抵抗素＋299G/A基因多态性与2型糖尿病并大血管病变的相关性研究
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摘要
目的探讨抵抗素+299G／A基因多态性与中国北方地区汉族人群2型糖尿病并大血管病变的关系，通过Logistic回归分析2型糖尿病及其大血管病变的独立危险因素。
方法实验组198例，按1999年WHO糖尿病诊断标准，随机选取山东大学附属省立医院内分泌科及保健内分泌科2006年4-12月期间临床诊断为2型糖尿病的住院患者，男105例，女93例，年龄59．33±10．92岁，根据有无大血管病变分为两个亚组：A组：单纯2型糖尿病组123例，男68例，女55例，年龄55．2±9．3岁；B组：2型糖尿病并大血管病变组75例，男37例，女38例，年龄60．8±6．7岁。正常对照组98例，男57例，女41例，年龄55．7±9．1岁，来自查体中心健康查体者，排除糖尿病、冠心病、高血压病、脑血管病，且无糖尿病及高血压病家族史。采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测不同组别抵抗素+299G／A基因多态性，体重指数、腰臀比、血压指定由同一人测量，应用全自动生化分析仪测定血清总胆固醇、甘油三酯、低密度脂蛋白-胆固醇、高密度脂蛋白-胆固醇、空腹血糖、纤维蛋白原水平，放免法测定空腹胰岛素水平，计算HOMA-IR。统计学处理使用SPSS 11．5软件完成，计数资料比较用χ~2检验，计量资料比较用t检验，组间计量资料均以均数±标准差(x±s)表示，用logistic回归分析多因素相关性。
结果
1．利用Hardy-Weinberg平衡法检验RSTN+299G／A多态性各基因型(A组χ~2= 0．601，P>0．50；B组χ~2=2．71，P>0．05；对照组χ~2=0．004，P>0．90)，具有群体代表性。对照组与DM合并大血管病变组(B组)的基因型分布及等位基因频率比较均有显著性差异；对照组与单纯糖尿病组(A组)等位基因频率的比较有显著性差异，P值依次为0．038，0．016，0．024。
2．实验组与正常对照组临床资料比较：两组间年龄、性别均匹配，实验组SBP、DBP、FPG、HOMA-IR、Fib、WHR、HbA_1c均高于对照组，差异具有统计学意义(P<0．05)。
3．单纯DM组与DM合并大血管病变组临床资料比较：年龄、SBP、HbA_1c、HOMA-IR、TC、LDL-C、Fib、WHR、糖尿病病程、高血压病程均高于单纯DM亚组，差异具有统计学意义(P<0．05)。
4．在实验组中，RSTN+299G／A多态与WHR，FPG有相关性，G／G基因型亚组WHR高于G／A基因型亚组，G／A亚组FPG值高于A／A组，差异均有统计学意义(P<0．05)，其余临床生化指标在各基因型间无明显相关性(P>0．05)。
5．在对照组中，G／G基因型亚组的BMI显著高于G／A基因型亚组(P=0．042)但与A／A亚组比较无统计学意义(P>0．05)；G／G基因型亚组的FPG显著高于G／A基因型亚组，A／A基因型亚组(P=0．001，P=0．006)，逐步回归分析显示，BMI、LDL-C、Fib是FPG的独立危险因素。
6．在单纯糖尿病组中，G／G基因型亚组的年龄、BMI、DBP、WHR、TG、FPG、HbA_1c、FINS、Fib有高于A／A基因型亚组的趋势，SBP、TC、HDL-C有低于A／A基因型亚组的趋势，但差异均无统计学意义(P>0．05)。
7．在糖尿病合并大血管病变组(B组)内，G／A基因型亚组的FPG显著高于A／A基因型亚组(P<0．05)；逐步回归分析显示，HbA_1c、TG是FPG升高的独立危险因素。
8．以A组和B组为研究对象，有无糖尿病为应变量Y(有=1，无=0)，利用Logistic回归分析显示HOMA-IR、FINS、SBP为糖尿病发生的独立危险因素。又以有无大血管病变为应变量Y(有=1，无=0)，年龄、BMI、SBP、DBP，FPG、HbA_1c、FINS，HOMA-IR、TC、TG、LDL-C，HDL-C、Fib、WHR、糖尿病病程、基因型(GG=0，GA+AA=1)等为自变量，SBP、DBP、LDL-C、家族史进入回归方程，是糖尿病大血管病变形成的独立危险因素。
结论RSTN基因+299G／A多态性与中国北方地区汉族人T2DM的发生有关，携带有A等位基因型者有较低的FPG，BMI水平，A等位基因可能是T2DM的微效保护因素；AA基因型者在糖尿病并大血管病变组中有较低的FPG。Logistic回归显示HOMA-IR、FINS、SBP为糖尿病发生的独立危险因素，SBP、DBP、LDL-C、家族史是糖尿病大血管病变形成的独立危险因素。
Objective: To investigate the correlation of resistin gene +299G/Apolymorphisms with type 2 diabetes mellitus and macroangiopathy in Han Chinese in the north. The independent risk factors of type 2 diabetes mellitus and its macroangiopathy are found by Logistic regression.
