The Interaction among Gene Polymorphisms of RANTES and Its Receptor CCR5 and Environmental Factors in the Development of T2DM in Kunming Han Nationality
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摘要:
目的 探讨RANTES基因启动子区rs2280788位点、CCR5基因启动子区rs1799987位点多态性及环境因素在昆明地区汉族2型糖尿病（Type 2 diabetes mellitus, T2DM）的发生中是否存在交互作用。 方法 收集92例昆明地区汉族血糖正常者和97例T2DM患者的一般资料及外周静脉血，采用Taqman实时荧光定量PCR检测RANTES基因 rs2280788位点及其受体CCR5基因rs1799987位点的多态性，运用多因子降维法（multifactor dimensionality reduction, MDR）分析RANTES及其受体基因多态性与环境因素在昆明地区汉族T2DM的发生中是否存在交互作用。 结果 CCR5 rs1799987与RANTES rs2280788间存在交互作用（测试组平衡精度为0.5314，训练组平衡精度为0.5820，交叉验证一致性为10/10，P < 0.05，OR：2.0465，95%CI：1.1118～3.7672）；高血压与中心性肥胖间存在交互作用（测试组平衡精度为0.7031，训练组平衡精度为0.7031，交叉验证一致性为10/10，P < 0.001，OR：8.1640，95%CI：3.8745～17.2026）；未发现CCR5 rs1799987与环境因素、RANTES rs2280788与环境因素间存在交互作用（P > 0.05）。 结论 RANTES基因启动子区-28（rs2280788）与CCR5基因启动子区59029（rs1799987）SNP位点之间、高血压与中心性肥胖之间均存在交互作用，具有交互作用的因素同时存在会增加昆明地区汉族T2DM的患病风险。 Abstract:Objective To investigate the interaction among RANTES gene promoter region rs2280788 C/G polymorphism, CCR5 gene promoter region rs1799987 G/A polymorphism and environmental factors in the development of Type 2 diabetes mellitus （T2DM） in the Han ethnic group in Kunming. Methods The general data and peripheral venous blood of 92 Han people with normal blood glucose and 97 Han T2DM patients in Kunming area were collected. Polymorphisms of RANTES gene rs2280788 and CCR5 gene rs1799987 were detected by TaqMan real-time quantitative PCR. Multifactor dimensionality reduction （MDR） was used to analyze the interaction among the gene polymorphisms of RANTES and its receptor and environmental factors in the occurrence of T2DM in Han nationality in Kunming. Results There was an interaction between CCR5 rs1799987 and RANTES rs2280788 （the testing balance accuracy was 0.5314, the training balance accuracy was 0.5820, and the cross validation consistency was 10/10, P < 0.05, OR: 2.0465, 95%CI: 1.1118-3.7672）; There was an interaction between hypertension and central obesity （the testing balance accuracy was 0.7031, the training balance accuracy was 0.7031, the cross validation consistency was 10/10, P < 0.001, OR: 8.1640, 95%CI: 3.8745-17.2026）; No interaction between CCR5 rs1799987 and environmental factors, as well as RANTES rs2280788 and environmental factors was found （P > 0.05）. Conclusions There are interactions between the RANTES gene promoter region -28 （rs2280788） and the CCR5 gene promoter region 59029 （rs1799987） SNP, as well as between hypertension and central obesity, the co-existence of interacting factors will increase the risk of T2DM in Han nationality in Kunming. -
Key words:
- RANTES /
- CCR5 /
- Gene polymorphism /
- Type 2 diabetes /
- Interaction
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图 1 RANTES rs2280788及CCR5 rs1799987基因型分型
