Clinical Reviews in Allergy & Immunology

, Volume 34, Issue 3, pp 352–355 | Cite as

Skewed X-Chromosome Inactivation in Scleroderma

  • Elif Uz
  • Laurence S. Loubiere
  • Vijayakrishna K. Gadi
  • Zeynep Ozbalkan
  • Jeffrey Stewart
  • J. Lee Nelson
  • Tayfun OzcelikEmail author


Scleroderma is a female-prevalent autoimmune disease of unclear etiology. Two fundamental gender differences, skewed X-chromosome inactivation (XCI) and pregnancy-related microchimerism, have been implicated in scleroderma. We investigated the XCI patterns of female scleroderma patients and the parental origin of the inactive X chromosome in those patients having skewed XCI patterns (>80%). In addition, we investigated whether a correlation exists between XCI patterns and microchimerism in a well-characterized cohort. About 195 female scleroderma patients and 160 female controls were analyzed for the androgen receptor locus to assess XCI patterns in the DNA extracted from peripheral blood cells. Skewed XCI was observed in 67 (44.9%) of 149 informative patients and in 10 of 124 healthy controls (8.0%) [odds ratio (OR) = 9.3 (95% confidence interval (CI) 4.3–20.6, P < 0.0001)]. Extremely skewed XCI (>90%) was present in 44 of 149 patients (29.5%) but only in 3 of 124 controls (2.4%; OR = 16.9; 95% CI 4.8–70.4, P < 0.0001). Parental origin of the inactive X chromosome was investigated for ten patients for whom maternal DNA was informative, and the inactive X chromosome was of maternal origin in eight patients and of paternal origin in two patients. Skewed XCI mosaicism could be considered as an important risk factor in scleroderma.


X-inactivation Microchimerism Mosaicism Scleroderma 



We would like to thank Iclal Ozcelik for critical reading of the manuscript. Supported by grants from the Scientific and Technical Research Council of Turkey–TUBITAK-SBAG 3334, International Centre for Genetic Engineering and Biotechnology–ICGEB-CRP/TUR04-01, and Bilkent University Research Fund (to Dr. Ozcelik).


  1. 1.
    Derk CT, Jimenez SA (2003) Systemic sclerosis: current views of its pathogenesis. Autoimmun Rev 2:181–191PubMedCrossRefGoogle Scholar
  2. 2.
    Silman AJ, Hochberg MC (1993) Scleroderma. In: Silman AJ, Hochberg MC (eds) Epidemiology of the rheumatic diseases. Oxford University Press, Oxford, pp 192–219Google Scholar
  3. 3.
    Whitacre CC (2001) Sex differences in autoimmune disease. Nat Immun 2:777–780CrossRefGoogle Scholar
  4. 4.
    Cutolo M, Capellino S, Sulli A, Serioli B, Secchi ME, Villaggio B, Straub RH (2006) Estrogens and autoimmune diseases. Ann N Y Acad Sci 1089:538–547PubMedCrossRefGoogle Scholar
  5. 5.
    Mullinax F (1993) Chimerism and autoimmunity. In: Feng PH, Boey ML, Chang HH, Fong KY, Howe HS, Leong KH (eds) Proceedings of the 4th ASEAN Congress of Rehumatology. Communication Consultants, Singapore, pp 39–40Google Scholar
  6. 6.
    Kast RE (1977) Predominance of autoimmune and rheumatic diseases in females. J Rheumatol 4:288–292PubMedGoogle Scholar
  7. 7.
    Stewart JJ (1998) The female X-inactivation mosaic in systemic lupus erythematosus. Immunol Today 19:352–357PubMedCrossRefGoogle Scholar
  8. 8.
    Nelson JL (1996) Maternal-fetal immunology and autoimmune diseases: is some autoimmune disease auto-alloimmune or allo-autoimmune? Arthritis Rheum 39:191–194PubMedCrossRefGoogle Scholar
  9. 9.
    Mullinax F, Mullinax GL (1996) Pregnancy-induced scleroderma: identification of offspring-derived cells in patients with scleroderma [abstract]. Arthritis Rheum 39(Suppl 9):231Google Scholar
  10. 10.
    Nelson JL, Furst DE, Maloney S, Gooley T, Evans PC, Smith A (1998) Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 351:559–562PubMedCrossRefGoogle Scholar
  11. 11.
    Artlett CM, Smith JB, Jimenez SA (1998) Identification of fetal DNA and cells in lesions from women with systemic sclerosis. N Engl J Med 321:1186–1191CrossRefGoogle Scholar
  12. 12.
    Ozbalkan Z, Bagislar S, Kiraz S, Akyerli CB, Ozer HT, Yavuz S, Birlik AM, Calguneri M, Ozcelik T (2005) Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum 52:1564–1570PubMedCrossRefGoogle Scholar
  13. 13.
    Loubiere LS, Lambert NC, Madeleine MM, Porter AJ, Mullarkey ME, Pang JM, Galloway DA, Furst DE, Nelson JL (2005) HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women. Rheumatology (Oxford) 44:318–322CrossRefGoogle Scholar
  14. 14.
    Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW (1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 51:1229–1239PubMedGoogle Scholar
  15. 15.
    Busque L, Mio R, Mattioli J, Brais E, Brais N, Lalonde Y, Maragh M, Gilliland DG (1996) Non-random X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 88:59–65PubMedGoogle Scholar
  16. 16.
    Sharp A, Robinson D, Jacobs P (2000) Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 107:343–349PubMedCrossRefGoogle Scholar
  17. 17.
    Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE, Longshore J, Willard HF (2006) X chromosome inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet 79:493–499PubMedCrossRefGoogle Scholar
  18. 18.
    Lambert NC, Erickson TD, Yan Z, Pang JM, Guthrie KA, Furst DE, Nelson JL (2004) Quantification of maternal microchimerism by HLA-specific real-time polymerase chain reaction: studies of healthy women and women with scleroderma. Arthritis Rheum 50:906–914PubMedCrossRefGoogle Scholar
  19. 19.
    Ozcelik T (2007) X chromosome inactivation and female predisposition to autoimmunity. Clin Rev Alergy Immunol (in press)Google Scholar
  20. 20.
    Puck JM, Willard HF (1998) X inactivation in females with X-linked disease. N Engl J Med 338:325–328PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Elif Uz
    • 1
  • Laurence S. Loubiere
    • 2
  • Vijayakrishna K. Gadi
    • 2
    • 3
  • Zeynep Ozbalkan
    • 4
  • Jeffrey Stewart
    • 5
  • J. Lee Nelson
    • 2
    • 3
  • Tayfun Ozcelik
    • 1
    • 6
    Email author
  1. 1.Department of Molecular Biology and Genetics, Faculty of ScienceBilkent UniversityAnkaraTurkey
  2. 2.Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  3. 3.Department of MedicineUniversity of WashingtonSeattleUSA
  4. 4.Rheumatology DepartmentAnkara Numune Education and Research HospitalAnkaraTurkey
  5. 5.Caldera PharmaceuticalsLos AlamosUSA
  6. 6.Institute for Materials Science and Nanotechnology (UNAM)Bilkent UniversityAnkaraTurkey

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