Matthews Abigail G, Li Jia, He Chunsheng, Ott Jurg, Andrade Mariza de
Laboratory of Statistical Genetics, Rockefeller University, Box 192, 1230 York Avenue, New York, NY 10065, USA.
BMC Proc. 2009 Dec 15;3 Suppl 7(Suppl 7):S12. doi: 10.1186/1753-6561-3-s7-s12.
There is a long-established association between rheumatoid arthritis and HLA-DRbeta1. The shared epitope (SE) allele is an indicator of the presence of any of the HLA-DRbeta1 alleles associated with RA. Other autoantibodies are also associated with RA, specifically rheumatoid factor IgM (RFUW) and anti-cyclic citrullinated peptide (anti-CCP).
Using the Genetic Analysis Workshop 16 North American Rheumatoid Arthritis Consortium genome-wide association data, we sought to find non-HLA-DRbeta1 genetic associations by stratifying across SE status, and using the continuous biomarker phenotypes of RFUW and anti-CCP. To evaluate the binary RA phenotype, we applied the recently developed FP test and compared it to logistic regression or a genotype count-based test. We adjusted for multiple testing using the Bonferroni correction, the Q value approach, or permutation-based p-values. A case-only analysis of the biomarkers RFUW and anti-CCP used linear regression and ANOVAs.
The initial genome-wide association analysis using all cases and controls provides substantial evidence of an association on chromosomes 9 and 2 within the immune system-related gene UBXD2. In SE-positive subjects, many single-nucleotide polymorphisms were significant, including some on chromosome 6. Due to very few SE negative cases, we had limited power to detect associations in SE negative subjects. We were also unable to find genetic associations with either RFUW or anti-CCP.
Our analyses have confirmed previous findings for genes PTPN22 and C5. We also identified a novel candidate gene on chromosome 2, UBXD2. Results suggest FP test may be more powerful than the genotype count-based test.
类风湿性关节炎与人类白细胞抗原-DRβ1（HLA-DRβ1）之间存在长期确立的关联。共享表位（SE）等位基因是与类风湿性关节炎相关的任何HLA-DRβ1等位基因存在的指标。其他自身抗体也与类风湿性关节炎相关，特别是类风湿因子IgM（RFUW）和抗环瓜氨酸肽（抗CCP）。
利用遗传分析研讨会16北美类风湿性关节炎联盟全基因组关联数据，我们试图通过对SE状态进行分层，并使用RFUW和抗CCP的连续生物标志物表型来寻找非HLA-DRβ1基因关联。为了评估二元类风湿性关节炎表型，我们应用了最近开发的FP检验，并将其与逻辑回归或基于基因型计数的检验进行比较。我们使用Bonferroni校正、Q值方法或基于置换的P值对多重检验进行校正。对生物标志物RFUW和抗CCP进行仅病例分析时使用了线性回归和方差分析。
使用所有病例和对照进行的初始全基因组关联分析提供了大量证据，表明在免疫系统相关基因UBXD2内的9号和2号染色体上存在关联。在SE阳性受试者中，许多单核苷酸多态性具有显著性，包括6号染色体上的一些多态性。由于SE阴性病例极少，我们检测SE阴性受试者中关联的能力有限。我们也未能找到与RFUW或抗CCP的基因关联。
我们的分析证实了先前关于蛋白酪氨酸磷酸酶非受体型22（PTPN22）基因和补体成分5（C5）基因的研究结果。我们还在2号染色体上鉴定出一个新的候选基因UBXD2。结果表明FP检验可能比基于基因型计数的检验更具效力。
