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目前,肥胖症在全世界呈流行趋势,它既是一种独立的疾病,又是2型糖尿病、心血管病、高血压、中风和多种癌症的危险因素,被世界卫生组织列为导致疾病负担的十大危险因素之一。正常人脂联素基因序列中存在相当数量的单核苷酸多态性(single nucleotide polymorphism,SNP),其中,脂联素基因第45位点SNP(SNP45)可能影响血浆中的脂联素水平,并与肥胖症患者的胰岛素抵抗有关。本研究通过测定血清胰岛素、脂联素水平及脂联素基因SNP45等指标,研究福建省泉州地区汉族肥胖人群脂联素基因SNP45与胰岛素抵抗的关系。
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脂联素基因SNP45可被限制性内切酶Eco88I识别,酶切后产物经琼脂糖凝胶电泳出现3种类型的条带分布:只于456 bp处出现条带为TT基因型(纯合子),于143 bp和313 bp两处出现条带者为GG型(纯合子),于143 bp、313 bp和456 bp 3处出现条带者为GT型(杂合子)(图 1)。由于脂联素基因SNP45的GG型数量较少,故与GT型合并为GT+GG型。肥胖症组和正常对照组中脂联素基因SNP45的GT+GG型的分布频率分别为61%和44%,差异有统计学意义(χ2=14.182,P < 0.01),G等位基因的分布频率分别为35%和25%,差异有统计学意义(χ2=10.708,P < 0.01)(表 1)。
组别 例数 基因型[例(%)] 等位基因[个(%) TT型 GT+GG型 T G 正常对照组 223 125(56.0) 98(44.0) 335(75.0) 111(25.0) 肥胖症组 248 96(39.0) 152(61.0) 324(65.0) 172(35.0) 表 1 脂联素基因第45位点单核苷酸多态性的不同基因型和等位基因在肥胖症组和正常对照组中的分布频率比较
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肥胖症组中,脂联素基因SNP45的GG+GT型与TT型相比,前者的BMI高于后者(t=2.497,P < 0.05),舒张压、TG、LDL-C显著高于后者(t=3.806,P < 0.01;t=2.604,P < 0.01;t=5.507,P < 0.01);而前者的腰臀比、脂联素和HDL-C水平均低于后者(t=1.880,P < 0.05;t=2.275,P < 0.05;t=10.100,P < 0.01)(表 2)。
组别 肥胖症组 正常对照组 TT型 GT+GG型 TT型 GT+GG型 例数(男/女) 96(34/62) 152(51/101) 125(39/86) 98(34/64) 年龄(岁) 45.17±7.78 45.55±8.94 45.43±10.17 45.35±8.68 BM(kg/m) 27.84±1.95 28.36±1.37 20.07±1.26 19.99±1.33 腰围 88.92±5.97 87.93±5.75 71.79±4.59 79.30±5.86 腰臀比 0.88±0.08 0.87±0.28 0.87±0.27 0.88±0.04 收缩压(mmHg) 128.04±14.79 131.74±14.09 120.36±14.33 117.24±10.69 舒张压(mmHg) 79.54±10.08 84.75±10.60 75.32±10.88 74.04±8.23 TG(mmol/L) 1.16±1.02 1.96±1.03 1.49±0.29 1.37±0.22 TC (mmol/L) 5.24±0.91 5.25±1.13 4.71±0.90 4.30±0.81 HDL-C(mmol/L) 1.37±0.25 1.01±0.28 1.46±0.35 1.39±0.33 LDL-C (mmol/L) 3.23±1.18 4.13±1.28 2.96±0.72 3.17±0.92 FPG(mmol/L) 4.98±0.70 5.01±0.62 4.70±0.70 4.56±0.76 FINS(mU/L) 12.02±4.04 14.12±3.78 5.26±1.71 5.86±1.58 HOMA-IR 2.69±1.07 3.16±1.02 1.11±0.45 1.19±0.38 脂联素(mg/L) 6.83±2.39 6.13±2.41 12.10±2.52 10.98±2.46 注:表中,BMI:体重指数;TG:甘油三酯;TC:总胆固醇;HDL-C:高密度脂蛋白胆固醇;LDL-C:低密度脂蛋白胆固醇;FPG:空腹血糖;FINS:空腹胰岛素;HOMA-IR:稳态模型胰岛素抵抗指数。 表 2 脂联素基因第45位点单核苷酸多态性的不同基因型在肥胖症组和正常对照组中的临床和生化指标比较
正常对照组中,脂联素基因SNP45的GG+GT型与TT型相比,前者的腰臀比、腰围、FINS(t =2.115,P < 0.05;t=10.269,P < 0.01;t=2.638,P < 0.01)水平均高于后者;而脂联素、TG、TC(t=2.510,P < 0.05;t=2.922,P < 0.01;t=3.272,P < 0.01)水平均显著低于后者(表 2)。
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在肥胖症组中,将TT型分为一组,GG+GT型分为另一组,进行二项Logistic回归分析,以脂联素基因型作为因变量(Y),其它临床和生化指标作为自变量(X1:年龄、X2:BMI、X3:腰围、X4:腰臀比、X5:SBP、X6:DBP、X7:TC、X8:TG、X9:LDL-C、X10:HDL-C、X11:FPG、X12:HOMA-IR、X13:脂联素),按照入选变量的显著性水准为0.05、剔除变量的显著性水准为0.10,通过Logistic回归分析,得到以下回归方程:
