Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus

被引:233
作者
Russell, AI
Graham, DSC
Shepherd, C
Roberton, CA
Whittaker, J
Meeks, J
Powell, RJ
Isenberg, DA
Walport, MJ
Vyse, TJ [1 ]
机构
[1] Hammersmith Hosp, Imperial Coll, Fac Med, Rheumatol Sect, London W12 0NN, England
[2] Univ London Imperial Coll Sci & Technol, Fac Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England
[3] Hammersmith Hosp, Imperial Coll, Fac Med, Dept Pathol, London W12 0NN, England
[4] Queens Med Ctr, Clin Immunol Unit, Nottingham NG7 2UH, England
[5] UCL, Middlesex Hosp, London W1T 4NJ, England
基金
英国惠康基金;
关键词
D O I
10.1093/hmg/ddh021
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.2 within an interval linked with SLE. We have investigated the candidate genes CRP and APCS in two cohorts totalling 586 UK simplex SLE families. The inheritance of an intronic dinucleotide repeat and seven single nucleotide polymorphisms in the CRP and APCS genes was examined by application of family-based tests of association and linkage. Basal levels of CRP were influenced independently by two polymorphisms at the CRP locus, CRP 2 and CRP 4. Furthermore, the latter polymorphism was linked/associated with SLE and antinuclear autoantibody production. Thus, the polymorphism associated with reduced basal CRP was also associated with the development of SLE. These data support the hypothesis that defective disposal of potentially immunogenic material is a contributory factor in lupus pathogenesis. The identification of polymorphisms that determine basal CRP levels has implications in ischaemic heart disease, where CRP level is an important predictor of risk.
引用
收藏
页码:137 / 147
页数:11
相关论文
共 55 条
[1]   Transactivation of c-reactive protein by IL-6 requires synergistic interaction of CCAAT/enhancer finding protein β (C/EBPβ) and Rel p50 [J].
Agrawal, A ;
Cha-Molstad, H ;
Samols, D ;
Kushner, I .
JOURNAL OF IMMUNOLOGY, 2001, 166 (04) :2378-2384
[2]  
[Anonymous], 1989, Molecular Cloning: A Laboratory Manual
[3]   ARED: human AU-rich element-containing mRNA database reveals an unexpectedly diverse functional repertoire of encoded proteins [J].
Bakheet, T ;
Frevel, M ;
Williams, BRG ;
Greer, W ;
Khabar, KSA .
NUCLEIC ACIDS RESEARCH, 2001, 29 (01) :246-254
[4]   Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity [J].
Bickerstaff, MCM ;
Botto, M ;
Hutchinson, WL ;
Herbert, J ;
Tennent, GA ;
Bybee, A ;
Mitchell, DA ;
Cook, HT ;
Butler, PJG ;
Walport, MJ ;
Pepys, MB .
NATURE MEDICINE, 1999, 5 (06) :694-697
[5]   AN ANALYSIS OF TRANSFORMATIONS [J].
BOX, GEP ;
COX, DR .
JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1964, 26 (02) :211-252
[6]  
BRULL DJ, 2003, ARTERIOSCLER THR JUL
[7]   Innate immunity in the etiopathology of autoimmunity [J].
Carroll, M .
NATURE IMMUNOLOGY, 2001, 2 (12) :1089-1090
[8]   Cleavage by granzyme B is strongly predictive of autoantigen status: Implications for initiation of autoimmunity [J].
Casciola-Rosen, L ;
Andrade, F ;
Ulanet, D ;
Wong, WB ;
Rosen, A .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (06) :815-825
[9]   Comparison of tests for association and linkage in incomplete families [J].
Cervino, ACL ;
Hill, AVS .
AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 67 (01) :120-132
[10]  
CHAPMAN JR, 1984, AM REV RESPIR DIS, V130, P439