Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome

doi:10.1016/j.clim.2016.04.002

Multicenter Study

. 2016 Jul:168:25-29.

doi: 10.1016/j.clim.2016.04.002. Epub 2016 Apr 22.

Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome

Valerie M Harris¹, Rohan Sharma², Joshua Cavett³, Biji T Kurien⁴, Ke Liu⁵, Kristi A Koelsch⁴, Astrid Rasmussen⁶, Lida Radfar⁷, David Lewis⁷, Donald U Stone⁸, C Erick Kaufman⁹, Shibo Li¹⁰, Barbara Segal¹¹, Daniel J Wallace¹², Michael H Weisman¹², Swamy Venuturupalli¹², Jennifer A Kelly⁶, Marta E Alarcon-Riquelme¹³, Bernardo Pons-Estel¹⁴, Roland Jonsson¹⁵, Xianglan Lu¹⁰, Jacques-Eric Gottenberg¹⁶, Juan-Manuel Anaya¹⁷, Deborah S Cunninghame-Graham¹⁸, Andrew J W Huang¹⁹, Michael T Brennan²⁰, Pamela Hughes¹⁹, Ilias Alevizos²¹, Corinne Miceli-Richard²², Edward C Keystone²³, Vivian P Bykerk²⁴, Gideon Hirschfield²⁵, Gang Xie²⁶, Katherine A Siminovitch, Wan-Fai Ng²⁷, Gunnel Nordmark²⁸, Sara Magnusson Bucher²⁹, Per Eriksson³⁰, Roald Omdal³¹, Nelson L Rhodus³², Maureen Rischmueller³³, Michael Rohrer¹⁹, Marie Wahren-Herlenius³⁴, Torsten Witte³⁵, Xavier Mariette²², Christopher J Lessard⁶, John B Harley³⁶, Kathy L Sivils¹, R Hal Scofield³⁷

Affiliations

¹ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
² Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA.
³ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁴ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA.
⁵ Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
⁶ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
⁷ Department of Oral Diagnosis and Radiology, College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
⁸ Dean McGee Eye Institute and Department of Ophthalmology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA.
⁹ Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
¹⁰ Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
¹¹ Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
¹² Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹³ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Center Pfizer, University of Granada, Andalusian Government for Genomics and Oncological Research, PTS Granada, 18016, Spain.
¹⁴ Sanatorio Parque, Rosario, Argentina.
¹⁵ Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen 5021, Norway; Department of Rheumatology, Haukeland University Hospital, Bergen 5021, Norway.
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, UK.
¹⁹ Department of Developmental and Surgical Sciences, University of Minnesota, Minneapolis, MN, USA.
²⁰ Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC 28232, USA.
²¹ Molecular Physiology & Therapeutic Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA.
²² Department of Rheumatology, Université Paris-Sud, AP-HP, INSERM U1012, Le Kremlin-Bicêtre, France.
²³ Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
²⁴ Hospital for Special Surgery, New York, USA.
²⁵ NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK.
²⁶ Samuel Lunenfeld and Toronto General Research Institutes, Departments of Medicine, Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
²⁷ Musculoskeletal Research Group, Institute of Cellular Medicine & NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
²⁸ Section of Rheumatology, Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
²⁹ Department of Rheumatology, Örebro University Hospital, Örebro, Sweden.
³⁰ Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
³¹ Rheumatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
³² Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, USA.
³³ Rheumatology Department, The Queen Elizabeth Hospital, Woodville South, SA 5011, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA 5000, Australia.
³⁴ Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁵ Clinic for Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany.
³⁶ Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Medical Service, Department of Veterans Affairs Medical Center, Cincinnati, OH, USA.
³⁷ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA. Electronic address: hal-scofield@omrf.ouhsc.edu.

PMID: 27109640
PMCID: PMC4940221
DOI: 10.1016/j.clim.2016.04.002

Multicenter Study

Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome

Valerie M Harris et al. Clin Immunol. 2016 Jul.

. 2016 Jul:168:25-29.

doi: 10.1016/j.clim.2016.04.002. Epub 2016 Apr 22.

Authors

Affiliations

¹ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
² Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA.
³ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁴ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA.
⁵ Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
⁶ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
⁷ Department of Oral Diagnosis and Radiology, College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
⁸ Dean McGee Eye Institute and Department of Ophthalmology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA.
⁹ Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
¹⁰ Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
¹¹ Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
¹² Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹³ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Center Pfizer, University of Granada, Andalusian Government for Genomics and Oncological Research, PTS Granada, 18016, Spain.
¹⁴ Sanatorio Parque, Rosario, Argentina.
¹⁵ Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen 5021, Norway; Department of Rheumatology, Haukeland University Hospital, Bergen 5021, Norway.
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, UK.
¹⁹ Department of Developmental and Surgical Sciences, University of Minnesota, Minneapolis, MN, USA.
²⁰ Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC 28232, USA.
²¹ Molecular Physiology & Therapeutic Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA.
²² Department of Rheumatology, Université Paris-Sud, AP-HP, INSERM U1012, Le Kremlin-Bicêtre, France.
²³ Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.
²⁴ Hospital for Special Surgery, New York, USA.
²⁵ NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK.
²⁶ Samuel Lunenfeld and Toronto General Research Institutes, Departments of Medicine, Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
²⁷ Musculoskeletal Research Group, Institute of Cellular Medicine & NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
²⁸ Section of Rheumatology, Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
²⁹ Department of Rheumatology, Örebro University Hospital, Örebro, Sweden.
³⁰ Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway.
³¹ Rheumatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
³² Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, USA.
³³ Rheumatology Department, The Queen Elizabeth Hospital, Woodville South, SA 5011, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA 5000, Australia.
³⁴ Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁵ Clinic for Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany.
³⁶ Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Medical Service, Department of Veterans Affairs Medical Center, Cincinnati, OH, USA.
³⁷ Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA. Electronic address: hal-scofield@omrf.ouhsc.edu.

