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

Ke Liu, Biji T Kurien, Sarah L Zimmerman, Kenneth M Kaufman, Diana H Taft, Leah C Kottyan, Sara Lazaro, Carrie A Weaver, John A Ice, Adam J Adler, James Chodosh, Lida Radfar, Astrid Rasmussen, Donald U Stone, David M Lewis, Shibo Li, Kristi A Koelsch, Ann Igoe, Mitali Talsania, Jay KumarJacen S Maier-Moore, Valerie M Harris, Rajaram Gopalakrishnan, Roland Jonsson, James A Lessard, Xianglan Lu, Jacques-Eric Gottenberg, Juan-Manuel Anaya, Deborah S Cunninghame-Graham, Andrew J W Huang, Michael T Brennan, Pamela Hughes, Gabor G Illei, Corinne Miceli-Richard, Edward C Keystone, Vivian P Bykerk, Gideon Hirschfield, Gang Xie, Wan-Fai Ng, Gunnel Nordmark, Per Eriksson, Roald Omdal, Nelson L Rhodus, Maureen Rischmueller, Michael Rohrer, Barbara M Segal, Timothy J Vyse, Marie Wahren-Herlenius, Torsten Witte, Bernardo Pons-Estel, Marta E Alarcon-Riquelme, Joel M Guthridge, Judith A James, Christopher J Lessard, Jennifer A Kelly, Susan D Thompson, Patrick M Gaffney, Courtney G Montgomery, Jeffrey C Edberg, Robert P Kimberly, Graciela S Alarcón, Carl L Langefeld, Gary S Gilkeson, Diane L Kamen, Betty P Tsao, W Joseph McCune, Jane E Salmon, Joan T Merrill, Michael H Weisman, Daniel J Wallace, Tammy O Utset, Erwin P Bottinger, Christopher I Amos, Katherine A Siminovitch, Xavier Mariette, Kathy L Sivils, John B Harley, R Hal Scofield

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Abstract

OBJECTIVE: More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.

METHODS: We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).

RESULTS: We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.

CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalArthritis & Rheumatology (Hoboken)
Early online date29 Dec 2015
DOIs
Publication statusPublished - May 2016

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