CD244 variant, previously reported to be associated with RA in Caucasian and Japanese populations, respectively. The CD40 and CCL21 genes both encode proteins that are involved in immune regulation. CD40 is expressed in a wide variety of immune cells, including B cells, monocytes and den- dritic cells, while its ligand, CD154, is expressed by activated CD4 T cells. Binding of CD154 to CD40 provides a critical stimulus for B cell proliferation, immunoglobulin production, isotype switching and upregulation of other costimulatory mol- ecules including B7-related molecules.16 CD40–CD154 inter- action appears to have an important role in RA, as expression of CD154 on CD4 T cells in RA promotes increased activation of CD4 T lymphocytes and is associated with active disease. Indeed, blockade of this pathway has been suggested as a poten- tially useful therapeutic approach in RA and in autoimmune disease in general.16 17 It is interesting to note that the CD40 marker was strongly associated with anti-CCP and RF-positive RA, which suggest that this polymorphism, or other/s in LD with it, could play a role in the regulation of B cell response and the production of autoantibodies. The CCL21 gene encodes a protein that is a homeostatic lymphoid chemokine instrumental in the recruitment and organisation of T cells and dendritic cells into secondary lymphoid organs, which participate in lymphoid tissue microanatomical organisation in RA.18 Both genes, there- fore, are plausible candidates in conferring risk of RA. Although we found statistically signiﬁcant evidence for association with the CCL21 locus, this would not have remained signiﬁcant if a correction for multiple testing had been applied and, therefore, conﬁrmation of this locus as an RA susceptibility region will require further investigation in other large data series. It is becoming well established that there exists an ethnic het- erogeneity of genetic susceptibility factors in RA, meaning that ﬁndings from one ethnic group may not be readily applicable to all. For example, rs2476601 in the PTPN22 gene, which is the most robustly validated RA marker in European populations after human leukocyte antigen (HLA), is not polymorphic in Asian populations.19 In contrast, polymorphisms in PADI4 are far more strongly associated with RA in Far East populations than European populations, despite having a comparable allele frequencies.19–21 Other RA susceptibility loci, such as STAT4, are common to European and Asian populations.9 22–24 More rele- vant to the current study, it has recently been reported that the CD40 and CCL21 variants tested in the present study, are not associated with RA in a Korean population.25 However, it is pos- sible that the CD244 SNP tested in the current study is in LD with the true causative variant in the Japanese population, but not in the UK population, which could explain the lack of repli- cation of the association of this marker. This is the ﬁrst study to test the association of CD244 with RA in a European population, but we have found no evidence for association, despite it being a functional polymorphism with a regulatory effect on the transcription of CD244.12 Insufﬁcient power is an unlikely cause of the lack of replication, since we achieved >98% power to detect an association with an effect size similar to that reported in the prior Japanese study12 at a 5% signiﬁcance level. However, the ‘winner’s curse’ means that effect sizes are often overestimated in the ﬁrst study in which they are reported. It is possible that the effect size at this locus is smaller and that, by chance, it has not been detected in the cur- rent study. The lack of power of individual studies may be over- come by meta-analysis where published data is available and this is particularly pertinent to the CDK6 rs42041 SNP where the power to detect association in the sample set tested in the current study was low (approximately 60%). The meta-analysis Ann Rheum Dis 2010;69:813–816. doi:10.1136/ard.2009.109579 Extended report presented here yielded a statistically signiﬁcant, yet modest, association (p=0.002, OR 1.08, 95% CI 1.03 to 1.14) of the CDK6 rs42041 marker with RA susceptibility. It should be noted that we detected some heterogeneity in the effect sizes between studies (pBreslow–Day=0.02), so the pooled OR should be consid- ered with caution and further validation in independent cohorts will be required in order to clarify the role of this variant in RA susceptibility. For the CD244 marker, by contrast, no evidence for association was detected even after pooled analysis of the UK WTCCC and validation datasets, which included approxi- mately 5400 patients with RA and approximately 5800 healthy controls. In this case, genetic heterogeneity would appear to explain the lack of replication as allele frequencies for the rs6682654 SNP are signiﬁcantly different between the Japanese and UK populations. In the past year, the ﬁrst wave of GWAS has improved our understanding of the genetic basis of common, complex dis- eases, including RA. These studies have made possible the iden- tiﬁcation of new RA susceptibility loci, such as those mapping to the 6q23, TRAF1/C5, PRKCQ, KIF5A, STAT4 and now CD40. However, these initial GWAS have shown that the effect sizes resulting from associations with common SNPs are modest and, therefore, the remaining RA susceptibility genes may have even smaller effect sizes. Validation studies using large sample sizes and ethnically different populations as well as meta-analysis will be essential to robustly deﬁne new potential susceptibility loci. Only then will the investment in ﬁne mapping and functional studies be justiﬁed to identify the aetiological variants within the validated loci. In conclusion, we have validated association of CD40 rs4810485 and detected weak evidence for association of CCL21 rs2812378 with RA in a UK population, laying the foundations for further studies of the functional and genetic effects of these variants in conferring risk of disease. Acknowledgements We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. IT support was provided by Mark Lay, statistical advice from Mark Lunt and technical support by Paul Gilbert, Bhaneeta Lad and Stephen G Martin. Nursing support was provided by Janet Grumley, Julie Shotton and Claire Farrar. This work was supported by the Arthritis Research Campaign (arc grant reference number 17552). We would also like to acknowledge the National Health Service (NHS) Research and Development Support Fund for Guy’s and St Thomas’ and Lewisham NHS Trusts. We acknowledge the arc, Leeds Teaching Hospitals Charitable Trustees and NIHR Leeds Musculoskeletal Biomedical Research Unit for supporting the establishment of the Leeds cohorts. We thank the Manchester Biomedical Research Centre for support. Competing interests None. Ethics approval This study was conducted with the approval of the North West Research Ethics Committee (MREC 99/8/84). Provenance and peer review Not commissioned; externally peer reviewed. For more information on the WTCCC and YEAR Consortiums, see supplementary material. REFERENCES 1. McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 2008;9:356–69. 2. Thomson W, Barton A, Ke X, et al. Rheumatoid arthritis association at 6q23. Nat Genet 2007;39:1431–3. 3. Plenge RM, Cotsapas C, Davies L, et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007;39:1477–82. 4. 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