Department of Genetics, University of Delhi, South Campus, New Delhi, India.
PLoS One. 2012;7(2):e31584. doi: 10.1371/journal.pone.0031584. Epub 2012 Feb 15.
Genome-wide association studies and meta-analysis indicate that several genes/loci are consistently associated with rheumatoid arthritis (RA) in European and Asian populations. To evaluate the transferability status of these findings to an ethnically diverse north Indian population, we performed a replication analysis. We investigated the association of 47 single-nucleotide polymorphisms (SNPs) at 43 of these genes/loci with RA in a north Indian cohort comprising 983 RA cases and 1007 age and gender matched controls. Genotyping was done using Infinium human 660w-quad. Association analysis by chi-square test implemented in plink was carried out in two steps. Firstly, association of the index or surrogate SNP (r2>0.8, calculated from reference GIH Hap-Map population) was tested. In the second step, evidence for allelic/locus heterogeneity at aforementioned genes/loci was assessed for by testing additional flanking SNPs in linkage equilibrium with index/surrogate marker.Of the 44 European specific index SNPs, neither index nor surrogate SNPs were present for nine SNPs in the genotyping array. Of the remaining 35, associations were replicated at seven genes namely PTPN22 (rs1217407, p = 3×10(-3)); IL2-21 (rs13119723, p = 0.008); HLA-DRB1 (rs660895, p = 2.56×10(-5); rs6457617, p = 1.6×10(-09); rs13192471, p = 6.7×10(-16)); TNFA1P3 (rs9321637, p = 0.03); CCL21 (rs13293020, p = 0.01); IL2RA (rs2104286, p = 1.9×10(-4)) and ZEB1 (rs2793108, p = 0.006). Of the three Asian specific loci tested, rs2977227 in PADI4 showed modest association (p<0.02). Further, of the 140 SNPs (in LE with index/surrogate variant) tested, association was observed at 11 additional genes: PTPRC, AFF3, CD28, CTLA4, PXK, ANKRD55, TAGAP, CCR6, BLK, CD40 and IL2RB. This study indicates limited replication of European and Asian index SNPs and apparent allelic heterogeneity in RA etiology among north Indians warranting independent GWAS in this population. However, replicated associations of HLA-DRB1, PTPN22 (which confer ∼50% of the heritable risk to RA) and IL2RA suggest that cross-ethnicity fine mapping of such loci is apposite for identification of causal variants.
全基因组关联研究和荟萃分析表明，在欧洲和亚洲人群中，有几个基因/位点与类风湿关节炎（RA）持续相关。为了评估这些发现对北印度种族多样化人群的可转移性，我们进行了一项复制分析。我们研究了北印度队列中 43 个基因/位点的 47 个单核苷酸多态性（SNP）与 RA 的关联，该队列包括 983 例 RA 病例和 1007 名年龄和性别匹配的对照。使用 Infinium 人类 660w-Quad 进行基因分型。采用 plink 中的卡方检验进行关联分析，分两步进行。首先，测试了索引或替代 SNP 的关联（根据参考 GIH Hap-Map 人群计算 r2>0.8）。在第二步中，通过测试与索引/替代标记物呈连锁平衡的额外侧翼 SNP，评估了上述基因/位点的等位基因/基因座异质性的证据。在 44 个欧洲特异性索引 SNP 中，有 9 个 SNP 在基因分型阵列中既没有索引 SNP 也没有替代 SNP。在剩下的 35 个中，在七个基因中复制了关联，即 PTPN22（rs1217407，p=3×10(-3)）；IL2-21（rs13119723，p=0.008）；HLA-DRB1（rs660895，p=2.56×10(-5)；rs6457617，p=1.6×10(-09)；rs13192471，p=6.7×10(-16)）；TNFA1P3（rs9321637，p=0.03）；CCL21（rs13293020，p=0.01）；IL2RA（rs2104286，p=1.9×10(-4)）和 ZEB1（rs2793108，p=0.006）。在测试的三个亚洲特异性基因座中，PADI4 中的 rs2977227 显示出适度的关联（p<0.02）。此外，在测试的 140 个 SNP（与索引/替代变体在 LE 中）中，在 11 个额外的基因中观察到关联：PTPRC、AFF3、CD28、CTLA4、PXK、ANKRD55、TAGAP、CCR6、BLK、CD40 和 IL2RB。这项研究表明，欧洲和亚洲索引 SNP 的复制有限，北印度人 RA 病因中的等位基因异质性明显，这需要在该人群中进行独立的全基因组关联研究。然而，HLA-DRB1、PTPN22（其赋予 RA 约 50%的可遗传风险）和 IL2RA 的复制关联表明，对这些基因座进行跨种族精细映射适合识别因果变异。