Methods: According to WHO 1999 diabetic criteria, 198 type 2 diabeticinpatients were selected ,male 105 cases,female 93 cases,age 59.33±10.92 years, from the medical ward of Endocrine and health care in provincial hospital affiliated to Shandong university during April to December in 2006. They were divided into two groups: group A were 123 cases without macroangiopathy,male 68 cases, female 55 cases, age 55.2±9.3 years;group B were 75 cases with macroangiopathy ,male 37 cases,female 38 cases,age 60.8±6.7 years.The control group was composed of healthy check-up outpatients ,male 57 cases,female 41 cases,age 55.7±9.1 years,without diabetes mellitus, cornary heart disease, hypertension, brain vascular disease, family history of diabetes mellitus or hypertension. The genotypes of +299G/A variant in resistin gene were determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.Meanwhile body mass index (BMI), waist-to-hip ratio(WHR), systolic blood pressure(SBP) and diastolic blood pressure(DBP) were measured by the same one appointed. Serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), fasting blood glucose (FPG) and fibrinogen (Fib) were measured using an autoanalyzer. Fasting insulin (FINS) were measured by radionimmunoassay (RIA).Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as (FINS×FPG)/22.5. All statistical tests were carried out using the SPSS 11.5-program.The differences in genotype frequencies between the cases and controls were tested usingχ~2-test.The associations in cases between genotype and clinical features were tested using T test. Measurement date interclass was indicated with x±s.Correlations of many factors were analysed by Logistic regression.
Results:
1. The colony has representative by Hardy-Weinberg equilibrium to all genotypes of +299G/A at resistin gene (χ~2 (A group) =3.07, P>0.50;χ~2 (B group) =2.71, P>0.05;χ~2 (control group) =0.004, P>0.05). Compared with the control group, the frequencies of genotype and allele were significantly different in group B, also having different allele frequency from group A (P=0.038, 0.016, 0.024).
2. Both age and gender of the experiment group matched the control.The number of SBP, DBP, FPG, HOMA-IR, Fib, WHR, HbA_1c in diabetic group were significantly higher than those in the control group (P<0.05).
3. Compared with type 2 diabetic patients without macroangiopathy, the diabetic patients with macroangiopathy had much higher levels of age (60.84±6.68 vs 55.19±9.26 years), SBP (149.15±21.83 vs 136.46±20.68 mmHg), HbA_1c(10.8±2.79 vs 9.85±2.37 %), HOMA-IR(5.35±3.47 vs 3.84±2.53) ,TC(5.43±1.25 vs 5.05±1.12 mmol/L), LDL-C(3.23±0.95 vs 2.85±0.65 mmol/L), Fib(3.83±1.03 vs 3.46±0.95 mmol/L ), WHR(0.97±0.007 vs 0.04±0.007), duration of diabetes (11.57±6.33 vs 8.49±5.53 years), duration of hypertension (8.39±10.06 vs 3.3±7.23 years)(P<0.05).
4. In diabetic group, there was association between resistin gene +299G/A polymorphisms and clinical characteristics, including WHR and FPG.The subgroup of G/A genotype had much lower WHR than G/G one (P<0.05), but having higher FPG than A/A one (P<0.05).There was no association between genotypes and other clinical characteristics (P>0.05).
5. In control group, people with GG genotype had higher FPG than those with G/A or A/A (P=0.001, P=0.006), but had higher BMI than those only with G/A (P=0.042). Stepwise regression analysis showed that BMI, LDL-C, Fib were independent risk factors for FPG.
6. In group A, there was no association between resistin gene +299G/A polymorphisms and clinical characteristics, such as BMI, SBP, DBP, FPG, FINS, HbA_1c, TC, TG, HDL-C, Fib and so on(P>0.05).
7. In group B, people with G/A genotype had higher FPG than those with A/A (P <0.05).Stepwise regression analysis showed that HbA_1c and TG were independent risk factors for FPG.
8. Logistic regression showed that HOMA-IR, FINS and SBP were major risk factors for diabetes and the major risk factors for macroangiopathy were SBP, DBP, LDL-C and diabetic family history.
Conclusion: Resistin gene +299G/A polymorphisms are associated withT2DM in Han Chinese of the north.People with A allele have lower FPG and BMI ,perhaps A allele is a tiny protective factor. People with A/A genotype have lower FPG in group B. Logistic regression shows that HOMA-IR, FINS and SBP are major risk factors for diabetes and the major risk factors for macroangiopathy are SBP, DBP, LDL-C and diabetic family history.