$ \;\;\;\;\;\;Y=38.996-0.187X_{3}-29.250X_{4}+0.089X_{6}+0.411X_{9}-\\ 7.355X_{10}+0.557X_{12}-0.211X_{13} $ 肥胖症组中脂联素基因SNP45的GG+GT型与TT型相比,血清脂联素水平降低(OR=0.810,95%CI: 0.673~0.975,P < 0.05);胰岛素抵抗风险增加(OR=1.746,95%CI:1.060~2.875,P < 0.05)。
在正常对照组中,将TT型分为一组,GG+GT型分为另一组,进行二项Logistic回归分析,以脂联素基因型作为因变量(Y),其他临床和生化指标作为自变量(X1:年龄、X2:BMI、X3:腰围、X4:腰臀比、X5:SBP、X6:DBP、X7:TC、X8:TG、X9:LDL-C、X10:HDL-C、X11:FPG、X12:HOMA-IR、X13:脂联素),按照入选变量的显著性水准为0.05、剔除变量的显著性水准为0.10,通过Logistic回归分析,得到以下回归方程:
$ \;\;\;\;\;Y=-6.263-0.465X_{2}+0.310X_{3}+0.644X_{9}-1.54X_{10}+\\ 1.377X_{12} $ 正常对照组中脂联素基因SNP45的GG+GT型与TT型相比,胰岛素抵抗风险增加(OR=3.962,95%CI:1.089~14.411,P < 0.05)。
肥胖患者脂联素基因第45位点单核苷酸多态性与血浆脂联素水平及胰岛素抵抗的相关性研究
Association of single nucleotide polymorphism at position 45 in adiponectin gene with plasma adiponectin level and insulin resistance in obesity
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摘要:
目的 研究福建省泉州地区汉族肥胖人群脂联素基因第45位点单核苷酸多态性(SNP45)与血浆脂联素水平及胰岛素抵抗的关系。 方法 随机选择肥胖症患者248例,正常对照者223例,采用液相平衡竞争放射免疫分析法测定血浆中空腹胰岛素(FINS)水平;利用自动生化分析仪测定空腹血糖(FPG)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)水平;计算体重指数(BMI)、腰臀比、稳态模型胰岛素抵抗指数(HOMA-IR);采用酶联免疫吸附试验测定空腹血浆脂联素水平;采用PCR-限制性片段长度多态性技术检测脂联素基因SNP45。 结果 ① 肥胖症组和正常对照组脂联素基因SNP45的GT+GG基因型的分布分别为61%和44%(χ2=14.182,P<0.01),G等位基因频率分别为35%和25%(χ2=10.708,P<0.01)。②肥胖症组中,脂联素基因SNP45的GG+GT型与TT型相比,前者的TG、LDL-C水平(t=2.604, P<0.01; t=5.507, P<0.01)升高,而脂联素和HDL-C水平(t=2.275,P<0.05;t=10.100,P<0.01)降低。③正常对照组中,脂联素基因SNP45的GG+GT型与TT型相比,前者的脂联素、TG、TC水平(t=2.510,P<0.05; t=2.922,P<0.01; t=3.272,P<0.01)显著低于后者。④以脂联素基因SNP45为因变量进行Logistic回归分析,肥胖症组中脂联素基因SNP45的GG+GT型与TT型相比,GG+GT型血清脂联素水平减少(OR=0.810,95%CI:0.673~0.975,P<0.05),胰岛素抵抗风险增加(OR=1.746,95%CI:1.060~2.875,P<0.05);正常组中GG+GT型胰岛素抵抗风险增加(OR=3.962,95%CI:1.089~14.411,P<0.05)。 结论 ① 脂联素基因SNP45的基因型和等位基因频率在肥胖症组与正常对照组中的分布有显著性差异。②脂联素基因SNP45与肥胖症患者的胰岛素抵抗及血脂水平相关。③肥胖症组中脂联素基因SNP45与脂联素水平相关。 Abstract:Objective To explore the association of single nucleotide polymorphism at position 45(SNP45) in adiponectin gene with plasma adiponectin level and insulin resistance in obesity in Quanzhou area of Fujian province. Methods Two hundred and forty-eight patients with obesity and 225 normal control subjects were enrolled in this study. Fasting insulin(FINS) were measured by radioimmunoassay and fasting plasma glucose(FPG), total cholesterol(TC), triglyceride(TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol(LDL-C) were