VDR基因Fok I多态性与T2DM及其合并动脉粥样硬化的相关性研究
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摘要
背景及目的:维生素D是人体必需的一种维生素,其功能主要是通过维生素D受体(vitamin D receptor,VDR)来介导的。近年来研究发现维生素D对胰岛具有保护作用,并且是维持正常胰岛素分泌和糖耐量所必需的物质。因此, VDR基因可以作为2型糖尿病( type 2 diabetes mellitus,T2DM)的候选基因。动脉粥样硬化(atherosclerosis,AS)是T2DM大血管并发症的主要致死、致残原因之一。最近不少研究表明,AS相关钙化的发生发展颇似于骨骼钙化过程。目前发现与个体生长发育及人类疾病相关的VDR基因多态性分别对应限制性内切酶BsmI、ApaI、TaqI、FokI的酶切位点。国内已有研究发现VDR基因FokI酶切位点各基因型在T2DM组和正常对照组中的分布差异具有显著统计学意义,但关于VDR基因FokI酶切位点在T2DM合并AS的分布频率的研究很少。本研究通过对三组研究对象其FokI基因多态性的表达,探讨VDR基因FokI的多态性与T2DM及其合并AS之间相关性。
对象及方法:将175例T2DM患者(按WHO 1999年推荐的诊断和分型标准,新诊断或已明确诊断后病程在1年以内)根据超声波大动脉内中膜厚度(intima media thickness,IMT)检测分为AS组69例(颈总动脉、髂总动脉及股动脉的IMT有一处>1.0mm或局部有斑块存在者),非AS组106例(以上三处动脉的IMT均≤1.0mm)。其中AS组男37例,女32例,平均年龄52.84±7.84;非AS组其中男56例,女50例,平均年龄51.90±7.70岁。对照组77例,其中男39例,女38例,平均年龄57.58±12.33,均无糖尿病,高血压,且肾、肝功能均正常。临床指标检测,提取全血DNA,PCR扩增VDR基因,FokI酶切扩增产物,检测基因型。用单因素非条件Logistic回归分析研究VDR基因变异对T2DM及T2DM合并AS的影响。
结果:1.三组临床参数比较:T2DM组WHR、SBP、DBP、FBG、BMI、TC、ISI、HDL-c和LDL-c水平均高于正常对照组,差异具有显著性意义(P<0.05)。2. VDR基因FokI酶切位点各基因型在T2DM组和对照组中的分布具有显著统计学意义(P<0.01),两组间等位基因频率分布差异有显著性(P<0.01)。3. T2DM AS组和非AS组VDR基因FokI酶切各基因型分布无统计学意义(P>0.05),两组间等位基因频率分布无差异(P>0.05)。4. VDR等位基因f与T2DM呈显著正相关,等位基因F与T2DM呈显著负相关。
结论:1. VDR基因FokI酶切位点各基因型在T2DM组和正常对照组中的分布差异具有显著统计学意义。2. FokI酶切位点各基因型在T2DM非AS和T2DM AS组中分布无显著统计学意义。3.等位基因f是T2DM的易感基因,而等位基因F对T2DM具有保护作用。
Background and Objective Vitamin D is an essential vitamin in human, and its functions are mediated by vitamin D receptor (VDR). Recent studies have found that vitamin D has a protective effect on the islet, and is the necessary material of maintaining the normal glucose tolerance and insulin secretion. Therefore, the VDR gene may be one of the candidate genes of type 2 diabetes mellitus (T2DM). However, atherosclerosis (AS) which is macroangiopathy of T2DM is main cause of death and disability in T2DM. Many studies showed that the process of AS calcification was like that of the bone calcification. There are four restriction endonuclease cutting sites including BsmI、ApaI、TaqI、FokI which are related to human growth and disease. Some studies discovered that FokI genotypes were significantly difference between T2DM and normal controls. But there is few research which involves T2DM with AS. So the purpose of this research is to investigate the relationship between vitamin D receptor gene FokI polymorphisms and T2DM as well as T2DM with AS.
Object and methods 175 T2DM patients (according to the criterion of diagnosis and classification of WHO 1999, newly diagnosed or identified diagnosed within one year )were divided to 69 AS patients and 106 non-AS patients by intima media thickness of great artery. 77 healthy physical examinees were enrolled as the controls group. Examing the clinical indicators of three groups. Blood DNA of three groups were extracted respectively. VDR gene polymorphism analysis was performed with polymerase chain reaction-restriction fragment length polymorphism in 175 T2DM patients and 77 controls. The genotype frequencies of VDR were calculated later according to Hardy-Weinberg equilibrium formula. Using single factor non -conditional Logistic regression analysis to study the incidence of VDR gene mutation in T2DM and T2DM with AS incidence.