方法实验组198例，按1999年WHO糖尿病诊断标准，随机选取山东大学附属省立医院内分泌科及保健内分泌科2006年4-12月期间临床诊断为2型糖尿病的住院患者，男105例，女93例，年龄59．33±10．92岁，根据有无大血管病变分为两个亚组：A组：单纯2型糖尿病组123例，男68例，女55例，年龄55．2±9．3岁；B组：2型糖尿病并大血管病变组75例，男37例，女38例，年龄60．8±6．7岁。正常对照组98例，男57例，女41例，年龄55．7±9．1岁，来自查体中心健康查体者，排除糖尿病、冠心病、高血压病、脑血管病，且无糖尿病及高血压病家族史。采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测不同组别抵抗素+299G／A基因多态性，体重指数、腰臀比、血压指定由同一人测量，应用全自动生化分析仪测定血清总胆固醇、甘油三酯、低密度脂蛋白-胆固醇、高密度脂蛋白-胆固醇、空腹血糖、纤维蛋白原水平，放免法测定空腹胰岛素水平，计算HOMA-IR。统计学处理使用SPSS 11．5软件完成，计数资料比较用χ~2检验，计量资料比较用t检验，组间计量资料均以均数±标准差(x±s)表示，用logistic回归分析多因素相关性。
结果
1．利用Hardy-Weinberg平衡法检验RSTN+299G／A多态性各基因型(A组χ~2= 0．601，P>0．50；B组χ~2=2．71，P>0．05；对照组χ~2=0．004，P>0．90)，具有群体代表性。对照组与DM合并大血管病变组(B组)的基因型分布及等位基因频率比较均有显著性差异；对照组与单纯糖尿病组(A组)等位基因频率的比较有显著性差异，P值依次为0．038，0．016，0．024。
2．实验组与正常对照组临床资料比较：两组间年龄、性别均匹配，实验组SBP、DBP、FPG、HOMA-IR、Fib、WHR、HbA_1c均高于对照组，差异具有统计学意义(P<0．05)。
3．单纯DM组与DM合并大血管病变组临床资料比较：年龄、SBP、HbA_1c、HOMA-IR、TC、LDL-C、Fib、WHR、糖尿病病程、高血压病程均高于单纯DM亚组，差异具有统计学意义(P<0．05)。
4．在实验组中，RSTN+299G／A多态与WHR，FPG有相关性，G／G基因型亚组WHR高于G／A基因型亚组，G／A亚组FPG值高于A／A组，差异均有统计学意义(P<0．05)，其余临床生化指标在各基因型间无明显相关性(P>0．05)。
5．在对照组中，G／G基因型亚组的BMI显著高于G／A基因型亚组(P=0．042)但与A／A亚组比较无统计学意义(P>0．05)；G／G基因型亚组的FPG显著高于G／A基因型亚组，A／A基因型亚组(P=0．001，P=0．006)，逐步回归分析显示，BMI、LDL-C、Fib是FPG的独立危险因素。
6．在单纯糖尿病组中，G／G基因型亚组的年龄、BMI、DBP、WHR、TG、FPG、HbA_1c、FINS、Fib有高于A／A基因型亚组的趋势，SBP、TC、HDL-C有低于A／A基因型亚组的趋势，但差异均无统计学意义(P>0．05)。
7．在糖尿病合并大血管病变组(B组)内，G／A基因型亚组的FPG显著高于A／A基因型亚组(P<0．05)；逐步回归分析显示，HbA_1c、TG是FPG升高的独立危险因素。
8．以A组和B组为研究对象，有无糖尿病为应变量Y(有=1，无=0)，利用Logistic回归分析显示HOMA-IR、FINS、SBP为糖尿病发生的独立危险因素。又以有无大血管病变为应变量Y(有=1，无=0)，年龄、BMI、SBP、DBP，FPG、HbA_1c、FINS，HOMA-IR、TC、TG、LDL-C，HDL-C、Fib、WHR、糖尿病病程、基因型(GG=0，GA+AA=1)等为自变量，SBP、DBP、LDL-C、家族史进入回归方程，是糖尿病大血管病变形成的独立危险因素。
结论RSTN基因+299G／A多态性与中国北方地区汉族人T2DM的发生有关，携带有A等位基因型者有较低的FPG，BMI水平，A等位基因可能是T2DM的微效保护因素；AA基因型者在糖尿病并大血管病变组中有较低的FPG。Logistic回归显示HOMA-IR、FINS、SBP为糖尿病发生的独立危险因素，SBP、DBP、LDL-C、家族史是糖尿病大血管病变形成的独立危险因素。
Objective: To investigate the correlation of resistin gene +299G/Apolymorphisms with type 2 diabetes mellitus and macroangiopathy in Han Chinese in the north. The independent risk factors of type 2 diabetes mellitus and its macroangiopathy are found by Logistic regression.
