Skip to main content
PMC home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2005 Apr 7;64(11):1611–1617. doi: 10.1136/ard.2004.032425

Oestrogen receptor α gene polymorphisms in systemic lupus erythematosus

M Johansson 1, L Arlestig 1, B Moller 1, T Smedby 1, S Rantapaa-Dahlqvis 1
PMCID: PMC1755265  PMID: 15817658

Abstract

Objective: To analyse associations of two oestrogen receptor α (ORα) gene polymorphisms in 260 patients with SLE from northern Sweden. The two polymorphisms, PvuII T/C and the XbaI A/G, are located in the first intron of the ORα gene.

Methods: All patients fulfilling at least four of the ACR criteria for SLE were consecutively recruited during one year. The SLEDAI score and SLICC damage index were recorded. 670 individuals from the same geographical area served as controls. DNA from the patients and controls was extracted and genotyped using the 5' nuclease assay with an ABI PRISM 7900HT instrument. The genotype/phenotype relationships were calculated using SPSS.

Results: The unusual PvuII C allele was associated with malar rash and the unusual XbaI G allele with photosensitivity (p = 0.001, OR = 2.53, 95% CI = 1.43 to 4.47 and p = 0.007, OR = 2.12, 95% CI = 1.22 to 3.66, respectively). The common XbaI AA genotype was associated with serositis (p = 0.013, OR = 1.92, 95% CI = 1.15 to 3.22). Based on the SLICC damage index associations of the common TT genotype and AA genotype with cognitive impairment were identified (p = 0.018, OR = 2.47, 95% CI = 1.17 to 5.25 and p = 0.018, OR = 2.75, 95% CI = 1.19 to 6.38 respectively). There was also an association of the XbaI AA genotype with the angina/coronary artery bypass variable (p = 0.042, OR = 2.58, 95% CI = 1.03 to 6.43). Of the variables describing disease severity and duration it was found that carriers of the unusual PvuII C allele showed a later onset of SLE (p = 0.02) and carriers of the unusual XbaI G allele a lower SLICC damage index.

Conclusions: The unusual PvuII C and XbaI G alleles were associated with a milder form of SLE characterised by skin manifestations, later onset, and less organ damage.

