ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 883

Sex Bias In Autoimmune Diseases: Increased Risk Of 47,XXX In Systemic Lupus Erythematosus (SLE) and Sjögren’s Syndrome (SS) Supports The Gene Dose Hypothesis

Ke Liu1, Kenneth M. Kaufman2,3, Judith A. James4,5, Roland Jonsson6,7, Biji T. Kurien4,5,8, Xavier Mariette9, Joan T. Merrill10, Roald Omdal11, Maureen Rischmueller12,13, Timothy J. Vyse14, Marie Wahren-Herlenius15, Torsten Witte16, Christopher J. Lessard4,5, Sarah L. Zimmerman17, Susan D. Thompson18, Gideon Hirschfield19, Gang Xie20,21, Courtney G. Montgomery8,22, Wan-Fai Ng23, Gunnel Nordmark24, Patrick M. Gaffney4,8, Katherine A. Siminovitch20,25, Kathy L. Sivils4,26, Slegen (International Consortium For The Genetics Of SLE)27 and R. Hal Scofield4,5,28, 1Center for Autoimmune Genomics and Etiology and Rheumatology Division, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, 2U.S. Department of Veterans Affairs Medical Center, Cincinnati, OH, 31Center for Autoimmune Genomics and Etiology and Rheumatology Division, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, 4Oklahoma Medical Research Foundation, Oklahoma City, OK, 5College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 6Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway, 7Department of Rheumatology, Haukeland University Hospital, Bergen, Norway, 8U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK, 9Paris-Sud University, Paris, France, 10Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 11Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway, 12Rheumatology Department, Queen Elizabeth Hospital, Adelaide, Australia, 13Discipline of Medicine, University of Adelaide, Adelaide, Australia, 14Division of Genetics and Molecular Medicine and Division of Immunology, Infection and Inflammatory Disease, King's College London, London, United Kingdom, 15Department of Medicine, Karolinska Institutet, Stockholm, Sweden, 16Clinical Immunology and Rheumatology, Medical University Hannover, Hanover, Germany, 17Divison of human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 18Division and Center for Autoimmune Disease Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 19Centre for Liver Research, Institute of Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom, 20Mount Sinai Hospital, Toronto, ON, Canada, 21University Of Toronto, Toronto, ON, Canada, 22Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 23Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle upon Tyne, United Kingdom, 24Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, 25University of Toronto, Toronto, ON, Canada, 26University of Oklahoma Health Sciences Center, Oklahoma City, OK, 27Center for Autoimmune Genomics and Etiology and Rheumatology Division, International Consortium For The Genetics Of Systemic Lupus Erythematosus, Cincinnati, OH, 28US Department of Veterans Affairs Medical Center, Oklahoma City, OK

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment: Lupus Nephritis and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Female preponderance is a hallmark of most autoimmune diseases, the mechanism for which is unknown. We hypothesize that this is a consequence of a gene dose effect from the X chromosome. Here we tested a prediction of the gene does hypothesis: that triple X (47,XXX , which is found in 1 in ~1,100 live female births) would be increased in female predominant diseases (e.g. Systemic Lupus Erythematosus [SLE], Sjogren’s Syndrome [SS], Primary Biliary Cirrhosis [PBC] and Rheumatoid Arthritis [RA]) compared to diseases without a female predominance (e.g. sarcoidosis, granulomatosis with polyangiitis [GP]) or to healthy controls.

Methods:

Chromosome X aneuploidies were identified using single nucleotide polymorphisms (SNP) array and confirmed by karyotyping, FISH, or quantitative PCR.

Results:

47,XXX was found in eight of 2,948 SLE patients and in three of 1,206 SS patients, but in none of the 4,976 controls, all female (OR≥28.64, 95% CI 1.65-∞, p=0.00037; and OR≥28.84, 95% CI 1.49-∞, p=0.00745; respectively). These data suggest that one female with SLE and one female with SS has 47,XXX of approximately every 391 female SLE cases and 351 SS female cases. In addition, we identified one individual with 47,XXX from 1,179 female cases with PBC and one from 943 female cases with Sarcoidosis. No individuals were identified with 47,XXX in 453 female cases with RA or 247 female cases with GP, providing no evidence in these underpowered samples that individual with a 47,XXX karyotype have an increased risk for PBC, RA, GP or Sarcoidosis (p>0.05 for each).

Conclusion:

The 47,XXX karyotype is present in excess among females with either SLE or SS, consistent with the X chromosome gene dose hypothesis of pathogenesis. We estimate the prevalence of SLE and SS is ~2.5 and ~2.8 times higher than expected in individuals with 47,XXX when compared to 46,XX females and ~25 and ~39 times higher when compared to 46,XY males respectively. That Klinefelter’s syndrome (47,XXY) males carry the same SLE disease risk as females with 46,XX karyotype further support the hypothesis that the X chromosome dose contributes to the sex-bias of SLE, independently of phenotypic sex and most hormone and cultural differences between male and female life.

Disclosure:

K. Liu,
None;

K. M. Kaufman,
None;

J. A. James,
None;

R. Jonsson,
None;

B. T. Kurien,
None;

X. Mariette,
None;

J. T. Merrill,
None;

R. Omdal,
None;

M. Rischmueller,
None;

T. J. Vyse,
None;

M. Wahren-Herlenius,
None;

T. Witte,
None;

C. J. Lessard,
None;

S. L. Zimmerman,
None;

S. D. Thompson,
None;

G. Hirschfield,
None;

G. Xie,
None;

C. G. Montgomery,
None;

W. F. Ng,
None;

G. Nordmark,
None;

P. M. Gaffney,
None;

K. A. Siminovitch,
None;

K. L. Sivils,
None;

S. (International Consortium For The Genetics Of SLE),
None;

R. H. Scofield,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sex-bias-in-autoimmune-diseases-increased-risk-of-47xxx-in-systemic-lupus-erythematosus-sle-and-sjogrens-syndrome-ss-supports-the-gene-dose-hypothesis/