Correlation between DDAH1 Gene 836A/T Polymorphism and Type 2 Diabetic Kidney Disease in Yunnan Han Population
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摘要:
目的 探讨DDAH1基因836A/T多态性与云南地区汉族人群2型糖尿病肾脏疾病发生的相关性。 方法 选取T2DM患者共660例，根据UACR检测结果，将患者分为3组：单纯2型糖尿病组（DN0组），合并早期肾病组（DN1组），合并临床期肾病组（DN2组）。 健康人群（NC组）304例。采用PCR-DNA测序技术对DDAH1基因836A/T多态性进行基因分型，ELISA 法检测血浆非对称性二甲基精氨酸（ADMA）浓度。 结果 DDAH1基因836位点AA基因型在DN1 + DN2组的分布频率高于DN0组 （P < 0.05）。A等位基因在DN1 + DN2组的分布频率高于DN0组 （P < 0.05）。T2DM患者中AA基因型携带者较AT+TT基因型个体具有更高的ADMA水平。ADMA水平在DN1 + DN2组高于DN0组（P < 0.05）。通过相关危险因素分析发现， 在T2DM患者中ADMA水平、DDAH1基因836位点AA基因型是发生DKD的危险因素。 结论 DDAH1基因836位点AA基因型可能是云南地区汉族T2DM 患者发生DKD的危险因素，AA基因型携带者ADMA水平升高。 Abstract:objective To investigate the association between DDAH1 gene 836A/T polymorphism and type 2 diabetic kidney disease （DKD） in Yunnan Han population. Methods A total of 660 patients with T2DM were included. Patients were divided into three groups based on UACR results: simple type 2 diabetes mellitus group （DN0 group）, complicated with early nephropathy group （DN1 group）, and complicated with clinical nephropathy group （DN2 group）. A total of 304 healthy people were included as normal control group （NC group）. The genotype of DDAH1 gene 836A/T polymorphism was determined by PCR-DNA sequencing. The plasma asymmetric dimethylarginine （ADMA）concentration was measured by ELISA. Results The distribution frequency of AA genotype and allele A at the 836 locus of DDAH1 gene in the DN1+DN2 group was significantly higher than those in the DN0 group （P < 0.05）. AA genotype carriers have higher ADMA levels than AT+TT genotype individuals in T2DM patients. The level of ADMA in DN1+DN2 group was higher than that in DN0 group （P < 0.05）. Logistic regression analysis showed that ADMA level and DDAH1 gene 836 AA genotype were risk factors for DKD in T2DM patients. Conclusions The DDAH1 gene 836 AA genotype may be a risk factor for diabetic kidney disease in T2DM patients of Han nationality in Yunnan Province, and patients with this genotype have higher ADMA levels. -
Key words:
- Type 2 diabetes mellitus /
- diabetic kidney disease /
- DDAH1 /
- ADMA /
- Genetic polymorphism
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表 1 PCR引物序列
Table 1. PCR primer sequences
基因多态性位点 上游引物序列 下游引物序列 DDAH1基因836A/T 5′- TGGTCTCCTCTGCCTCTGAC -3′ 5′-GGTGATCGCTTCCTGAACAT-3′ 
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表 2 各组间临床资料比较（
$\bar x \pm s $ ）Table 2. Comparison of clinical data of each group （
$\bar x \pm s $ ）指标 NC DN0 DN1 DN2 DN1+DN2 F P 年龄（岁） 54.62 ± 10.58 54.64 ± 10.73 55.75 ± 10.42 57.28 ± 11.67 56.36 ± 11.36 2.758 0.13 病程（月） − 72.13 ± 25.09 92.23 ± 43.62△ 109.18 ± 45.69△▲ 100.24 ± 51.46△▲ 9.364 < 0.001 收缩压（mmHg） 117.59 ± 13.26 122.64 ± 16.72 133.52 ± 18.54*△ 142.65 ± 21.17*△#▲ 138.83 ± 19.82*△ 11.5 < 0.001 舒张压（mmHg） 77.15 ± 7.63 78.25 ± 10.02 82.42 ± 11.54 81.76 ± 12.22 82.05 ± 12.09 0.831 0.598 血肌酐（mmol/L） 63.2 ± 18.55 65.7 ± 18.25 69.43 ± 19.43* 79.17 ± 24.64*△# 