Results 1. Clinical parameter comparison of three group: WHR、BMI、DBP、FBG、TG、TC and LDL-c、HDL-c lever of T2DM group were higher than normal controls, the difference is significant(P>0.05). 2. A significant difference was seen in the frequency distribution of VDR FokI genotype between T2DM and normal controls. 3. VDR FokI restriction Enzyme cutting site genotypes were no significant difference between T2DM and T2DM with AS. 4. Allele f was positively correlated to T2DM; allele F was negative correlated to T2DM.
Conclusions 1. VDR FokI restriction Enzyme cutting site genotypes were significant difference between T2DM and normal controls. 2. There were no difference in VDR FokI restriction Enzyme cutting sites genotypes between T2DM and T2DM with AS. 3. Allele f maybe a susceptible gene contributing to the development of T2DM, whereas allele F maybe protective gene for T2DM.
对象及方法:将175例T2DM患者(按WHO 1999年推荐的诊断和分型标准,新诊断或已明确诊断后病程在1年以内)根据超声波大动脉内中膜厚度(intima media thickness,IMT)检测分为AS组69例(颈总动脉、髂总动脉及股动脉的IMT有一处>1.0mm或局部有斑块存在者),非AS组106例(以上三处动脉的IMT均≤1.0mm)。其中AS组男37例,女32例,平均年龄52.84±7.84;非AS组其中男56例,女50例,平均年龄51.90±7.70岁。对照组77例,其中男39例,女38例,平均年龄57.58±12.33,均无糖尿病,高血压,且肾、肝功能均正常。临床指标检测,提取全血DNA,PCR扩增VDR基因,FokI酶切扩增产物,检测基因型。用单因素非条件Logistic回归分析研究VDR基因变异对T2DM及T2DM合并AS的影响。
结果:1.三组临床参数比较:T2DM组WHR、SBP、DBP、FBG、BMI、TC、ISI、HDL-c和LDL-c水平均高于正常对照组,差异具有显著性意义(P<0.05)。2. VDR基因FokI酶切位点各基因型在T2DM组和对照组中的分布具有显著统计学意义(P<0.01),两组间等位基因频率分布差异有显著性(P<0.01)。3. T2DM AS组和非AS组VDR基因FokI酶切各基因型分布无统计学意义(P>0.05),两组间等位基因频率分布无差异(P>0.05)。4. VDR等位基因f与T2DM呈显著正相关,等位基因F与T2DM呈显著负相关。
结论:1. VDR基因FokI酶切位点各基因型在T2DM组和正常对照组中的分布差异具有显著统计学意义。2. FokI酶切位点各基因型在T2DM非AS和T2DM AS组中分布无显著统计学意义。3.等位基因f是T2DM的易感基因,而等位基因F对T2DM具有保护作用。
Background and Objective Vitamin D is an essential vitamin in human, and its functions are mediated by vitamin D receptor (VDR). Recent studies have found that vitamin D has a protective effect on the islet, and is the necessary material of maintaining the normal glucose tolerance and insulin secretion. Therefore, the VDR gene may be one of the candidate genes of type 2 diabetes mellitus (T2DM). However, atherosclerosis (AS) which is macroangiopathy of T2DM is main cause of death and disability in T2DM. Many studies showed that the process of AS calcification was like that of the bone calcification. There are four restriction endonuclease cutting sites including BsmI、ApaI、TaqI、FokI which are related to human growth and disease. Some studies discovered that FokI genotypes were significantly difference between T2DM and normal controls. But there is few research which involves T2DM with AS. So the purpose of this research is to investigate the relationship between vitamin D receptor gene FokI polymorphisms and T2DM as well as T2DM with AS.
Object and methods 175 T2DM patients (according to the criterion of diagnosis and classification of WHO 1999, newly diagnosed or identified diagnosed within one year )were divided to 69 AS patients and 106 non-AS patients by intima media thickness of great artery. 77 healthy physical examinees were enrolled as the controls group. Examing the clinical indicators of three groups. Blood DNA of three groups were extracted respectively. VDR gene polymorphism analysis was performed with polymerase chain reaction-restriction fragment length polymorphism in 175 T2DM patients and 77 controls. The genotype frequencies of VDR were calculated later according to Hardy-Weinberg equilibrium formula. Using single factor non -conditional Logistic regression analysis to study the incidence of VDR gene mutation in T2DM and T2DM with AS incidence.
Results 1. Clinical parameter comparison of three group: WHR、BMI、DBP、FBG、TG、TC and LDL-c、HDL-c lever of T2DM group were higher than normal controls, the difference is significant(P>0.05). 2. A significant difference was seen in the frequency distribution of VDR FokI genotype between T2DM and normal controls. 3. VDR FokI restriction Enzyme cutting site genotypes were no significant difference between T2DM and T2DM with AS. 4. Allele f was positively correlated to T2DM; allele F was negative correlated to T2DM.
