Lenert Aleksander, Fardo David W
Department of Internal Medicine, Division of Rheumatology, University of Kentucky, Kentucky Clinic J507, Lexington, USA.
Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, USA.
Clin Exp Rheumatol. 2017 Jul-Aug;35(4):586-592. Epub 2017 Jan 27.
To identify novel risk genes by gene-based association analysis in rheumatoid arthritis (RA).
We performed gene-based association testing with GATES (Gene-based Association Test using Extended Simes procedure) to augment the power of genomewide-association study (GWAS) results from the largest meta-GWAS by Okada et al. in 14,361 RA cases and 43,923 controls of European ancestry using 8,694,488 SNPs.
We identified 115 genes significantly associated with RA by gene-based association testing corresponding to 43 RA risk loci; 23 risk loci contained a single top risk gene, while 20 risk loci contained two or more risk genes. We replicated 39 of the genomewide significant risk loci identified by Okada et al. in Europeans with RA; we found identical top genes for 26 loci. Our gene-based testing identified 6 new top gene hits for each of the following 6 RA risk loci: RPP14 (for DNASE1L3-ABHD6-PXK), PXT1 (for ETV7), MIR5708 (for TPD52), DDX6 (for CXCR5), SUOX (for CDK2), and PCAT29 (for LOC145837). We also identified a potential novel RA risk locus (11q23.3, start position 118528941 bp) which contains the following 3 genes: TREH-PHLDB1-MIR6716; the locus was not identified previously but may be a proxy for CXCR5.
Through novel comprehensive gene-based association testing in >50,000 Europeans with RA using ~8 million SNPs, we confirmed prior RA risk loci and identified novel risk genes including non-coding regulatory miRNAs, providing further insight into the complex genetics of RA.
通过基于基因的关联分析在类风湿关节炎（RA）中鉴定新的风险基因。
我们使用GATES（使用扩展Simes程序的基于基因的关联测试）进行基于基因的关联测试，以增强冈田等人在最大的荟萃全基因组关联研究（GWAS）中的结果效力，该研究纳入了14361例RA病例和43923例欧洲血统对照，使用了8694488个单核苷酸多态性（SNP）。
通过基于基因的关联测试，我们鉴定出115个与RA显著相关的基因，对应43个RA风险位点；23个风险位点包含单个顶级风险基因，而20个风险位点包含两个或更多风险基因。我们在欧洲RA患者中重复验证了冈田等人鉴定出的39个全基因组显著风险位点；我们发现26个位点的顶级基因相同。我们基于基因的测试为以下6个RA风险位点中的每一个鉴定出6个新的顶级基因命中：RPP14（对应DNASE1L3 - ABHD6 - PXK）、PXT1（对应ETV7）、MIR5708（对应TPD52）、DDX6（对应CXCR5）、SUOX（对应CDK2）和PCAT29（对应LOC145837）。我们还鉴定出一个潜在的新RA风险位点（11q23.3，起始位置118528941 bp），其包含以下3个基因：TREH - PHLDB1 - MIR6716；该位点之前未被鉴定出，但可能是CXCR5的替代物。
通过对超过50000例欧洲RA患者使用约800万个SNP进行新颖的综合基于基因的关联测试，我们证实了先前的RA风险位点，并鉴定出包括非编码调控微小RNA（miRNA）在内的新风险基因，为深入了解RA复杂的遗传学提供了进一步的见解。
