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Arthritis Rheumatol. 2016 May;68(5):1290-1300. doi: 10.1002/art.39560.

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

Author information

1
Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
2
College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
3
College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
4
Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
5
U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.
6
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
7
U.S. Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
8
Department of Ophthalmology, Howe Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
9
Department of Oral Diagnosis and Radiology, College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
10
Dean McGee Eye Institute and Department of Ophthalmology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA.
11
Department of Clinical Laboratory Sciences, University of Texas at El Paso, El Paso, TX 79968.
12
Department of Developmental and Surgical Sciences, University of Minnesota, Minneapolis, MN, USA.
13
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.
14
Department of Rheumatology, Haukeland University Hospital, Bergen 5021, Norway.
15
Valley Bone & Joint Clinic, 3035 DeMers Avenue, Grand Forks, ND 58201, USA.
16
Strasbourg University, Strasbourg, France.
17
Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
18
Division of Genetics and Molecular Medicine and Division of Immunology, Infection and Inflammatory Disease, King's College London, London.
19
Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC 28232, USA.
20
Sjögren's Syndrome Clinic, National Institute of Dental and Craniofacial Research, Molecular Physiology and Therapeutics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
21
Department of Rheumatology, Université Paris-Sud, AP-HP, INSERM U1012, Le Kremlin-Bicêtre, France.
22
Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario.
23
Hospital for Special Surgery, New York, USA.
24
NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK.
25
Lunenfeld Tanenbaum and Toronto General Research Institutes, Departments of Medicine, Immunology and Molecular Genetics, University of Toronto, Toronto Ontario.
26
Musculoskeletal Research Group, Institute of Cellular Medicine & NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom.
27
Section of Rheumatology, Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
28
Rheumatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
29
Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
30
Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, USA.
31
Rheumatology Department, The Queen Elizabeth Hospital, Woodville South, SA 5011, Australia.
32
Discipline of Medicine, University of Adelaide, Adelaide, SA 5000, Australia.
33
Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
34
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
35
Clinic for Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany.
36
Sanatorio Parque, Rosario, Argentina.
37
Center Pfizer, University of Granada, Andalusian Government for Genomics and Oncological Research, PTS Granada, 18016, Spain.
38
Division of Clinical Immunology and Rheumatology, University of Alabama, Birmingham, AL.
39
Center for Public Health Genomics and Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC.
40
Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC.
41
Ralph H. Johnson VA Medical Center, Charleston, SC.
42
Division of Rheumatology, Department of Medicine, UCLA School of Medicine.
43
Division of Rheumatology, Department of Medicine, University of Michigan College of Medicine, Ann Arbor, Michigan.
44
Division of Rheumatology, Hospital for Special Surgery and Weill Cornell Medical College, New York, NY.
45
Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA.
46
University of Chicago Pritzker School of Medicine, Chicago, IL.
47
Charles R. Bronfman Institute for personalized medicine, Mount Sinai Hospital, 1468 Madison Avenue, New York, NY 10029.
48
Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
49
Rhumatologie, Responsable de l'Unité de Recherche Clinique Hôpitaux Universitaire Paris-Sud Université Paris-Sud, INSERM U1184 Head of Autoimmunity team, IMVA : Immunology of viral Infections and Autoimmune Diseases.
#
Contributed equally

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.

PMID:
26713507
PMCID:
PMC5019501
DOI:
10.1002/art.39560
[Indexed for MEDLINE]
Free PMC Article

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