Exclusion of the coding sequence of the doublecortin gene as a susceptibility locus in autistic disorder.

Tumour necrosis factor (TNF)-α plays a key role in the pathogenesis of rheumatoid arthritis (RA). It binds to two receptors, namely TNF receptor (TNFR)I and TNFRII. Several studies have suggested an association between TNFRII 196R/ R genotype and RA. The objective of the present study was to evaluate the predictive value of the TNFRII 196R allele for RA diagnosis and prognosis in a cohort of patients with very early arthritis. We followed up a total of 278 patients recruited from the community, who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for less than 6 months, and who had not received disease-modifying antirheumatic drugs or steroid therapy. At 2 years, patients were classified according to the American College of Rheumatology criteria. All patients were genotyped with respect to TNFRII 196M/R polymorphism. Radiographs of hands and feet (read according to the modified Sharp method) and the Health Assessment Questionnaire were used to quantify structural and functional severity. The cohort of 278 patients was found to include 156 and 122 RA and non-RA patients, respectively. The TNFRII 196R allele was found to be associated with RA (P = 0.002). However, progression of radiographic severity and Health Assessment Questionnaire scores over 1 year did not differ between carriers of the 196R allele and noncarriers. Our findings suggest that the TNFRII 196R allele may be associated with RA diagnosis but that it does not predict early radiographic progression or functional severity in patients with very early, unclassified arthritis. Introduction Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease, and it can lead to progressive joint destruction, deformity and severe disability. Early diagnosis of RA and timely initiation of disease-modifying antirheumatic drugs (DMARDs) are necessary to limit joint damage and optimise the functional outcome (i.e. the concept of a 'window of opportunity') [1,2]. No diagnosis criteria for RA are yet available, the 1987 American College of Rheumatology (ACR) criteria being classification criteria [3]. With the overall objective being to manage patients better, identification of markers that would allow one to establish a diagnosis of RA at the very beginning of the disease process remains an important goal. Certain autoantibodies have been reported to be specific for RA [4] and thus may help in the diagnosis of RA. Autoantibodies against cyclic citrullinated peptides (anti-CCP) are specific for RA but lack sensitivity; this contrasts with rheumatoid factor, which has strong sensitivity but low specificity for RA. ACR = American College of Rheumatology; CCP = cyclic citrullinated peptides; CI = confidence interval; DMARD = disease-modifying antirheumatic drug; F-HAQ = French version of the Health Assessment Questionnaire; IL = interleukin; NPV = negative predictive value; OR = odds ratio; PPV = positive predictive value; RA = rheumatoid arthritis; TNF = tumour necrosis factor; TNFR = tumour necrosis factor receptor. Arthritis Research & Therapy Vol 7 No 5 Goëb et al. R1057 Recently, a study conducted in blood donors [5] showed that positivity for IgM rheumatoid factor and anti-CCP may precede the clinical manifestations of RA. However, although concomitant positivity of both markers has been shown to be highly predictive of a diagnosis of RA, it has a low sensitivity (<50%) [6,7]. Thus, new RA diagnosis markers are needed, such as autoantibody populations and/or genetic markers. The latter have the particular advantages of being present from the onset of the disease and of remaining unchanged by therapy. To date, the only genetic susceptibility factor identified for RA is HLA-DRB1. This association is restricted to HLA-DRB1 alleles encoding a specific conserved amino acid sequence referred to as the shared epitope [8]. The predictive value of the shared epitope alleles for diagnosis of RA was studied in a cohort of 680 patients with early unclassified arthritis and was found to be lower than expected [9]. The contribution of HLA to the overall genetic risk has been estimated to range from 30% to 50% [10]. These data suggest that non-HLA genes are involved in RA susceptibility and could represent a very helpful tool for diagnosis of RA. Genome scans have implicated 1p36 as a susceptibility locus for RA [11,12], and TNFRII, which encodes the tumour necrosis factor (TNF)-α receptor (TNFR)II, is located within this locus [13]. Recent studies have reported an association between the TNFRII 196R/R genotype and familial RA in UK and French Caucasian populations [14,15] and RA in the Japanese population [16]. In the UK and French populations, the association was restricted to familial RA [14,15]. However, a case-control study conducted in the Swedish population [17] failed to replicate the association between RA and the TNFRII 196M/R polymorphism. That study revealed that RA patients carrying the TNFRII 196R allele were significantly younger at disease onset than were those homozygous for the TNFRII 196M