Govind Nimmisha, Choudhury Ananyo, Hodkinson Bridget, Ickinger Claudia, Frost Jacqueline, Lee Annette, Gregersen Peter K, Reynolds Richard J, Bridges S Louis, Hazelhurst Scott, Ramsay Michèle, Tikly Mohammed
Division of Rheumatology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.
Mol Med. 2014 Aug 14;20(1):341-9. doi: 10.2119/molmed.2014.00097.
The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10(-5)). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.
本研究的目的是在南非黑人中鉴定与类风湿关节炎（RA）风险相关的基因变异。将南非黑人RA患者（n = 263）与健康对照者（n = 374）进行比较。使用免疫芯片进行基因分型，并通过外显子2的DNA测序进行四位数高分辨率人类白细胞抗原（HLA）分型。对数据实施了标准质量控制措施。最强的关联位于HLA-DRB1和HLA-DQA1基因座之间的基因间区域。在对HLA-DRB1等位基因进行条件分析后，扩展的主要组织相容性复合体（MHC）其余部分的效应减弱。基因间区域LOC389203|RBPJ、LOC100131131|IL1R1、KIAA1919|REV3L、LOC643749|TRAF3IP2中的非HLA单核苷酸多态性（SNP），以及IRF1内含子和非翻译区（UTR）以及ICOS和KIAA1542内含子区域中的SNP与RA相关（p < 5 × 10(-5)）。在先前与白种人中RA相关的SNP中，位于基因间区域LOC389203|RBPJ的一个SNP，rs874040，在本研究中得到了重复验证。PTPN22基因中的变异均未显示出显著关联。血清阳性亚组的结果与总体队列相似。在HLA区域观察到的效应很可能归因于HLA-DRB1，并且无法检测到扩展MHC中的次要效应。七个非HLA基因座与南非黑人的RA相关。与白种人相似，LOC38920和RBPJ之间的基因间区域在该人群中与RA相关。由于PTPN22基因的R620W变异在我们的研究中是单态的，因此未重复验证其与白种人中RA的强关联，但PTPN22基因的其他SNP变异在南非黑人中也与RA无关，这表明该基因座在该人群的RA中不发挥主要作用。
