Effect of the MTHFR C677T and A1298C Polymorphisms on Survival in Patients With Advanced CKD and ESRD: A Prospective Study
Effect of the MTHFR C677T and A1298C Polymorphisms on Survival in Patients With Advanced CKD and ESRD: A Prospective Study
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DOI：
10.1053/j.ajkd.2008.12.023
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发表时间：
2009-05-01
影响因子：
13.2
通讯作者：
Lavori, Philip
中科院分区：
文献类型：
--
作者：
Jamison, Rex L.;Shih, Mei-Chiung;Lavori, Philip
背景资料：亚甲基四氢叶酸还原酶（MTHFR）基因的缺失与正常和慢性肾脏病（CKD）人群中同型半胱氨酸水平的升高和死亡率的增加有关。研究设计：基因关联研究。这是一项来自21个退伍军人事务医疗中心的677名患者参与的随机临床试验的子研究（肾和终末期肾病[HOST]中的同型半胱氨酸血症）维生素诱导的血浆同型半胱氨酸水平降低对全因死亡率的影响。在677例患者中，213例（31%）接受了透析治疗（终末期肾病[ESRD]），464例（69%）Cockcroft-Gault估计肌酐清除率低于30 mL/min（晚期CKD）。预测因子：多态性C677 T（rs 1801133）和A1298 C（rs 1801131）的MTHFR基因。结果：未校正和校正的全因死亡率。测量：从血液样品中提取DNA并通过聚合酶链反应扩增。结果：在所有患者中，C677 T多态性与全因死亡率之间关系的隐性模型中，校正风险比为1.47（95%置信区间，1.00 - 2.16; P = 0.05）。在携带突变TT基因型的ESRD患者中，所有患者死亡率的校正风险比为2.27（95%置信区间，1.07 - 4.84; P = 0.03）;晚期CKD患者显示出相似的趋势，尽管不显著。在核苷酸677处突变T等位基因的ESRD患者中，心肌梗死的风险（P = 0.05）和心肌梗死、卒中、下肢截肢和死亡的复合风险（P = 0.02）更高。A1298 C多态性与死亡率之间的总体关系并不显著（P = 0.6）。局限性：98%的参与者为男性; DNA样本在入组HOST时未获得;与另一种因果多态性的连锁不平衡是一个潜在的混杂因素;并且由于参与者人数有限，功效降低。这些发现为以下假设提供了额外的支持，即MTHFR活性调节基因的核苷酸677处的突变TT基因型可能增加ESRD患者的死亡风险。美国肾脏病杂志53：779-789。由Elsevier Inc代表National Kidney Foundation，Inc.发布。这是美国政府的工作。其使用没有限制。
Background: Abnormalities in the gene regulating methylenetetrahydrofolate reductase (MTHFR) are associated with increased homocysteine levels and increased mortality in normal and chronic kidney disease (CKD) populations.Study Design: Gene association study.Setting & Participants: This was a substudy of 677 patients from 21 Veterans Affairs medical centers participating in a randomized clinical trial (Homocysteinemia in Kidney and End-Stage Renal Disease [HOST]) of the effect on all-cause mortality of vitamin-induced lowering of plasma homocysteine levels. Of 677 patients, 213 (31%) were treated by using dialysis (end-stage renal disease [ESRD]) and 464 (69%) had a Cockcroft-Gault estimated creatinine clearance less than 30 mL/min (advanced CKD).Predictor: Polymorphisms C677T (rs1801133) and A1298C (rs1801131) of the MTHFR gene.Outcomes: Unadjusted and adjusted all-cause mortality.Measurements: DNA was extracted from blood samples and amplified by means of polymerase chain reaction.Results: The adjusted hazard ratio in a recessive model of the relationship between the C677T polymorphism and all-cause mortality in all patients was 1.47 (95% confidence interval, 1.00 to 2.16; P = 0.05). In patients with ESRD with the mutant TT genotype, the adjusted hazard ratio for mortality in all patients was 2.27 (95% confidence interval, 1.07 to 4.84; P = 0.03); patients with advanced CKD showed a similar, although not significant, trend. The risk of myocardial infarction (P = 0.05) and composite risk of myocardial infarction, stroke, lower-extremity amputation, and mortality (P = 0.02) were greater in patients with ESRD with the mutant T allele at nucleotide 677. The overall relationship between the A1298C polymorphism and mortality was not significant (P = 0.6).Limitations: Participants were 98% men; DNA samples were not obtained at enrollment in HOST; linkage disequilibrium with another causal polymorphism is a potential confounding factor; and power was reduced by the limited number of participants.Conclusions: These findings provide additional support for the hypothesis that the mutant TT genotype at nucleotide 677 of the gene regulating MTHFR activity may increase the mortality risk in patients with ESRD. Am J Kidney Dis 53:779-789. Published by Elsevier Inc on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use.