Full Text

The Full Text of this article is available as a PDF (96.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abu-Shakra M., Urowitz M. B., Gladman D. D., Gough J. Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol. 1995 Jul;22(7):1259–1264. [PubMed] [Google Scholar]
  2. Andersen T. I., Heimdal K. R., Skrede M., Tveit K., Berg K., Børresen A. L. Oestrogen receptor (ESR) polymorphisms and breast cancer susceptibility. Hum Genet. 1994 Dec;94(6):665–670. doi: 10.1007/BF00206961. [DOI] [PubMed] [Google Scholar]
  3. Ansar Ahmed S., Penhale W. J., Talal N. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol. 1985 Dec;121(3):531–551. [PMC free article] [PubMed] [Google Scholar]
  4. Beaumont V., Gioud-Paquet M., Kahn M. F., Beaumont J. L. Antiestrogen antibodies, oral contraception and systemic lupus erythematosus. Clin Physiol Biochem. 1989;7(5):263–268. [PubMed] [Google Scholar]
  5. Beeson P. B. Age and sex associations of 40 autoimmune diseases. Am J Med. 1994 May;96(5):457–462. doi: 10.1016/0002-9343(94)90173-2. [DOI] [PubMed] [Google Scholar]
  6. Bombardier C., Gladman D. D., Urowitz M. B., Caron D., Chang C. H. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992 Jun;35(6):630–640. doi: 10.1002/art.1780350606. [DOI] [PubMed] [Google Scholar]
  7. Enmark E., Gustafsson J. A. Oestrogen receptors - an overview. J Intern Med. 1999 Aug;246(2):133–138. doi: 10.1046/j.1365-2796.1999.00545.x. [DOI] [PubMed] [Google Scholar]
  8. Ferrero Valeria, Ribichini Flavio, Matullo Giuseppe, Guarrera Simonetta, Carturan Sonia, Vado Antonello, Vassanelli Corrado, Piazza Alberto, Uslenghi Eugenio, Wijns William. Estrogen receptor-alpha polymorphisms and angiographic outcome after coronary artery stenting. Arterioscler Thromb Vasc Biol. 2003 Oct 16;23(12):2223–2228. doi: 10.1161/01.ATV.0000101181.81022.BF. [DOI] [PubMed] [Google Scholar]
  9. Garovich M., Agudelo C., Pisko E. Oral contraceptives and systemic lupus erythematosus. Arthritis Rheum. 1980 Dec;23(12):1396–1398. doi: 10.1002/art.1780231213. [DOI] [PubMed] [Google Scholar]
  10. Gladman D., Ginzler E., Goldsmith C., Fortin P., Liang M., Urowitz M., Bacon P., Bombardieri S., Hanly J., Hay E. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1996 Mar;39(3):363–369. doi: 10.1002/art.1780390303. [DOI] [PubMed] [Google Scholar]
  11. González-Gómez Francisco, Vergara Francisco, Fernández Ana, Pedrosa Concepción, Ramirez Juan P., Castilla José A., Ruiz Rocio, Galán José J., Ruiz Agustin, Real Luis M. Detection of pvull polymorphism within intron 1 of ESR1 gene by real-time PCR. Clin Chem Lab Med. 2003 Mar;41(3):392–393. doi: 10.1515/CCLM.2003.060. [DOI] [PubMed] [Google Scholar]
  12. Hayslett J. P., Reece E. A. Systemic lupus erythematosus in pregnancy. Clin Perinatol. 1985 Oct;12(3):539–550. [PubMed] [Google Scholar]
  13. Herrington David M., Howard Tim D. ER-alpha variants and the cardiovascular effects of hormone replacement therapy. Pharmacogenomics. 2003 May;4(3):269–277. doi: 10.1517/phgs.4.3.269.22686. [DOI] [PubMed] [Google Scholar]
  14. Herrington David M., Howard Timothy D., Brosnihan K. Bridget, McDonnell Donald P., Li Xiaolin, Hawkins Gregory A., Reboussin David M., Xu Jianfeng, Zheng Siqun L., Meyers Deborah A. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation. 2002 Apr 23;105(16):1879–1882. doi: 10.1161/01.cir.0000016173.98826.88. [DOI] [PubMed] [Google Scholar]
  15. Herrington David M., Howard Timothy D., Hawkins Gregory A., Reboussin David M., Xu Jianfeng, Zheng Siqun L., Brosnihan K. Bridget, Meyers Deborah A., Bleecker Eugene R. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med. 2002 Mar 28;346(13):967–974. doi: 10.1056/NEJMoa012952. [DOI] [PubMed] [Google Scholar]
