Byun Ja Min, Kim Hea-Lim, Shin Dong-Yeop, Koh Youngil, Yoon Sung-Soo, Seong Moon-Woo, Park Sung Sup, Kim Jin Hee, Lee Yun-Gyoo, Kim Inho
Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
Graduate School of Public Health, Seoul National University, Seoul, Korea.
PLoS One. 2016 Oct 26;11(10):e0163998. doi: 10.1371/journal.pone.0163998. eCollection 2016.
Pharmacogenomics can explain the inter-individual differences in response to drugs, including methotrexate (MTX) used for acute graft-versus-host disease (aGVHD) prophylaxis during hematopoietic stem cell transplantation (HSCT). In real-world practice, preplanned MTX dose is arbitrarily modified according to observed toxicity which can lead to unexpected and severe aGVHD development. We aimed to validate the influence of MTHFR C677T polymorphism on the outcomes of allogenic HSCT in a relatively under-represented homogenous Asian population. A total of 177 patients were divided into 677TT group versus 677C-carriers (677CT+677CC), and clinical outcomes along with baseline characteristics were analyzed and compared. Although there was a tendency towards increased peak liver function test results and accordingly greater delta values between the highest and the baseline in 677TT group, we found no associations between genotypes and hepatotoxicity. However, the incidence of acute liver GVHD (≥ grade 2) was significantly higher in the 677TT group than in the 677CC + 677CT group (P = 0.016). A total of 25 patients (14.1%) expired due to transplantation related mortality (TRM) during the first 180 days after HSCT. Patients carrying 677TT genotype were more likely to experience early TRM than 677C-carriers. The same pattern was observed in the cumulative TRM rate, and 677TT genotype patients were more prone to cumulative TRM (P = 0.010). This translated into shorter OS for patients with 677TT compared to 677C-carriers (P = 0.010). The 3-year survival after HSCT was 29.9% for 677TT cases and 47.1% for 677C-carriers. The multivariate analysis identified 677TT genotype (HR = 1.775. 95% CI 1.122-2.808, P = 0.014) and non-CR state (HR = 2.841. 95% CI 1.627-4.960, P<0.001) as predictors for survival. In conclusion, the MTHFR 677TT genotype appears to be associated with acute liver GVHD, and represent a risk factor for TRM and survival in patients undergoing HSCT with MTX as GVHD prophylaxis.
药物基因组学可以解释个体对药物反应的差异，包括用于造血干细胞移植（HSCT）期间预防急性移植物抗宿主病（aGVHD）的甲氨蝶呤（MTX）。在实际临床实践中，预先计划的MTX剂量会根据观察到的毒性进行随意调整，这可能导致意外且严重的aGVHD发生。我们旨在验证亚甲基四氢叶酸还原酶（MTHFR）C677T基因多态性对相对代表性不足的同质亚洲人群同种异体HSCT结局的影响。总共177例患者被分为677TT组和677C携带者组（677CT + 677CC），并对临床结局和基线特征进行了分析和比较。尽管677TT组肝功能检查峰值结果有升高趋势，因此最高值与基线之间的差值更大，但我们发现基因型与肝毒性之间无关联。然而，677TT组急性肝GVHD（≥2级）的发生率显著高于677CC + 677CT组（P = 0.016）。共有25例患者（14.1%）在HSCT后的前180天内死于移植相关死亡率（TRM）。携带677TT基因型的患者比677C携带者更易发生早期TRM。累积TRM率也观察到相同模式，677TT基因型患者更易发生累积TRM（P = 0.010）。这意味着与677C携带者相比，677TT患者的总生存期更短（P = 0.010）。677TT病例HSCT后的3年生存率为29.9%，677C携带者为47.1%。多变量分析确定677TT基因型（风险比[HR] = 1.775，95%置信区间[CI] 1.122 - 2.808，P = 0.014）和非完全缓解（CR）状态（HR = 2.841，95% CI 1.627 - 4.960，P<0.001）为生存的预测因素。总之，MTHFR 677TT基因型似乎与急性肝GVHD相关，并且是接受MTX预防GVHD的HSCT患者TRM和生存的危险因素。
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