Dataset Information

X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjogren's Syndrome.

ABSTRACT: OBJECTIVE:More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ?1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. METHODS:All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. RESULTS:We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P?=?0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P?=?0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. CONCLUSION:The estimated prevalence of SLE and SS in women with 47,XXX was ?2.5 and ?2.9 times higher, respectively, than that in women with 46,XX and ?25 and ?41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

SUBMITTER: Liu K

PROVIDER: S-EPMC5019501 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome.

Liu Ke K Kurien Biji T BT Zimmerman Sarah L SL Kaufman Kenneth M KM Taft Diana H DH Kottyan Leah C LC Lazaro Sara S Weaver Carrie A CA Ice John A JA Adler Adam J AJ Chodosh James J Radfar Lida L Rasmussen Astrid A Stone Donald U DU Lewis David M DM Li Shibo S Koelsch Kristi A KA Igoe Ann A Talsania Mitali M Kumar Jay J Maier-Moore Jacen S JS Harris Valerie M VM Gopalakrishnan Rajaram R Jonsson Roland R Lessard James A JA Lu Xianglan X Gottenberg Jacques-Eric JE Anaya Juan-Manuel JM Cunninghame-Graham Deborah S DS Huang Andrew J W AJW Brennan Michael T MT Hughes Pamela P Illei Gabor G GG Miceli-Richard Corinne C Keystone Edward C EC Bykerk Vivian P VP Hirschfield Gideon G Xie Gang G Ng Wan-Fai WF Nordmark Gunnel G Eriksson Per P Omdal Roald R Rhodus Nelson L NL Rischmueller Maureen M Rohrer Michael M Segal Barbara M BM Vyse Timothy J TJ Wahren-Herlenius Marie M Witte Torsten T Pons-Estel Bernardo B Alarcon-Riquelme Marta E ME Guthridge Joel M JM James Judith A JA Lessard Christopher J CJ Kelly Jennifer A JA Thompson Susan D SD Gaffney Patrick M PM Montgomery Courtney G CG Edberg Jeffrey C JC Kimberly Robert P RP Alarcón Graciela S GS Langefeld Carl L CL Gilkeson Gary S GS Kamen Diane L DL Tsao Betty P BP McCune W Joseph WJ Salmon Jane E JE Merrill Joan T JT Weisman Michael H MH Wallace Daniel J DJ Utset Tammy O TO Bottinger Erwin P EP Amos Christopher I CI Siminovitch Katherine A KA Mariette Xavier X Sivils Kathy L KL Harley John B JB Scofield R Hal RH

Arthritis & rheumatology (Hoboken, N.J.) 20160501 5

<h4>Objective</h4>More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheu ...[more]

PMID: 26713507

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Project description:BackgroundThe chemokine receptor CCR7 is a key organizer of the immune system. Gene targeting in mice revealed that Ccr7-deficient animals are severely impaired in the induction of central and peripheral tolerance. Due to these defects, Ccr7-deficient mice spontaneously develop multi-organ autoimmunity showing symptoms similar to those observed in humans suffering from connective tissue autoimmune diseases. However, it is unknown whether mutations of CCR7 are linked to autoimmunity in humans.ResultsDNA samples were collected from 160 patients suffering from connective tissue autoimmune disease (Sjogren's syndrome, n = 40; systemic lupus erythematosus, SLE, n = 20 and systemic sclerosis, n = 100) and 40 health subjects (n = 40). All participants in this study were of German descent. Samples were screened for single nucleotide polymorphisms (SNP) by sequencing the coding region of the CCR7 gene as well asthe exon flaking intron sites and parts of the regions encoding for the 5'- and 3'-UTR. CCR7 variants were rare. We identified six different sequence variants, which occurred in heterozygosis. The identified SNP were observed at position -60 C/T (observed 1x), +6,476 A/G (7x), +6,555 C/T (15x), +6,560 C/T (6x), +10,440 A/G (3x) and +11,475 C/A (1x). Four of these variants (+6,476 A/G, +6,555 C/T, +6,560 C/T and +10,440 A/G) display allelic frequencies between 1% and 5 % and were present in both patients and control groups. The variants +6,476 A/G, +6,555 C/T, +6,560 C/T are located in the intron 2, while the +10,440 A/G variant corresponds to a silent mutation in exon 3. The variants -60 C/T and +11,475 C/A which are located at the 5'-UTR and 3-UTR respectively, display allelic frequencies below 1%. No correlation between these variants and the autoimmune diseases investigated could be observed. However, reporter gene expression assay demonstrated that the mutation at the -60 C/T position in homozygosis leads to reduced luciferase activity.ConclusionThese results suggest that variants of CCR7 gene occur at an extremely low frequency in the German population and that neither Sjogren's syndrome, systemic lupus erythematosus, nor systemic sclerosis are associated with these variants. Nevertheless, the decreased luciferase activity observed in cells transfected with the promoter region bearing the -60 C/T mutation suggests that this CCR7 variant could potentially lead to increased susceptibility to autoimmunity.

Dataset Information

X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjogren's Syndrome.

Publications

X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome.

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