Association of A Four-Amino Acid Residue Insertion Polymorphism of the HS1 Gene with Systemic Lupus Erythematosus: Molecular and Functional Analysis

Junji Otsuka, Takahiko Horiuchi, Shigeru Yoshizawa, Hiroshi Tsukamoto, Takuya Sawabe, Yuji Kikuchi, Daisuke Himeji, Takako Koyama, Hiroki Mitoma, Takeshi Watanabe, Mine Harada

研究成果: Contribution to journalArticle査読

12 被引用数 (Scopus)

抄録

Objective. To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cell-specific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE). Methods. The entire coding region of the HS1 gene was analyzed by reverse transcriptase-polymerase chain reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI-231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometiric analysis and MTT assay. Results. We identified a glutamic acid-proline-glutamic acid-proline insertion between codons 366 and 367 (EPEP366-367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP+ aliele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P = 0.016). The allele frequency of EPEP366-367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P = 0.006). WEHI-231 cells transfected with EPEP+ HS1 were 100-fold more sensitive to B cell receptor (BCR)-mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP+ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele. Conclusion. These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.

本文言語英語
ページ(範囲)871-881
ページ数11
ジャーナルArthritis and rheumatism
50
3
DOI
出版ステータス出版済み - 3 2004

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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