measured by BECKMAN DXC800 biochemistry analyzer. Body mass index(BMI), waist to hip ratio, homeostasis model assessment of insulin resistance(HOMA-IR) were calculated. Plasma adiponectin levels were examined by means of enzyme-linked immunosorbentassy. The adiponectin gene SNP45 was identified by PCR-restriction fragment length polymorphism. Results ① Frequencies of GG+GT genotype in obesity group and normal control group were 61% and 44%respectively(χ2=14.182, P < 0.01), and G allele frequencies were 35% and 25%(χ2=10.708, P < 0.01). ②In obesity group, the subjects with SNP45 GG+GT genotype had higher TG and LDL-C levels than those with TT genotype(t=2.604, P < 0.01; t=5.507, P < 0.01), and had lower adiponectin level than those with TT genotype(t=2.275, P < 0.05), and had significantly lower HDL-L level than those with TT genotype(t=10.100, P < 0.01). ③In normal control group, the subjects with SNP45 GG+GT genotype had significantly lower adiponectin, TG, TC levels than those with TT genotype(t=2.510, P < 0.05; t=2.922, P < 0.01; t=3.272, P < 0.01). ④Logistic analysis proved that the SNP45 GG+GT genotype in obesity group was associated with decreased risk of plasma adiponectin level(OR=0.810, 95%CI: 0.673-0.975, P < 0.05), and with increased risk of HOMA-IR(OR=1.746, 95%CI: 1.060-2.875, P < 0.05). The SNP45 GG+GT genotype in normal control group was associated with increased risk of HOMA-IR(OR=3.962, 95%CI: 1.089-14.411, P < 0.05). Conclusions ① The distribution of adiponection of genotype and allele frequencies of the SNP45 were different in obesity and normal control groups. ②The SNP45 in adiponectin was associated with obesity, insulin resistance and the total cholesterol, triglyceride, high density lipoprotein, low density lipoprotein levels. ③The SNP45 in adiponectin was associated with the fasting adiponectin levels in obesity group. -
Key words:
- Obesity /
- Adiponectin /
- Single nucleotide, polymorphism /
- Insulin resistance /
- Radioimmunoassay
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表 1 脂联素基因第45位点单核苷酸多态性的不同基因型和等位基因在肥胖症组和正常对照组中的分布频率比较
组别 例数 基因型[例(%)] 等位基因[个(%) TT型 GT+GG型 T G 正常对照组 223 125(56.0) 98(44.0) 335(75.0) 111(25.0) 肥胖症组 248 96(39.0) 152(61.0) 324(65.0) 172(35.0) 表 2 脂联素基因第45位点单核苷酸多态性的不同基因型在肥胖症组和正常对照组中的临床和生化指标比较
