title: X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.|U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
authors.forename: Biji T
authors.initials: BT
authors.lastname: Kurien
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Zimmerman
authors.affiliation: Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|U.S. Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.affiliation: Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
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authors.initials: DH
authors.lastname: Taft
authors.affiliation: Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
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authors.initials: LC
authors.lastname: Kottyan
authors.affiliation: Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
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authors.lastname: Lazaro
authors.affiliation: Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Carrie A
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authors.lastname: Weaver
authors.affiliation: Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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authors.affiliation: Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.|U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
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authors.initials: AJ
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authors.affiliation: Department of Ophthalmology, Howe Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
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authors.affiliation: Department of Oral Diagnosis and Radiology, College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
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authors.affiliation: Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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authors.affiliation: Dean McGee Eye Institute and Department of Ophthalmology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA.
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authors.affiliation: Department of Oral Diagnosis and Radiology, College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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authors.initials: KA
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.|U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.|Department of Clinical Laboratory Sciences, University of Texas at El Paso, El Paso, TX 79968.
authors.forename: Jacen S
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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authors.initials: X
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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authors.initials: KL
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authors.affiliation: Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.|U.S. Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
authors.forename: John B
authors.initials: JB
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authors.affiliation: College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.|Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.|U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
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mesh_terms: D001172:Arthritis, Rheumatoid / Q000453:epidemiology*; D001327:Autoimmune Diseases / Q000453:epidemiology; D016022:Case-Control Studies; D041321:Chromosomes, Human, X; D005260:Female; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008105:Liver Cirrhosis, Biliary / Q000453:epidemiology*; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology*; D015995:Prevalence; D012507:Sarcoidosis / Q000453:epidemiology; D012729:Sex Chromosome Aberrations; D058533:Sex Chromosome Disorders of Sex Development / Q000453:epidemiology*; D017678:Sex Distribution; D012859:Sjogren's Syndrome / Q000453:epidemiology*; D014314:Trisomy