TNFRSF1B基因内的遗传变异与类风湿关节炎易感性及抗TNF药物反应：一项多中心研究
Genetic variants within the TNFRSF1B gene and susceptibility to rheumatoid arthritis and response to anti-TNF drugs: a multicenter study.
作者信息
Canet Luz M, Filipescu Ileana, Cáliz Rafael, Lupiañez Carmen B, Canhão Helena, Escudero Alejandro, Segura-Catena Juana, Soto-Pino María J, Ferrer Miguel A, García Antonio, Romani Lurdes, Pérez-Pampin Eva, González-Utrilla Alfonso, López Nevot Miguel A, Collantes Eduardo, Fonseca João E, Sainz Juan
机构信息
aGenomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, PTS Granada Departments of bImmunology cRheumatology, Virgen de las Nieves University Hospital, Granada dRheumatology Department, Reina Sofía Hospital, IMIBIC, University of Córdoba, Córdoba eRheumatology Unit, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain fRheumatology Research Unit, Molecular Medicine Institute, Medicine Faculty of Lisbon University gRheumatology Department, Santa Maria Hospital - CHLN, Lisbon, Portugal hRheumatology Department, University of Medicine and Pharmacy 'Iuliu Hatieganu' Cluj-Napoca, Romania.
出版信息
Pharmacogenet Genomics. 2015 Jul;25(7):323-33. doi: 10.1097/FPC.0000000000000140.
BACKGROUND
Recent research suggests that genetic variants in the tumor necrosis factor receptor 2 (TNFRSF1B) gene may have an impact on susceptibility to rheumatoid arthritis (RA) and drug response. The present population-based case-control study was carried out to evaluate whether 5 tagging single-nucleotide polymorphisms (SNPs) within the TNFRSF1B gene are associated with the risk of RA and response to antitumor necrosis factor (TNF) drugs.
METHODS
The study population included 1412 RA patients and 1225 healthy controls. A subset of 596 anti-TNF-naive RA patients was selected to assess the association of TNFRSF1B SNPs and drug response according to the EULAR response criteria.
RESULTS
We found that carriers of the TNFRSF1Brs3397C allele had a significantly increased risk of developing RA (P=0.0006). Importantly, this association remained significant after correction for multiple testing. We also confirmed the lack of association of the TNFRSF1Brs1061622 SNP with the risk of RA in the single-SNP analysis (P=0.89), but also through well-powered meta-analyses (PDOM=0.67 and PREC=0.37, respectively). In addition, our study showed that carriers of the TNFRSF1Brs3397C/C, TNFRSF1Brs1061622G/G, and TNFRSF1Brs1061631A/A genotypes had an increased risk of having a worse response to anti-TNF drugs at the level of P less than 0.05 (P=0.014, 0.0085 and 0.028, respectively). We also observed that, according to a log-additive model, carriers of the TNFRSF1Brs3397C or TNFRSF1Brs1061622G alleles showed an increased risk of having worse response to anti-TNF medications (P=0.018 and 0.0059). However, the association of the TNFRSF1Brs1061622 SNP only reached marginal significance after correction for multiple testing according to a log-additive model (P=0.0059) and it was not confirmed through a meta-analysis (PDOM=0.12).
CONCLUSION
Our results suggest that the TNFRSF1Brs3397 variant may play a role in modulating the risk of RA, but does not provide strong evidence of an impact of TNFRSF1B variants in determining response to anti-TNF drugs.
背景
近期研究表明，肿瘤坏死因子受体2（TNFRSF1B）基因中的遗传变异可能会影响类风湿关节炎（RA）的易感性和药物反应。本基于人群的病例对照研究旨在评估TNFRSF1B基因内的5个标签单核苷酸多态性（SNP）是否与RA风险及抗肿瘤坏死因子（TNF）药物反应相关。
方法
研究人群包括1412例RA患者和1225例健康对照。选择596例未使用过抗TNF药物的RA患者子集，根据欧洲抗风湿病联盟（EULAR）反应标准评估TNFRSF1B基因SNP与药物反应的相关性。
结果
我们发现TNFRSF1B rs3397 C等位基因携带者患RA的风险显著增加（P = 0.0006）。重要的是，在进行多重检验校正后，这种关联仍然显著。我们还在单SNP分析中证实TNFRSF1B rs1061622 SNP与RA风险缺乏关联（P = 0.89），并且通过效能充分的荟萃分析也得到了同样结果（PDOM = 0.67，PREC = 0.37）。此外，我们的研究表明，TNFRSF1B rs3397 C/C、TNFRSF1B rs1061622 G/G和TNFRSF1B rs1061631 A/A基因型携带者对抗TNF药物反应较差的风险增加，P值均小于0.05（分别为P = 0.014、0.0085和0.028）。我们还观察到，根据对数相加模型，TNFRSF1B rs3397 C或TNFRSF1B rs1061622 G等位基因携带者对抗TNF药物反应较差的风险增加（P = 0.018和0.0059）。然而，根据对数相加模型，TNFRSF1B rs1061622 SNP的关联在多重检验校正后仅达到边缘显著性（P = 0.0059），并且未通过荟萃分析得到证实（PDOM = 0.12）。
结论
我们的结果表明，TNFRSF1B rs3397变异可能在调节RA风险中起作用，但没有提供强有力的证据表明TNFRSF1B变异在决定对抗TNF药物反应方面有影响。
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