X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome - PubMed (original) (raw)

. 2016 May;68(5):1290-1300.

doi: 10.1002/art.39560.

Biji T Kurien 3 4 5, Sarah L Zimmerman 6, Kenneth M Kaufman 1 7, Diana H Taft 1, Leah C Kottyan 1, Sara Lazaro 1, Carrie A Weaver 1, John A Ice 4, Adam J Adler 4 5, James Chodosh 8, Lida Radfar 9, Astrid Rasmussen 4, Donald U Stone 10, David M Lewis 9, Shibo Li 3, Kristi A Koelsch 3 4, Ann Igoe 3 4, Mitali Talsania 3, Jay Kumar 3 4, Jacen S Maier-Moore 3 4 5 11, Valerie M Harris 3 4, Rajaram Gopalakrishnan 12, Roland Jonsson 13 14, James A Lessard 15, Xianglan Lu 3, Jacques-Eric Gottenberg 16, Juan-Manuel Anaya 17, Deborah S Cunninghame-Graham 18, Andrew J W Huang 12, Michael T Brennan 19, Pamela Hughes 12, Gabor G Illei 20, Corinne Miceli-Richard 21, Edward C Keystone 22, Vivian P Bykerk 23, Gideon Hirschfield 24, Gang Xie 25, Wan-Fai Ng 26, Gunnel Nordmark 27, Per Eriksson 28, Roald Omdal 29, Nelson L Rhodus 30, Maureen Rischmueller 31 32, Michael Rohrer 12, Barbara M Segal 33, Timothy J Vyse 18, Marie Wahren-Herlenius 34, Torsten Witte 35, Bernardo Pons-Estel 36, Marta E Alarcon-Riquelme 4 37, Joel M Guthridge 3 4, Judith A James 3 4, Christopher J Lessard 3 4, Jennifer A Kelly 4, Susan D Thompson 1, Patrick M Gaffney 4, Courtney G Montgomery 4, Jeffrey C Edberg 38, Robert P Kimberly 38, Graciela S Alarcón 38, Carl L Langefeld 39, Gary S Gilkeson 40 41, Diane L Kamen 40, Betty P Tsao 42, W Joseph McCune 43, Jane E Salmon 44, Joan T Merrill 3, Michael H Weisman 45, Daniel J Wallace 45, Tammy O Utset 46, Erwin P Bottinger 47, Christopher I Amos 48, Katherine A Siminovitch 25, Xavier Mariette 49, Kathy L Sivils 3 4, John B Harley # 1 2 7, R Hal Scofield # 3 4 5

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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

Ke Liu et al. Arthritis Rheumatol. 2016 May.

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.

© 2016, American College of Rheumatology.

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Figures

Fig. 1

Fig. 1. 47,XXX identification

B allele frequency and logR ratio plot of 46,XY from a representative normal man (first panel, for comparison purposes only as men were not included in the present study), 46,XX from a normal woman (second panel) and 47,XXX from a trisomy X syndrome patient (third panel).

Fig. 2

Fig. 2. 47,XXX validation by fluorescence in situ hybridization assay (FISH)

Validation of 46,XX from a normal female (upper) and 47,XXX from a trisomy X syndrome patient (bottom). The images are showing a single representative nucleus. 200 nuclei were counted.

Fig. 3

Fig. 3. 47,XXX validation by PCR

DNA amplification validation of 47,XXX for two systemic lupus erythematosus patients (SLE1, SLE2), two primary Sjögren's syndrome patients (SS1, SS2) and one primary biliary cirrhosis patient (PBC1). As calibrators, we used known 47,XXX (shown in blue), 46,XX (shown in red) and 45X (shown in purple) samples. Calibrators were all validated by FISH and used to determine copy number in the experimental samples.

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