叶酸依赖性酶的风险基因型及其与类风湿关节炎中与甲氨蝶呤相关副作用的关联。

Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis.

作者信息

Weisman Michael H, Furst Daniel E, Park Grace S, Kremer Joel M, Smith Katie M, Wallace Daniel J, Caldwell Jacques R, Dervieux Thierry

机构信息

Cedars-Sinai Medical Center, Los Angeles, California, USA.

出版信息

Arthritis Rheum. 2006 Feb;54(2):607-12. doi: 10.1002/art.21573.

DOI:10.1002/art.21573

PMID:16447238

Abstract

OBJECTIVE

Methotrexate (MTX) is an antifolate agent that is often associated with toxicity. This study investigated whether risk genotypes for folate-dependent enzymes are associated with the toxicity of MTX in patients with rheumatoid arthritis (RA).

METHODS

Blood was collected for analysis in a muticenter, cross-sectional study of RA patients who had been receiving MTX for at least 1 month prior to enrollment, and side effects occurring at the time of a single study visit were recorded. Low-penetrance risk genotypes in methylenetetrahydrofolate reductase (MTHFR) 677TT, thymidylate synthase (TSER) *2/*2 (variable number of tandem repeats), amino imidazole ribonucleotide transformylase (ATIC) 347GG, and serine hydroxymethyltransferase (SHMT1) 1420CC were measured and summed to constitute the toxicogenetic index specific to each patient. Statistical analyses consisted of logistic regression models with clustered-center effects, and associations with risk genotypes were expressed as adjusted odds ratios (ORs).

RESULTS

Among 214 patients enrolled at 4 study sites, a total of 67 patients (31%) presented with a side effect (gastrointestinal event, headache, lethargy, alopecia, cough, or dyspnea). Risk genotypes associated with side effects in the central nervous system were MTHFR 677TT (OR 3.3, P < 0.01) and SHMT1 1420CC (OR 2.4, P < 0.05). ATIC 347GG was associated with gastrointestinal side effects (OR 3.0, P < 0.01), while TSER*2/*2 (OR 5.4, P < 0.01) and SHMT1 1420CC (OR 3.2, P < 0.01) were associated with alopecia. The toxicogenetic index ranged from 0 to 3 (median 1). An index of 3 was associated with an approximately 7-fold higher likelihood of having a side effect compared with an index of 0 (P < 0.01).

CONCLUSION

These data suggest that a composite index of the cumulative risk genotypes in folate-dependent enzymes may be an effective means of profiling RA patients who develop side effects to MTX.

摘要

目的

甲氨蝶呤（MTX）是一种抗叶酸剂，常伴有毒性。本研究调查了叶酸依赖性酶的风险基因型是否与类风湿关节炎（RA）患者中MTX的毒性相关。

方法

在一项多中心横断面研究中，收集了在入组前至少接受MTX治疗1个月的RA患者的血液进行分析，并记录在单次研究访视时出现的副作用。检测亚甲基四氢叶酸还原酶（MTHFR）677TT、胸苷酸合成酶（TSER）*2/*2（串联重复可变数目）、氨基咪唑核糖核苷酸转甲酰酶（ATIC）347GG和丝氨酸羟甲基转移酶（SHMT1）1420CC中的低 penetrance风险基因型，并将其相加构成每个患者的毒理遗传学指数。统计分析包括具有聚类中心效应的逻辑回归模型，与风险基因型的关联以调整后的比值比（OR）表示。

结果

在4个研究地点入组的214例患者中，共有67例患者（31%）出现了副作用（胃肠道事件、头痛、嗜睡、脱发、咳嗽或呼吸困难）。与中枢神经系统副作用相关的风险基因型为MTHFR 677TT（OR 3.3，P < 0.01）和SHMT1 1420CC（OR 2.4，P < 0.05）。ATIC 347GG与胃肠道副作用相关（OR 3.0，P < 0.01），而TSER*2/*2（OR 5.4，P < 0.01）和SHMT1 1420CC（OR 3.2，P < 0.01）与脱发相关。毒理遗传学指数范围为0至3（中位数为1）。指数为3时出现副作用的可能性比指数为0时高约7倍（P < 0.01）。