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中华肾病研究电子杂志

中华肾病研究电子杂志 ›› 2019, Vol. 08 ›› Issue (03) : 109 -113. doi: 10.3877/cma.j.issn.2095-3216.2019.03.003

所属专题： 文献；

论著

环磷酰胺代谢酶基因多态性与中国汉族难治性狼疮肾炎的相关性
周君1,†(), 杨侦1   
  1. 1. 570208　海口，中南大学湘雅医学院附属海口医院肾病风湿科
  • 收稿日期:2018-05-11 出版日期:2019-06-28
  • 通信作者: 周君
  • 基金资助:
    海口市重点科技项目(2015-32)

Association between gene polymorphism of cyclophosphamide-metabolizing enzyme and refractory lupus nephritis in Chinese Han people

Jun Zhou1,†(), Zhen Yang1   

  1. 1. Department of Nephrology and Rheumatology, Haikou People′s Hospital Affiliated to Xiangya School of Medicine of Central South University, Haikou 570208, Hainan Province, China
  • Received:2018-05-11 Published:2019-06-28
  • Corresponding author: Jun Zhou
  • About author:
    Corresponding author: Zhou Jun, Email:
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引用本文：

周君, 杨侦. 环磷酰胺代谢酶基因多态性与中国汉族难治性狼疮肾炎的相关性[J]. 中华肾病研究电子杂志, 2019, 08(03): 109-113.

Jun Zhou, Zhen Yang. Association between gene polymorphism of cyclophosphamide-metabolizing enzyme and refractory lupus nephritis in Chinese Han people[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2019, 08(03): 109-113.

目的

探讨中国汉族难治性狼疮肾炎(LN)和环磷酰胺(CTX)代谢酶基因多态性的相关性。

方法

对2012年1月至2015年12月在海口市人民医院初发系统性红斑狼疮(SLE)的132例患者进行分析，其中LN组88例，非LN组44例；LN组中难治性LN 46例，非难治性LN 42例。比较各组临床指标差异。采用PCR-RELP检测CTX代谢酶基因，采用单因素方差分析CYP2C19*2、CYP2C19*3、CYP2B6*4、CYP2C9*3和CYP3A5与LN及难治性LN、非难治性LN的相关性。

结果

(1)CYP2C19*2、CYP2C19*3、CYP2B6*4和CYP3A5频率分布符合Hardy-Weinberg平衡分布；(2)LN组较非LN组，血肌酐(Scr)(t＝2.68，P＝0.008)和SLEDAI明显升高(t＝4.07，P≤0.001)，血红蛋白(Hb)(t＝－2.368，P＝0.019)和血白蛋白(ALB)(t＝－4.514，P＝0.000)明显降低，差异具有统计学意义；(3)单因素方差分析显示LN组CYP2C19*3 GC携带者与CC、GG携带者比较血尿素氮(BUN)显著升高[(13.3±13.02)mmol/L与(6.57±5.22)mmol/L与(7.08±6.11) mmol/L，F＝5.770，P＝0.004]；难治性LN组中，GC携带者较CC、GG携带者Scr显著升高：[(436.22±286.38)μmol/L与(161.7±144.33)μmol/L与(66±19.02)μmol/L, F＝8.411, P＝0.001]差异均有统计学意义；(4) CYP3A5*3 GG携带者肾脏受累明显增多(χ2＝6.991，P＝0.03)；在难治性LN组中CYP3A5*3 GG基因型Scr较高(F＝0.213，P＝0.81)但差异无统计学意义。

结论

CTX代谢酶CYP2C19*3基因多态性对中国汉族难治性LN的疗效可能有影响，GC携带者疗效更差；CYP3A5*3 GG基因型携带者的肾脏受累更多见。

关键词: 环磷酰胺代谢酶, 基因多态性, 系统性红斑狼疮, 狼疮肾炎
Objective

To investigate the association between Chinese Han refractory lupus nephritis (LN) and cyclophosphamide-metabolizing enzyme gene polymorphism.

Methods

From January 2012 to December 2015 in Haikou People′s Hospital, 132 patients with initial SLE were analyzed, including 88 patients in the LN group, and 44 patients in the non-LN group. In the LN group, 46 patients had refractory LN, and 42 patients had non-refractory LN. The CTX metabolic enzyme gene was detected by PCR-RELP method, and the correlation of CYP2C19*2, CYP2C19*3, CYP2B6*4, CYP2C9*3, and CYP3A5 with LN, refractory LN, and non-refractory LN was analyzed by one-way analysis of variance.

