Letters Kim K, Park S-Y, Kim T, et al. Ann Rheum Dis (2011). doi:10.1136/ard.2010.147249 1 of 2 Single-nucleotide polymorphisms (SNPs) of the human interferon γ gene ( IFNG) were found to be associated with susceptibility to systemic lupus erythematosus (SLE) in our recent case–control study on 1759 unrelated Korean participants (742 SLE patients and 1017 controls). 1 In particular, the SLE-susceptible (minor) allele in an SNP (rs2430561) located on an NF-κB binding site in the first intron was associated with elevated IFNG expression, 2 –4 consistent with previous functional implications of high expres- sion levels of IFNG in lupus pathogenesis in human disease and murine models, 5 –7 although this SNP showed no association in several previous small studies. 8 –10 In our original study, 1 the effect size of this SNP was con- siderable with an OR of 2.48 in a recessive model, but its asso- ciation was marginal (p=0.022, higher than a significance level α=0.0066 of multiple-testing correction), which was likely because the risk-associated allele homozygotes were too few (2.6% in SLE patients and 1.1% in controls), whereas another SNP (rs2069705) showed a significant association. In this study, the SLE association of these two SNPs was re-examined with 2355 unrelated Korean participants (853 SLE patients and 1502 controls), none of whom were included in the original study. The association of rs2430561 with SLE susceptibility was positively replicated (table 1), and the largest effect size was observed in a recessive genetic model (adjusted OR 2.19 and p=0.030), being similar to the values observed in the original study (adjusted OR 2.48 and p=0.022). 1 When the effect sizes of these two studies were combined (n=4114 including 1595 SLE patients and 2519 controls) using a meta-analysis, the association was significant (adjusted OR 2.32 and p=0.0017 in a recessive model; p in Q-statistic=0.81) passing even the significance level of the original study, although the risk-allele homozygote was still infrequent (2.4% in SLE and 1.1% in controls). In contrast, the association of rs2069705 was not reproduced with p=0.32 in a recessive model (table 1). However, the direc- tion of the effect size (adjusted OR 1.26) was the same as that in the original study (adjusted OR 2.27), and the meta-analysis of the two study results still showed a significant association (adjusted OR 1.61 and p=0.0066 in a recessive model; p in Q-statistic=0.094). The participants in this validation cohort were recruited from six hospitals (Hanyang University Hospital for Rheumatic Diseases, Kyungpook National University Hospital, Eulji University Hospital, Ajou University Hospital, Yonsei University Severance Hospital and Chungnam National University Hospital) and the patients fulfilled the American College of Rheumatology criteria. Genomic DNA was obtained from the peripheral blood cells of the subjects and genotyped using the MassARRAY plat- form of Sequenom, Inc. (San Diego, California). OR and p values were calculated using logistic regression analysis with adjust- ment for age and gender. The average call rate was 97.7% and the control subject genotypes were under Hardy–Weinberg equilibrium (p≥0.33). The combined effect sizes were calculated by fixed-effects meta-analysis (p values in Q-statistic ≥0.094). In summary, SLE association of the cis-regulatory SNP rs2430561 in IFNG was reproduced in two independent cohorts, supporting the previous association of increased expression of IFNG with increased susceptibility to SLE. Funding This work was supported by grants from the Research Program for New Drug Target Discovery (20090083335) and the Korean Healthcare Technology Research and Development Project (A080588). Competing interests None. Patient consent Obtained. Ethics approval This study was approved by the Institutional Review Boards of Hanyang University Hospital for Rheumatic Diseases, Kyungpook National University Kwangwoo Kim, 1 So-Yeon Park, 2 Taehyeung Kim, 1 Young Mo Kang, 3 Seung-Cheol Shim, 4 Chang-Hee Suh, 5 Yong-Beom Park, 6 Chang-sik Kim, 7 Changwon Kang, 1 Sang-Cheol Bae 2 1 Korea Advanced Institute of Science and Technology, Daejeon, Korea 2 Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea 3 Kyungpook National University Hospital, Daegu, Korea 4 Eulji University Hospital, Daejeon, Korea 5 Ajou University Hospital, Suwon, Korea 6 Yonsei University Severance Hospital, Seoul, Korea 7 Chungnam National University Hospital, Daejeon, Korea Correspondence to Professor Changwon Kang, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; ckang@kaist.ac.kr or Professor Sang-Cheol Bae, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Korea; scbae@hanyang.ac.kr KK and SYP contributed equally to this work and are joint first authors. CK and SCB contributed equally to this work. Replicated association of a regulatory polymorphism in the interferon γ gene with lupus susceptibility Table 1 Meta-analysis showing the association of rs2430561 and rs2069705 with SLE susceptibility SNP/cohort SLE cases Controls Codominant model Recessive model OR (95% CI) p OR (95% CI) P rs2430561 ( T> A) TT/ TA/ AA TT/ TA/ AA Original study 1 503/167/18 765/225/11 1.28 (1.04 to 1.58) 0.029 2.48 (1.14 to 5.41) 0.022 This study 629/177/19 1146/301/15 1.20 (0.99 to 1.45) 0.060 2.19 (1.08 to 4.44) 0.030 Meta-analysis 1.24 (1.08 to 1.42) 0.0029 2.32 (1.37 to 3.91) 0.0017 rs2069705 ( C> T) CC/ CT/ TT CC/ CT/ TT Original study 1 406/240/38 634/336/26 1.28 (1.07 to 1.53) 0.0047 2.27 (1.34 to 3.87) 0.0024 This study 541/265/37 953/466/52 1.07 (0.91 to 1.25) 0.58 1.26 (0.80 to 1.97) 0.32 Meta-analysis 1.16 (1.03 to 1.30) 0.015 1.61 (1.14 to 2.26) 0.0066 OR, 95% CI and p values were calculated using logistic regression analysis with adjustment for age and gender or using meta-analysis. SLE, systemic lupus erythematosus; SNP, single-nucleotide polymorphism. ARD Online First, published on April 24, 2011 as 10.1136/ard.2010.147249 Copyright Article author (or their employer) 2011. Produced by BMJ Publishing Group Ltd (& EULAR) under licence. group.bmj.com on April 25, 2011 - Published by ard.bmj.com Downloaded from