Genetic and genomic studies of PADI4 in rheumatoid arthritis

Objectives. Strong genetic association of rheumatoid arthritis (RA) with PADI4 (peptidyl arginine deiminase) has previously been described in Japanese, although this was not confirmed in a subsequent study in the UK. We therefore undertook a further study of genetic association between PADI4 and RA...

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Published in:	Rheumatology (Oxford, England) England), 2005-07, Vol.44 (7), p.869-872
Main Authors:	Harney, S. M. J., Meisel, C., Sims, A.-M., Woon, P. Y., Wordsworth, B. P., Brown, M. A.
Format:	Article
Language:	eng
Subjects:	Anti-CCP antibodies Arthritis, Rheumatoid - enzymology Arthritis, Rheumatoid - genetics Arthritis, Rheumatoid - immunology Autoantibodies - blood Biological and medical sciences Biomarkers - blood Case-Control Studies Diseases of the osteoarticular system Genetic polymorphism Genotype Humans Hydrolases - blood Hydrolases - genetics Inflammatory joint diseases Medical sciences Peptides, Cyclic - immunology Polymorphism, Restriction Fragment Length Polymorphism, Single Nucleotide Protein-Arginine Deiminases Real-time PCR
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Summary:	Objectives. Strong genetic association of rheumatoid arthritis (RA) with PADI4 (peptidyl arginine deiminase) has previously been described in Japanese, although this was not confirmed in a subsequent study in the UK. We therefore undertook a further study of genetic association between PADI4 and RA in UK Caucasians and also studied expression of PADI4 in the peripheral blood of patients with RA. Methods. Seven single-nucleotide polymorphisms (SNP) were genotyped using polymerase chain reaction (PCR)–restriction fragment length polymorphism in 111 RA cases and controls. A marker significantly associated with RA (PADI4_100, rs#2240339) in this first data set (P = 0.03) was then tested for association in a larger group of 439 RA patients and 428 controls. PADI4 transcription was also assessed by real-time quantitative PCR using RNA extracted from peripheral blood mononuclear cells from 13 RA patients and 11 healthy controls. Results. A single SNP was weakly associated with RA (P = 0.03) in the initial case–control study, a single SNP (PADI4_100) and a two marker haplotype of that SNP and the neighbouring SNP (PADI4_104) were significantly associated with RA (P = 0.02 and P = 0.03 respectively). PADI4_100 was not associated with RA in a second sample set. PADI4 expression was four times greater in cases than controls (P = 0.004), but expression levels did not correlate with the levels of markers of inflammation. Conclusion. PADI4 is significantly overexpressed in the blood of RA patients but genetic variation within PADI4 is not a major risk factor for RA in Caucasians.
ISSN:	1462-0324 1462-0332