PMID: 27109640
PMCID: PMC4940221
DOI: 10.1016/j.clim.2016.04.002

Erratum in

Corrigendum to "Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome" [Clin. Immunol. 168 (2016) 25-29].
Harris VM, Sharma R, Cavett J, Kurien BT, Liu K, Koelsch KA, Rasmussen A, Radfar L, Lewis D, Stone DU, Kaufman CE, Li S, Segal B, Wallace DJ, Weisman MH, Venuturupalli S, Kelly JA, Alarcon-Riquelme ME, Pons-Estel B, Jonsson R, Lu X, Gottenberg JE, Anaya JM, Cunninghame-Graham DS, Huang AJW, Brennan MT, Hughes P, Alevizos I, Miceli-Richard C, Keystone EC, Bykerk VP, Hirschfield G, Xie G, Siminovitch KA, Ng WF, Nordmark G, Bucher SM, Eriksson P, Omdal R, Rhodus NL, Rischmueller M, Rohrer M, Wahren-Herlenius M, Witte T, Mariette X, Lessard CJ, Harley JB, Sivils KL, Scofield RH. Harris VM, et al. Clin Immunol. 2018 Feb;187:137-138. doi: 10.1016/j.clim.2017.11.012. Epub 2017 Dec 7. Clin Immunol. 2018. PMID: 29195081 No abstract available.

Abstract

Primary Sjögren's syndrome (pSS) has a strong female bias. We evaluated an X chromosome dose effect by analyzing 47,XXY (Klinefelter's syndrome, 1 in 500 live male births) among subjects with pSS. 47,XXY was determined by examination of fluorescence intensity of single nucleotide polymorphisms from the X and Y chromosomes. Among 136 pSS men there were 4 with 47,XXY. This was significantly different from healthy controls (1 of 1254 had 47,XXY, p=0.0012 by Fisher's exact test) as well men with rheumatoid arthritis (0 of 363 with 47,XXY), but not different compared to men with systemic lupus erythematosus (SLE) (4 of 136 versus 8 of 306, Fisher's exact test p=NS). These results are consistent with the hypothesis that the number of X chromosomes is critical for the female bias of pSS, a property that may be shared with SLE but not RA.

Keywords: Klinefelter's syndrome; Sex bias; Sjögren's syndrome; X chromosome.

Published by Elsevier Inc.

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Figures

**Figure 1**
X chromosome B plot of a Klinefelter's syndrome subject with 2 diffferent X chromosomes as demonstrated by heterogeneity of X chromosome single nucleotide markers at 0.5 (top panel), and a Klinefelter's syndrome subject with 2 identical X chromosomes as demonstrated by homozygosity of X chromosome single nucleotide markers at 0.0 and 1.0 with none at 0.5 (bottom panel). Both subjects demonstrate a 4 band pattern (0.0, 0.33, 0.67, 1.0) in the pseudoautosomal region 1 (far left) indicating three total sex chromosomes. The X chromosome centromere and banding patterns are represented in the middle diagram.

See this image and copyright information in PMC

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References

1. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15–25. - PubMed
1. Patel R, Shahane A. The epidemiology of Sjogren's syndrome. Clin Epidemiol. 2014;6:247–55. - PMC - PubMed
1. Orbach H, Shoenfeld Y. Hyperprolactinemia and autoimmune diseases. Autoimmunity Reviews. 2007;6:537–42. - PubMed
1. Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M, et al. Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008;58:2511–7. - PMC - PubMed
1. Dillon S, Aggarwal R, Harding JW, Li LJ, Weissman MH, Li S, et al. Klinefelter's syndrome (47,XXY) among men with systemic lupus erythematosus. Acta Paediatr. 2011;100:819–23. - PMC - PubMed

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[1] Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15–25. - PubMed

[2] Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15–25. - PubMed

[3] Patel R, Shahane A. The epidemiology of Sjogren's syndrome. Clin Epidemiol. 2014;6:247–55. - PMC - PubMed

[4] Patel R, Shahane A. The epidemiology of Sjogren's syndrome. Clin Epidemiol. 2014;6:247–55. - PMC - PubMed

[5] Orbach H, Shoenfeld Y. Hyperprolactinemia and autoimmune diseases. Autoimmunity Reviews. 2007;6:537–42. - PubMed

[6] Orbach H, Shoenfeld Y. Hyperprolactinemia and autoimmune diseases. Autoimmunity Reviews. 2007;6:537–42. - PubMed

[7] Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M, et al. Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008;58:2511–7. - PMC - PubMed

[8] Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M, et al. Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008;58:2511–7. - PMC - PubMed

[9] Dillon S, Aggarwal R, Harding JW, Li LJ, Weissman MH, Li S, et al. Klinefelter's syndrome (47,XXY) among men with systemic lupus erythematosus. Acta Paediatr. 2011;100:819–23. - PMC - PubMed

[10] Dillon S, Aggarwal R, Harding JW, Li LJ, Weissman MH, Li S, et al. Klinefelter's syndrome (47,XXY) among men with systemic lupus erythematosus. Acta Paediatr. 2011;100:819–23. - PMC - PubMed

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Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome

Affiliations

Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome

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