注：图A-C分别为CCR5基因rs1799987 AA基因型、CCR5基因rs1799987 GG基因型、CCR5基因rs1799987 AG基因型的PCR产物熔解曲线；图D-F分别为RANTES基因rs2280788 CC基因型、RANTES基因rs2280788 GG基因型、RANTES基因rs2280788 CG基因型的PCR产物熔解曲线。
Figure 1. Genotyping of RANTES rs2280788 and CCR5 rs1799987
图 2 CCR5 rs1799987 -RANTES rs2280788两因素交互模型单元格图
Figure 2. CCR5 rs1799987-RANTES rs2280788 Two-factor interactive model cell diagram
图 3 高血压-中心性肥胖两因素交互模型单元格图
Figure 3. Hypertension-central obesity Two-factor interactive model cell diagram
表 1 研究对象的基线资料比较 （
$\bar x \pm s$ ）Table 1. Comparison of baseline data of the subjects （
$ \bar x \pm s$ ）特征 NC组
（n = 92）DM组
（n = 97）t/Z/χ2 P 年龄（岁） 46.22 ± 11.77 49.53 ± 12.52 −1.87 0.063 性别[n（%）] 女性 49（53.30） 40（41.20） 2.74 0.098 男性 43（46.70） 57（58.80） FPG （mmol/L） 5.03 ± 0.69 8.38 ± 2.95* −10.892 < 0.001 HbA1c （%） 5.58 ± 0.39 9.20 ± 2.21* −15.915 < 0.001 腰围 （cm） 83.83 ± 11.84 90.79 ± 10.09* −4.359 < 0.001 BMI （kg/m2） 24.02 ± 3.73 25.17 ± 3.85* −2.086 0.038 收缩压 （mmHg） 119.68 ± 16.92 130.65 ± 19.35* −4.138 < 0.001 舒张压 （mmHg） 79.38 ± 9.94 77.82 ± 11.44 0.996 0.321 TC （mmol/L） 4.99 ± 0.88 4.47 ± 1.13* 3.49 0.001 HDL （mmol/L） 1.34（1.11,1.64） 1.00（0.85,1.17） * −6.411 < 0.001 TG （mmol/L） 1.25（0.90,1.99） 1.61（1.07,2.31） * −2.148 0.032 LDL （mmol/L） 2.88（2.50,3.66） 3.08（2.32,3.45） −0.16 0.873 与NC组比较，*P < 0.05。 
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表 2 DM组和NC组的CCR5 rs1799987及RANTES rs2280788基因型及等位基因频率 [n（%）]
Table 2. Genotypes and allele frequencies of CCR5 rs1799987 and RANTES rs2280788 in DM and NC groups [n（%）]
组别 基因型频率 等位基因频率 CCR5 rs1799987 AA AG GG A G NC组 19（20.70） 49（53.30） 24（26.10） 87（47.28） 97（52.72） DM组 18（18.60） 47（48.50） 32（33.00） 83（42.78） 111（57.22） RANTES rs2280788 CC + CG GG − C G NC组 20（21.70） 72（78.30） − 22（11.96） 162（88.04） DM组 23（23.70） 74（76.30） − 24（12.37） 170（87.63） 注：因RANTES rs2280788CC基因型仅3例，RANTES rs2280788 CG基因型40例，因此将这两个基因型合并到RANTES rs2280788 CC + CG组一起分析。
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表 3 基因-基因交互作用的多因子降维法模型
Table 3. MDR models of gene-gene interactions
模型 训练组平衡精度 测试组平衡精度 交叉验证一致性 P值 OR 95%CI X1 0.5371 0.4338 7/10 0.2989 1.3949 0.7436～2.6166 X1、X2 0.5820 0.5314 10/10 0.0205 2.0465 1.1118～3.7672 X1：CCR5 rs1799987基因型；X2：RANTES rs2280788基因型。
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表 4 MDR软件中各变量赋值情况
Table 4. Variable assignment in MDR
变量 赋值 CCR5 rs1799987基因型 1 = AA，2 = AG，3 = GG RANTES rs2280788基因型 1 = CC，2 = CG，3 = GG 吸烟 0 = 否，1 = 是 饮酒 0 = 否，1 = 是 高血压 0 = 否，1 = 是 BMI 0 = < 18.5，1 = 18.5-23.9，2 = ≥ 24.0 中心性肥胖 0 = 否，1 = 是 血脂 0 = 血脂正常，1 = 血脂异常
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表 5 基因与环境因素交互作用的多因子降维法模型
Table 5. MDR models of the interaction of genes and environmental factors
模型 训练组平衡精度 测试组平衡精度 交叉验证一致性 P OR 95%CI X1 0.6748 0.6748 10/10 < 0.001 4.7143 2.4914-8.9206 X1、X2 0.7031 0.7031 10/10 < 0.001 8.1640 3.8745-17.2026 X1、X2、X3 0.7333 0.6691 6/10 < 0.001 9.5000 4.5822-19.6956 注：X1：高血压，X2：中心性肥胖；X3：饮酒。
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