  16. Hochberg M. C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725–1725. doi: 10.1002/art.1780400928. [DOI] [PubMed] [Google Scholar]
  17. Jungers P., Dougados M., Pélissier C., Kuttenn F., Tron F., Lesavre P., Bach J. F. Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. Arthritis Rheum. 1982 Jun;25(6):618–623. doi: 10.1002/art.1780250603. [DOI] [PubMed] [Google Scholar]
  18. Jungers P., Dougados M., Pélissier C., Kuttenn F., Tron F., Lesavre P., Bach J. F. Lupus nephropathy and pregnancy. Report of 104 cases in 36 patients. Arch Intern Med. 1982 Apr;142(4):771–776. doi: 10.1001/archinte.142.4.771. [DOI] [PubMed] [Google Scholar]
  19. Kanda N., Tsuchida T., Tamaki K. Estrogen enhancement of anti-double-stranded DNA antibody and immunoglobulin G production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum. 1999 Feb;42(2):328–337. doi: 10.1002/1529-0131(199902)42:2<328::AID-ANR16>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
  20. Khosla Sundeep, Riggs B. Lawrence, Atkinson Elizabeth J., Oberg Ann L., Mavilia Carmelo, Del Monte Francesca, Melton L. Joseph, 3rd, Brandi Maria Luisa. Relationship of estrogen receptor genotypes to bone mineral density and to rates of bone loss in men. J Clin Endocrinol Metab. 2004 Apr;89(4):1808–1816. doi: 10.1210/jc.2003-031448. [DOI] [PubMed] [Google Scholar]
  21. Lee Y. J., Shin K. S., Kang S. W., Lee C. K., Yoo B., Cha H. S., Koh E. M., Yoon S. J., Lee J. Association of the oestrogen receptor alpha gene polymorphisms with disease onset in systemic lupus erythematosus. Ann Rheum Dis. 2004 Oct;63(10):1244–1249. doi: 10.1136/ard.2003.012583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Liu Zhi-Hong, Cheng Zhao-Hong, Gong Ru-Jun, Liu Hao, Liu Dong, Li Lei-Shi. Sex differences in estrogen receptor gene polymorphism and its association with lupus nephritis in Chinese. Nephron. 2002 Feb;90(2):174–180. doi: 10.1159/000049039. [DOI] [PubMed] [Google Scholar]
  23. Livak K. J., Marmaro J., Todd J. A. Towards fully automated genome-wide polymorphism screening. Nat Genet. 1995 Apr;9(4):341–342. doi: 10.1038/ng0495-341. [DOI] [PubMed] [Google Scholar]
  24. Lockshin M. D. Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis Rheum. 1989 Jun;32(6):665–670. doi: 10.1002/anr.1780320602. [DOI] [PubMed] [Google Scholar]
  25. Maki P. M., Zonderman A. B., Resnick S. M. Enhanced verbal memory in nondemented elderly women receiving hormone-replacement therapy. Am J Psychiatry. 2001 Feb;158(2):227–233. doi: 10.1176/appi.ajp.158.2.227. [DOI] [PubMed] [Google Scholar]
  26. Manzi S., Meilahn E. N., Rairie J. E., Conte C. G., Medsger T. A., Jr, Jansen-McWilliams L., D'Agostino R. B., Kuller L. H. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997 Mar 1;145(5):408–415. doi: 10.1093/oxfordjournals.aje.a009122. [DOI] [PubMed] [Google Scholar]
  27. Masi A. T., Kaslow R. A. Sex effects in systemic lupus erythematosus: a clue to pathogenesis. Arthritis Rheum. 1978 May;21(4):480–484. doi: 10.1002/art.1780210413. [DOI] [PubMed] [Google Scholar]
  28. Mattila K. M., Axelman K., Rinne J. O., Blomberg M., Lehtimäki T., Laippala P., Röyttä M., Viitanen M., Wahlund L., Winblad B. Interaction between estrogen receptor 1 and the epsilon4 allele of apolipoprotein E increases the risk of familial Alzheimer's disease in women. Neurosci Lett. 2000 Mar 17;282(1-2):45–48. doi: 10.1016/s0304-3940(00)00849-1. [DOI] [PubMed] [Google Scholar]
  29. McMurray R. W. Estrogen, prolactin, and autoimmunity: actions and interactions. Int Immunopharmacol. 2001 Jun;1(6):995–1008. doi: 10.1016/s1567-5769(01)00045-5. [DOI] [PubMed] [Google Scholar]
