLE. The androgen is important in clinical treatment of SLE [ 51 ] and the correlation between the androgen receptor and SLE has been investigated by different studies [ 52 , 53 ]. For other associated SNVs, we did not detect sufficient evidence and signals at the transcriptional level.…”

Section: Discussionmentioning

confidence: 99%

Association analyses confirm five susceptibility loci for systemic lupus erythematosus in the Han Chinese population

Yu¹,

Xu²,

Wu³

et al. 2015

Arthritis Res Ther

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IntroductionSystemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Currently, numerous genetic loci of SLE have been confirmed. Here we try to further explore additional genes contributing to SLE susceptibility in this study.MethodsForty nine single nucleotide polymorphisms (SNPs) with moderate-risk for SLE in previous study were genotyped in a large-scale replication study with a total of 3,522 cases and 8,252 controls using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate through PLINK 1.07 software.ResultsThis replication effort confirmed five reported SLE susceptibility loci reaching genome-wide levels of significance (Pmeta <5.00 × 10−08): TNFSF4 (rs1418190, odds ratio (OR) = 0.81, Pmeta = 1.08 × 10−08; rs4916219, OR = 0.80, Pmeta = 7.77 × 10−09), IRF8 (rs2934498, OR = 1.25, Pmeta = 4.97 × 10−09), miR-146a (rs2431697, OR = 0.69, Pmeta = 1.15 × 10−22), CD44 (rs2732547, OR = 0.82, Pmeta = 1.55 × 10−11), and TMEM39A (rs12494314, OR = 0.84, Pmeta = 1.01 × 10−09). Further logistic regression analysis indicated that the genetic effects within TNFSF4 detected in this study are independent from our previously reported signals.ConclusionsThis study increases the number of established susceptibility loci for SLE in Han Chinese population and highlights the contribution of multiple variants of modest effect. Although further studies will be required to identify the causal alleles within these loci, the findings make a significant step forward in our understanding of the genetic contribution to SLE in Chinese population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0602-9) contains supplementary material, which is available to authorized users.

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“…We therefore investigated the effects of hormones, specifically E2, on the IFN-dependent and IFN-independent activation of cDCs from female and male lupus-prone mice. Different hormone receptor polymorphisms have been reported to modify SLE disease severity [ 46 ] and may affect different murine strains as well. Therefore, we investigated the effects of E2 and sex differences on cDC activation using TCSle mice [ 13 ] compared to its wild-type strain C67BL/6 (B6) to minimize possible differences in estrogen receptor signaling.…”

Section: Introductionmentioning

confidence: 99%

Conventional DCs from Male and Female Lupus-Prone B6.NZM Sle1/Sle2/Sle3 Mice Express an IFN Signature and Have a Higher Immunometabolism That Are Enhanced by Estrogen

Lee

Chakhtoura

Sriram

et al. 2018

Journal of Immunology Research

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Type I interferons (IFN) are pathogenic in systemic lupus erythematosus (SLE) and were proposed to control the immunometabolism of dendritic cells (DCs). We previously reported that DCs from female lupus-prone mice constitutively overexpress IFN-responsive genes resembling the IFN signature found in SLE patients. As SLE has higher incidence in women than men, more so in women of reproductive age, estrogens are suggested to affect lupus pathogenesis. We investigated the effects of sex and estrogens on the IFN signature in conventional GM-CSF-bone marrow-derived DCs (cDCs), from male and female Triple Congenic B6.NZM.Sle1/Sle2/Sle3 (TCSle) lupus-prone mice or from wild-type C57BL/6 mice, generated with titrations of 17-beta-estradiol (E2). We found that cDCs from prediseased TCSle male mice express the IFN signature as female TCSle cDCs do. Estrogens are necessary but not sufficient to express this IFN signature, but high doses of E2 can compensate for other steroidal components. E2 stimulation, regardless of sex, modulates type I IFN-dependent and type I IFN-independent activation of cDCs in response to TLR stimulation. Finally, we found that TCSle cDCs from both sexes have elevated markers of immunometabolism and estrogens enhance the metabolic pathways in cDCs, suggesting a mechanistic link between estrogens, immunometabolism, and the IFN signature in lupus.

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Androgen receptor (CAG)n polymorphism and androgen levels in women with systemic lupus erythematosus and healthy controls

Cited by 17 publications

References 29 publications

Variation in the androgen receptor gene exon 1 CAG repeat correlates with manifestations of autoimmunity in women with lupus

Variation in the androgen receptor gene exon 1 CAG repeat correlates with manifestations of autoimmunity in women with lupus

Association analyses confirm five susceptibility loci for systemic lupus erythematosus in the Han Chinese population

Conventional DCs from Male and Female Lupus-Prone B6.NZM Sle1/Sle2/Sle3 Mice Express an IFN Signature and Have a Higher Immunometabolism That Are Enhanced by Estrogen

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