Results

(1) The frequency distribution of CYP2C19*2, CYP2C19*3, CYP2B6*4, and CYP3A5 accorded with the Hardy-Weinberg equilibrium distribution; (2) Compared with the non-LN group, the LN group had significantly higher levels of serum creatinine (Scr) (t=2.68, P=0.008) and SLEDAI (t=4.07, P≤0.001), but had significantly lower levels of hemoglobin (Hb) (t=-2.368, P=0.019) and serum albumin (ALB) (t=-4.514, P=0.000); (3) One-way analysis of variance showed that the CYP2C19*3 GC carriers in the LN group had significantly higher level of blood urea nitrogen (BUN) compared with those CC and GG carriers [(13.3±13.02) mmol/L and (6.57±5.22) mmol/L and (7.08±6.11) mmol/L, F=5.770, P=0.004]. In the refractory LN group, GC carriers had significantly higher levels of Scr than those CC and GG carriers [(436.22±286.38) μmol/L, (161.7±144.33) μmol/L, (66±19.02)μmol/L, F=8.411, P=0.001]; (4) CYP3A5*3 GG carriers had significantly-increased renal involvement (χ2=6.991, P=0.03). In the refractory LN group, patients with the CYP3A5*3 GG genotype had higher level of Scr (F=0.213, P=0.81), but the difference was not statistically significant.

Conclusion

The CYP2C19*3 gene polymorphism of the cyclophosphamide-metabolizing enzyme might have an influence on the treatment efficacy in the the Chinese Han patients with refractory LN, with the GC carriers having less treatment efficacy, and the kidney involvement being more common in the CYP3A5*3 GG genotype carriers.

Key words: Cyclophosphamide-metabolizing enzyme, Gene polymorphism, Systemic lupus erythematosus, Lupus nephritis
表1 各基因型引物序列
基因SNP位点 引物序列5′-3′
CYP2B6*4 A/G F：GGCACACAGGCAAGTTTACA
R: GACCCCACTTTTTCCATGTG
CYP2C19*2A/G F: CAGAGCTTGGCATATTGTATC
R：GTAAACACAACTAGTCAATG
CYP2C19*3G/A F: TTCATCCTGGGCTGTGCT
R：TGGTTTCTCAGGAAGCAAAAA
CYP3A5 *3C/T F: ATGGAGAGTGGCATAGGAGATA
R: TGTGGTCCAAACAGGGAAGAGAT
CYP2C9*3A/C F：AGGAAGAGATTGAACGTGTGA
R：GGCAGGCTGGTGGGGAGAAGGCCAA
表2 SLE合并狼疮肾炎组与非狼疮肾炎组患者的一般情况和实验室指标比较(±s)
组别 例数 性别[女性，例(%)] 年龄(岁) Hb(g/L) Scr (μmol/L) ALB(g/L) IgG (g/L) 补体C3(mmol/L) SLEDAI
LN组 88 74(84) 34.65±13.64 95.90±26.25 171.69±243.78 25.51±8.38 18.71±16.73 0.84±0.28 12.51±6.88
非LN 44 41(93.2) 35.89±13.02 107.27±25.54 72.86±18.59 31.94±6.14 24.38±34.34 0.90±0.27 7.25±7.24
t值 ? －1.471 －0.499 －2.368 2.68 －4.514 －1.243 －1.161 4.07
P值 ? 0.144 0.618 0.019 0.008 <0.001 0.216 0.248 <0.001
表3 132例SLE患者各基因频率、基因分型和Hardy-Weinberg平衡试验
基因型 等位基因/频率 等位基因/频率 基因型/频数 基因型/频数 基因型/频数 χ2值 P值
CYP2C19*3G/C G/0.899 C/0.101 GG/106 GC/22 CC/4 1.224 0.542
CYP2C19*2A/G A/0.269 G/0.731 AA/15 AG/44 GG/73 1.352 0.509
CYP3A5*3 G/A G/0.708 C/0.292 GG/69 GA/47 AA/16 1.375 0.503
CYP2B6*4 A/G A/0.647 G/0.353 AA/56 AG/58 GG/18 0.083 0.959
表4 46例难治性LN病理类型与人口资料、生化指标、SLEDAI的相关性(±s)
病理类型(型) 例数 年龄(岁) Hb(g/L) Scr(μmol/L) ALB(g/L) IgG(g/L) C3(mmol/L) 24 h尿蛋白(g) SLEDAI
Ⅲ 5 40.00±8.72 99.20±12.68 96.60±30.45 29.99±4.45 25.63±26.30 0.92±0.29 0.38±0.15 8.00±3.74
Ⅲ＋Ⅳ 3 32.52±12.68 96.48±30.80 209.72±359.30 27.29±8.49 13.25±7.90 0.90±0.32 1.70±1.60 12.76±9.53
Ⅳ 25 31.60±12.24 108.40±29.41 323.80±303.86 23.65±10.11 10.71±8.58 0.79±0.19 1.63±0.39 8.80±4.76
Ⅳ＋Ⅴ 8 26.67±4.73 96.33±13.61 139.00±67.98 20.63±9.67 11.59±9.14 0.90±0.30 1.79±0.51 12.00±2.00
Ⅴ 5 29.71±13.98 107.00±19.39 133.14±58.40 22.31±10.33 17.90±12.97 0.76±0.15 2.51±2.23 12.43±6.48
F值 ? 0.737 0.291 0.439 1.212 1.194 1.588 1.462 0.539
P值 ? 0.600 0.915 0.818 0.365 0.331 0.187 0.223 0.745
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