组别 肥胖症组 正常对照组 TT型 GT+GG型 TT型 GT+GG型 例数(男/女) 96(34/62) 152(51/101) 125(39/86) 98(34/64) 年龄(岁) 45.17±7.78 45.55±8.94 45.43±10.17 45.35±8.68 BM(kg/m) 27.84±1.95 28.36±1.37 20.07±1.26 19.99±1.33 腰围 88.92±5.97 87.93±5.75 71.79±4.59 79.30±5.86 腰臀比 0.88±0.08 0.87±0.28 0.87±0.27 0.88±0.04 收缩压(mmHg) 128.04±14.79 131.74±14.09 120.36±14.33 117.24±10.69 舒张压(mmHg) 79.54±10.08 84.75±10.60 75.32±10.88 74.04±8.23 TG(mmol/L) 1.16±1.02 1.96±1.03 1.49±0.29 1.37±0.22 TC (mmol/L) 5.24±0.91 5.25±1.13 4.71±0.90 4.30±0.81 HDL-C(mmol/L) 1.37±0.25 1.01±0.28 1.46±0.35 1.39±0.33 LDL-C (mmol/L) 3.23±1.18 4.13±1.28 2.96±0.72 3.17±0.92 FPG(mmol/L) 4.98±0.70 5.01±0.62 4.70±0.70 4.56±0.76 FINS(mU/L) 12.02±4.04 14.12±3.78 5.26±1.71 5.86±1.58 HOMA-IR 2.69±1.07 3.16±1.02 1.11±0.45 1.19±0.38 脂联素(mg/L) 6.83±2.39 6.13±2.41 12.10±2.52 10.98±2.46 注:表中,BMI:体重指数;TG:甘油三酯;TC:总胆固醇;HDL-C:高密度脂蛋白胆固醇;LDL-C:低密度脂蛋白胆固醇;FPG:空腹血糖;FINS:空腹胰岛素;HOMA-IR:稳态模型胰岛素抵抗指数。 -
[1] 陈灏珠.实用内科学. 12版.北京:人民卫生出版社, 2006: 918-919.
[2] 武阳丰, 马冠生, 胡永华, 等.中国居民的超重和肥胖流行现状.中华预防医学杂志, 2005, 39(5):316-320. doi: 10.3760/j:issn:0253-9624.2005.05.006
[3] Francke S, Manraj M, Lacquemant C, et al. A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. Hum Mol Genet, 2001, 10(24): 2751-2765. doi: 10.1093/hmg/10.24.2751 [4] Barnea M, Shamay A, Stark AH, et al. A high-fat diet has a tissue-specific effect on adiponectin and related enzyme expression. Obesity, 2006, 14(12): 2145-2153. doi: 10.1038/oby.2006.251 [5] Yamamoto Y, Hirose H, Saito I, et al. Adiponectin, an adipocyted-erived protein, predicts future insulin-resistance: two-year follow-up study in Japanese population. J Clin Endocrinol Metab, 2004, 89(1): 89-90. [6] Mousavinasab F, T.a.htinen T, Jokelainen J, et al. Common polymor-phisms (single-nucleotide polymorphisms SNP+45 and SNP+276) of the adiponectin gene regulate serum adiponectin concentrations and blood pressure in young Finnish men. Mol Genet Metab, 2006, 87(2): 147-151. doi: 10.1016/j.ymgme.2005.08.010 [7] Katsuda Y, Asano A, Murase Y, et al. Association of genetic variation of the adiponectin gene with body fat distribution and carotid atherosclerosis in Japanese obese subjects. J Atheroscler Thromb, 2007, 14(1): 19-26. doi: 10.5551/jat.14.19 [8] Tsuzaki K, Kotani K, Nagai N, et al. Adiponectin gene single-nucleotide polymorphisms and treatment response to obesity. J Endocrinol Invest, 2009, 32(5):395-400. doi: 10.1007/BF03346474 [9] 王遂军, 贾伟平, 包玉倩, 等.脂联素基因多态性与肥胖、血清脂联素水平的相关性.中国组织工程研究与临床康复, 2008, 12(7):1295-1299. doi: 10.3321/j.issn:1673-8225.2008.07.029
[10] 王长江, 王佑民, 汝颖, 等.脂联素基因第45位点单核苷酸多态性与肥胖及胰岛素抵抗的相关性.中华糖尿病杂志, 2005, 13(5):324-325. doi: 10.3321/j.issn:1006-6187.2005.05.002