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.
Bibliographical noteFunding Information:
Supported by the NIH (grants AR 062755, AI 024717, AI 031584, AI 062629, AI 063274, AI 082714, AI 083194, AI 101934, AR 042460, AR 048204, AR 048940, AR 049084, AR 052125, AR 053483, AR 053734, AR 056360, AR 058959, AR 062277, AR 043814, AR 065626, DE 015223, DE 018209, RR 020143, GM 103510, GM 104938, HG 008667, TR 001475, and HG 006828 and the National Institute of Dental and Craniofacial Research Intramural Research Program), University of Oklahoma Health Sciences Center (Clinical and Translational Science OCTSI Summer Scholar Program), US Department of Veterans Affairs (award IMMA9 to Drs. Harley and Scofield), US Department of Defense (award PR094002), Alliance for Lupus Research (award to Dr. Harley), Kirkland Scholar Program (awards to Drs. James and Harley), Strategic Research Program at Helse Bergen, Western Norway Regional Health Authority, Broegelmann Foundation, French Ministry of Health (EvASSESS Programme Hospitalier de Recherche Clinique 2006), Swedish Rheumatism Foundation, Arthritis Australia, Research to Prevent Blindness (unrestricted grant to the Dean McGee Eye Institute and the Department of Ophthalmology, University of Oklahoma College of Medicine, and Senior Scientific Investigator Award to Dr. Chodosh), Medical Research Council, UK (award G0800629), DFG (award KFO 250 WI 1031/6 1 to Dr. Witte), Canadian Institutes of Health Research (awards MOP89955 and MOP74621), Ontario Research Fund (award RE05 075), Canada Research Chair Program (award to Dr. Siminovitch), and Instituto de Salud Carlos III (ISCIII award 02558 through FEDER funds, to Dr. Alarcn Riquelme).
© 2016, American College of Rheumatology.