73.76 ± 26.78* 15.684 < 0.001 尿酸（mmol/L） 337.36 ± 87.62 337.89 ± 86.72 335.58 ± 104.05 354.32 ± 102.91*△# 346.62 ± 103.42 7.275 < 0.001 TC（mmol/L） 4.39 ± 1.07 4.38 ± 1.25 4.51 ± 1.34 4.43 ± 1.27 4.49 ± 1.33 1.26 0.289 TG （mmol/L） 1.25 ± 0.98 2.63 ± 1.42* 2.67 ± 1.78* 2.31 ± 1.45* 2.52 ± 1.79* 10.24 < 0.001 HLD（mmol/L） 1.29 ± 0.34 1.03 ± 0.35 1.01 ± 0.29 0.98 ± 0.75 1.00 ± 0.31 0.75 0.52 LDL （mmol/L） 2.52 ± 1.22 2.58 ± 1.52 2.83 ± 2.14*△ 2.79 ± 1.86*△ 2.82 ± 1.75*△ 5.19 0.002 HbA1C （%） 6.17 ± 2.25 8.50 ± 2.12* 8.57 ± 2.06* 8.66 ± 2.63* 8.61 ± 2.05* 11.04 < 0.001 ADMA （μmol/L） 0.62 ± 0.23 1.06 ± 0.27* 1.23 ± 0.42*△ 1.29 ± 0.53*△ 1.27 ± 0.41*△▲ 12.424 < 0.001 与NC组比较，* P < 0.05；与DN0组比较，△P < 0.05；与DN1组比较，#P < 0.05；协方差分析，▲P < 0.05。
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表 3 各组间基因型频率和等位基因频率[n（%）]（1）
Table 3. The genotype and allele frequencies in each group [n（%）]（1）
组别 n 基因型 χ2 P AA AT+TT NC组 304 128（42.1） 176（57.9） 11.863 0.013 DN0组 296 146（49.6）* 150（50.4） DN1组 190 112（58.9）* 78（41.1） DN2组 174 98（56.3）*# 76（43.7） DN1+DN2组 364 210（57.7）*# 154（42.3） 与NC组比较，*P < 0.05；与DN0组比较，#P < 0.05。
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表 3 各组间基因型频率和等位基因频率[n（%）]（2）
Table 3. The genotype and allele frequencies in each group [n（%）]（2）
组别 n 等位基因 χ2 P A T NC组 304 398 （65.5） 210（34.5） 19.318 0.001 DN0组 296 416（70.3）* 176（29.7） DN1组 190 290（76.3）* 90（23.7） DN2组 174 262（75.3）*# 86（24.7） DN1+DN2组 364 552（75.8）*# 176（24.2） 与NC组比较，*P < 0.05；与DN0组比较，#P < 0.05。
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表 4 T2DM患者中不同基因型间临床资料比较（
$\bar x \pm s $ ）（1）Table 4. Comparison of clinical data of DDAH1 genotype of T2DM patients （
$\bar x \pm s $ ）（1）基因型 收缩压（mmHg） 舒张压（mmHg） 血肌酐（mmol/L） 尿酸（mmol/L） TC（mmol/L） AA 130.26 ± 17.43 79.53 ± 9.76 74.62 ± 23.64 344.41 ± 103.42 4.48 ± 1.04 AT+TT 129.82 ± 17.84 78.05 ± 10.62 72.58 ± 21.93 338.51 ± 91.45 4.38 ± 126
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表 4 T2DM患者中不同基因型间临床资料比较（
$\bar x \pm s $ ）（2）Table 4. Comparison of clinical data of DDAH1 genotype of T2DM patients （
$\bar x \pm s $ ）（2）基因型 收缩压（mmHg） 舒张压（mmHg） 血肌酐（mmol/L） 尿酸（mmol/L） TC（mmol/L） AA 2.50 ± 1.42 1.06 ± 0.27 2.92 ± 1.68 9.12 ± 2.21 1.39 ± 0.34 AT+TT 2.57 ± 1.82 1.01 ± 0.33 2.85 ± 1.74 8.71 ± 2.08 1.09 ± 0.27 * 2组间比较，*P < 0.05。
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表 5 T2DM-DKD发生的危险因素的Logistic分析
Table 5. Logistic regression analysis of T2DM-DKD occurence
进入回归方程的变量 B S.E. Wald P OR OR值的95%CI 下限 上限 病程（月）） 0.821 0.476 5.365 0.021 1.103 1.152 3.275 ADMA（μmol/L） 1.374 0.602 5.473 0.029 3.973 1.228 10.876 AA基因型 1.538 0.452 10.384 0.001 4.421 1.734 9.326
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表 6 T2DM-DKD发展的危险因素的Logistic分析
Table 6. Logistic regression analysis of T2DM-DKD development
进入回归方程的变量 B S.E. Wald P OR OR值的95%CI 下限 上限 病程（月） 0.862 0.368 11.178 0.001 2.410 1.476 4.632 SBP（mmHg） 1.423 0.574 6.692 0.023 4.335 1.431 12.795
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