  30. McMurray Robert W., May Warren. Sex hormones and systemic lupus erythematosus: review and meta-analysis. Arthritis Rheum. 2003 Aug;48(8):2100–2110. doi: 10.1002/art.11105. [DOI] [PubMed] [Google Scholar]
  31. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nilsson N., Carlsten H. Estrogen induces suppression of natural killer cell cytotoxicity and augmentation of polyclonal B cell activation. Cell Immunol. 1994 Oct 1;158(1):131–139. doi: 10.1006/cimm.1994.1262. [DOI] [PubMed] [Google Scholar]
  33. Ruiz-Irastorza G., Lima F., Alves J., Khamashta M. A., Simpson J., Hughes G. R., Buchanan N. M. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol. 1996 Feb;35(2):133–138. doi: 10.1093/rheumatology/35.2.133. [DOI] [PubMed] [Google Scholar]
  34. Schuit Stephanie C. E., Oei Hok-Hay S., Witteman Jacqueline C. M., Geurts van Kessel Corine H., van Meurs Joyce B. J., Nijhuis Rogier L., van Leeuwen Johannes P. T. M., de Jong Frank H., Zillikens M. Carola, Hofman Albert. Estrogen receptor alpha gene polymorphisms and risk of myocardial infarction. JAMA. 2004 Jun 23;291(24):2969–2977. doi: 10.1001/jama.291.24.2969. [DOI] [PubMed] [Google Scholar]
  35. Shearman Amanda M., Cupples L. Adrienne, Demissie Serkalem, Peter Inga, Schmid Christopher H., Karas Richard H., Mendelsohn Michael E., Housman David E., Levy Daniel. Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA. 2003 Nov 5;290(17):2263–2270. doi: 10.1001/jama.290.17.2263. [DOI] [PubMed] [Google Scholar]
  36. Shughrue P. J., Lane M. V., Merchenthaler I. Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol. 1997 Dec 1;388(4):507–525. doi: 10.1002/(sici)1096-9861(19971201)388:4<507::aid-cne1>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  37. Steinberg A. D., Steinberg B. J. Lupus disease activity associated with menstrual cycle. J Rheumatol. 1985 Aug;12(4):816–817. [PubMed] [Google Scholar]
  38. Tan E. M., Cohen A. S., Fries J. F., Masi A. T., McShane D. J., Rothfield N. F., Schaller J. G., Talal N., Winchester R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. doi: 10.1002/art.1780251101. [DOI] [PubMed] [Google Scholar]
  39. Tanriverdi F., Silveira L. F. G., MacColl G. S., Bouloux P. M. G. The hypothalamic-pituitary-gonadal axis: immune function and autoimmunity. J Endocrinol. 2003 Mar;176(3):293–304. doi: 10.1677/joe.0.1760293. [DOI] [PubMed] [Google Scholar]
  40. Ushiyama T., Mori K., Inoue K., Huang J., Nishioka J., Hukuda S. Association of oestrogen receptor gene polymorphisms with age at onset of rheumatoid arthritis. Ann Rheum Dis. 1999 Jan;58(1):7–10. doi: 10.1136/ard.58.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Ward M. M. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum. 1999 Feb;42(2):338–346. doi: 10.1002/1529-0131(199902)42:2<338::AID-ANR17>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  42. Yaffe K., Browner W., Cauley J., Launer L., Harris T. Association between bone mineral density and cognitive decline in older women. J Am Geriatr Soc. 1999 Oct;47(10):1176–1182. doi: 10.1111/j.1532-5415.1999.tb05196.x. [DOI] [PubMed] [Google Scholar]
  43. Yaffe Kristine, Lui Li Yung, Grady Deborah, Stone Katie, Morin Philip. Estrogen receptor 1 polymorphisms and risk of cognitive impairment in older women. Biol Psychiatry. 2002 Apr 15;51(8):677–682. doi: 10.1016/s0006-3223(01)01289-6. [DOI] [PubMed] [Google Scholar]
  44. Zhang Y., Seshadri S., Ellison R. C., Heeren T., Felson D. T. Bone mineral density and verbal memory impairment: Third National Health and Nutrition Examination Survey. Am J Epidemiol. 2001 Nov 1;154(9):795–802. doi: 10.1093/aje/154.9.795. [DOI] [PubMed] [Google Scholar]

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Publishing Group

RESOURCES