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Human Molecular Genetics Advance Access originally published online on November 25, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 1 137-147
DOI: 10.1093/hmg/ddh021
© 2004 Oxford University Press

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

Andrew I. Russell1, Deborah S. Cunninghame Graham1, Christopher Shepherd1, Cheri A. Roberton1, John Whittaker2, John Meeks3, Richard J. Powell4, David A. Isenberg5, Mark J. Walport1,{dagger} and Timothy J. Vyse1,*

1Rheumatology Section, Imperial College Faculty of Medicine, Hammersmith Hospital, London W12 0NN, UK, 2Department of Epidemiology and Public Health, Imperial College Faculty of Medicine, St Mary's Campus, Norfolk Place, London W2 1PG, UK, 3Department of Pathology, Imperial College Faculty of Medicine, Hammersmith Hospital, London W12 0NN, UK, 4Clinical Immunology Unit, Queen's Medical Centre, Nottingham NG7 2UH, UK and 5The Middlesex Hospital, University College London, Arthur Stanley House, Tottenham Street, London W1T 4NJ, UK

Received September 29, 2003; Accepted November 6, 2003

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.

* To whom correspondence should be addressed. Tel: +44 2083832339; Fax: +44 2087433109; Email: t.vyse{at}imperial.ac.uk

{dagger} Present address:

The Wellcome Trust, Euston Road, London NW1 2BE, UK.


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