Methods: According to WHO 1999 diabetic criteria, 198 type 2 diabeticinpatients were selected ,male 105 cases,female 93 cases,age 59.33±10.92 years, from the medical ward of Endocrine and health care in provincial hospital affiliated to Shandong university during April to December in 2006. They were divided into two groups: group A were 123 cases without macroangiopathy,male 68 cases, female 55 cases, age 55.2±9.3 years;group B were 75 cases with macroangiopathy ,male 37 cases,female 38 cases,age 60.8±6.7 years.The control group was composed of healthy check-up outpatients ,male 57 cases,female 41 cases,age 55.7±9.1 years,without diabetes mellitus, cornary heart disease, hypertension, brain vascular disease, family history of diabetes mellitus or hypertension. The genotypes of +299G/A variant in resistin gene were determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.Meanwhile body mass index (BMI), waist-to-hip ratio(WHR), systolic blood pressure(SBP) and diastolic blood pressure(DBP) were measured by the same one appointed. Serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), fasting blood glucose (FPG) and fibrinogen (Fib) were measured using an autoanalyzer. Fasting insulin (FINS) were measured by radionimmunoassay (RIA).Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as (FINS×FPG)/22.5. All statistical tests were carried out using the SPSS 11.5-program.The differences in genotype frequencies between the cases and controls were tested usingχ~2-test.The associations in cases between genotype and clinical features were tested using T test. Measurement date interclass was indicated with x±s.Correlations of many factors were analysed by Logistic regression.
Results:
1. The colony has representative by Hardy-Weinberg equilibrium to all genotypes of +299G/A at resistin gene (χ~2 (A group) =3.07, P>0.50;χ~2 (B group) =2.71, P>0.05;χ~2 (control group) =0.004, P>0.05). Compared with the control group, the frequencies of genotype and allele were significantly different in group B, also having different allele frequency from group A (P=0.038, 0.016, 0.024).
2. Both age and gender of the experiment group matched the control.The number of SBP, DBP, FPG, HOMA-IR, Fib, WHR, HbA_1c in diabetic group were significantly higher than those in the control group (P<0.05).
3. Compared with type 2 diabetic patients without macroangiopathy, the diabetic patients with macroangiopathy had much higher levels of age (60.84±6.68 vs 55.19±9.26 years), SBP (149.15±21.83 vs 136.46±20.68 mmHg), HbA_1c(10.8±2.79 vs 9.85±2.37 %), HOMA-IR(5.35±3.47 vs 3.84±2.53) ,TC(5.43±1.25 vs 5.05±1.12 mmol/L), LDL-C(3.23±0.95 vs 2.85±0.65 mmol/L), Fib(3.83±1.03 vs 3.46±0.95 mmol/L ), WHR(0.97±0.007 vs 0.04±0.007), duration of diabetes (11.57±6.33 vs 8.49±5.53 years), duration of hypertension (8.39±10.06 vs 3.3±7.23 years)(P<0.05).
4. In diabetic group, there was association between resistin gene +299G/A polymorphisms and clinical characteristics, including WHR and FPG.The subgroup of G/A genotype had much lower WHR than G/G one (P<0.05), but having higher FPG than A/A one (P<0.05).There was no association between genotypes and other clinical characteristics (P>0.05).
5. In control group, people with GG genotype had higher FPG than those with G/A or A/A (P=0.001, P=0.006), but had higher BMI than those only with G/A (P=0.042). Stepwise regression analysis showed that BMI, LDL-C, Fib were independent risk factors for FPG.
6. In group A, there was no association between resistin gene +299G/A polymorphisms and clinical characteristics, such as BMI, SBP, DBP, FPG, FINS, HbA_1c, TC, TG, HDL-C, Fib and so on(P>0.05).
7. In group B, people with G/A genotype had higher FPG than those with A/A (P <0.05).Stepwise regression analysis showed that HbA_1c and TG were independent risk factors for FPG.
8. Logistic regression showed that HOMA-IR, FINS and SBP were major risk factors for diabetes and the major risk factors for macroangiopathy were SBP, DBP, LDL-C and diabetic family history.
Conclusion: Resistin gene +299G/A polymorphisms are associated withT2DM in Han Chinese of the north.People with A allele have lower FPG and BMI ,perhaps A allele is a tiny protective factor. People with A/A genotype have lower FPG in group B. Logistic regression shows that HOMA-IR, FINS and SBP are major risk factors for diabetes and the major risk factors for macroangiopathy are SBP, DBP, LDL-C and diabetic family history.
引文
[1] 王吉耀．内科学[M]．北京：人民卫生出版社，2006(1)：978-979．
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