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

Lookup NU author(s): Professor Fai NgORCiD


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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 similar to 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogren'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 similar to 2.5 and similar to 2.9 times higher, respectively, than that in women with 46, XX and similar to 25 and similar to 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.

Publication metadata

Author(s): Liu K, Kurien BT, Zimmerman SL, Kaufman KM, Taft DH, Kottyan LC, Lazaro S, Weaver CA, Ice JA, Adler AJ, Chodosh J, Radfar L, Rasmussen A, Stone DU, Lewis DM, Li SB, Koelsch KA, Igoe A, Talsania M, Kumar J, Maier-Moore JS, Harris VM, Gopalakrishnan R, Jonsson R, Lessard JA, Lu XL, Gottenberg JE, Anaya JM, Cunninghame-Graham DS, Huang AJW, Brennan MT, Hughes P, Mei GG, Miceli-Richard C, Keystone EC, Bykerk VP, Hirschfield G, Xie G, Ng WF, Nordmark G, Eriksson P, Omda R, Rhodus NL, Rischmueller M, Rohrer M, Sega BM, Vvse TJ, Wahren-Herlenius M, Witte T, Pons-Este B, Alarcon-Riquelme ME, Guthridge JM, James JA, Lessard CJ, Kelly JA, Thompson SD, Gaffney PM, Montgomery CG, Edberg JC, Kimberly RP, Alarcon GS, Langefeld CL, Gilkeson GS, Kamen DL, Tsao BP, McCune WJ, Salmon JE, Merrill JT, Weisman MH, Wallace DJ, Utset T, Bottinger EP, Amos CI, Siminovitch KA, Mariette X, Sivils KL, Harley JB, Scofield RH

Publication type: Article

Publication status: Published

Journal: Arthritis & Rheumatology

Year: 2016

Volume: 68

Issue: 5

Pages: 1290-1300

Print publication date: 01/05/2016

Online publication date: 29/12/2015

Acceptance date: 15/12/2015

ISSN (print): 2326-5191

ISSN (electronic): 2326-5205

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1002/art.39560


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Funder referenceFunder name
Arthritis Australia
Broegelmann Foundation
Canada Research Chair Program
Kirkland Scholar Program
NIH (National Institute of Dental and Craniofacial Research Intramural Research Program)
Research to Prevent Blindness
Swedish Rheumatism Foundation
University of Oklahoma Health Sciences Center (Clinical and Translational Science OCTSI Summer Scholar Program)
Alliance for Lupus Research
French Ministry of Health (EvASSESS Programme Hospitalier de Recherche Clinique)
Strategic Research Program at Helse Bergen
Western Norway Regional Health Authority
02558Instituto de Salud Carlos III (ISCIII through FEDER)
AR-049084The NIH
AR-056360The NIH
AR-065626The NIH
AR-042460The NIH
AR-043814The NIH
AR-048204The NIH
AR-048940The NIH
AR-052125The NIH
AR-053483The NIH
AR-053734The NIH
AR-058959The NIH
AR-062277The NIH
DE-015223The NIH
DE-018209The NIH
G0800629Medical Research Council, UK
HG-006828The NIH
IMMA9US Department of Veterans Affairs
MOP74621Canadian Institutes of Health Research
MOP89955Canadian Institutes of Health Research
GM-103510The NIH
GM-104938The NIH
HG-008667The NIH
KFO 250 WI 1031/6-1DFG
PR094002US Department of Defense
RE05-075Ontario Research Fund
RR-020143The NIH
TR-001475The NIH