Conclusions 1. VDR FokI restriction Enzyme cutting site genotypes were significant difference between T2DM and normal controls. 2. There were no difference in VDR FokI restriction Enzyme cutting sites genotypes between T2DM and T2DM with AS. 3. Allele f maybe a susceptible gene contributing to the development of T2DM, whereas allele F maybe protective gene for T2DM.
引文
1 Ferrari S, Rizzoli R, Manen D, et al. Vitamin D receptor gene start codon polymorphisms (FokI) and bone mineral density:Interaction with age, dietary calcium, and 3’end region polymorphisms[J] . J Bone Miner Res , 1998,13(6) :925 - 930.
2 Kanshi M, Yoshihito T, Minagawa Y, et al. Difference in height associated with a translation start site polymorphism in the vitamin D receptor gene[J]. Pediatric Res , 1998,44(5) :628 - 632.
3 UKPDS group. UK prospective diabetes study 17. A nine-year update of a randomized. controlled trial on the effect of improved metabolic control on complications in non-insulin-dependant diabetes mellitus[J] . Ann Intern Med, 1996,124-134.
4 Chiu K C ,Chuang L M, Yoon C. The vitamin D receptor polymorphism in the translation initiation codon is a risk factor for insulin resistance in glucose tolerant Caucasians[J] .BMC Med Genet,2001,2 :2-11.
5 WHO专家咨询报告.关于糖尿病的新诊断标准与分型[J].中国糖尿病杂志, 2000, 8 : 5-6.
6 Khoury Z, Schwartz R , Gottlieb S ,et al. Relation of coronary artery disease to atherosclerotic disease in the aorta, carotid, and femoral arteries evaluated by ultrasound. Am J Cardiol ,1997 , 80(11) :1429 - 1433.
7 Kallikazaros I, Tsioufis C, Sideris S , et al. Carotid artery disease as a marker for the presence of severe coronary artery dis2ease in patients evaluated for chest pain. Stroke, 1999, 30(5) :1002 -1007.
8 Mack WJ,La Bree L,Liu C, et al. Correlations between measures of athero- sclerosis change using carotid ultrasongraphy and coronary angiography. Atherosclerosis ,2000 , 150(2) :371- 379.
9 Xing shaoji, Zhou lishe, Xu xiuju. Polymorphism of vitamin D receptor gene FokⅠin Mongolian population of China. Chin J Med Genet , April 2006, Vol . 23 , No. 2,236-237.
10 Bid HK, Mittal RD. Study of vitaminD receptor (VDR) gene start codon polymorphism(Fok1) in healthy individuals from north india. Indian J Hum Genet ,2003,9∶51-54.
11 Minamitani K, Takahashi Y, Minagawa M, et al . Difference in heightassociated with a translation start site polymorphism in the vitamin D receptor gene. Pediatr Res, 1998, 44∶628-632.
12 Sergeev INRhoten W B. 1,25-Dihydroxyvitamin D3 evokes oscillations of intracellular calcium in a pancreatic beta-cell line.Endocnnology 1995,136(7):2852-2861.
13 Bodssova AM, Tankova T, Kirilov G, et a1.The efect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients.Int J Clin Pract 2003,57(4):258-261.
14 Lee S, Clark SA , Gill RK, et al. 1, 25-dihydroxyvitam in D3 and pancreatic B-cell function: vitamin D receptors, gene expression and insulin secretion. Endocrinology, 1994, 134: 1602-1610.
15 Rab inovitch A, Suarez-Pinzon WL, Sooy K,et a1. Expression of Calbindin- D(28k)in a pancreatic islet beta-cell line protects against cytokine- induced apoptosis and necrosis[J].Endocrinology,2001,142(8):3649-4655
16 Arai H, Miyamoto K, Taketani Y, et al. A vitamin D receptor gene poly- morphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J BoneM iner Res, 1997, 12∶915-921.
17李慧敏,缪珩,鲁一兵,等.维生素D受体基因多态性与2型糖尿病易感性的研究[J].中国现代医学杂志, 2005, 15(7):989-992.
18 Duguid JB. Vitamin D sclerosis in the rat,s aorta. J Pathol Bact, 1980,33(4):697.
19 Kamio A, Kummerow FA, Imai H.Degeneration of aortic smooth muscle cell in swine fed excess vitamin D, Arch Pathol Lab Med,1997,101(7):378.
20 Lee Co,Herrmann RG.Effect of vitamin D,sucrose,corn oil and endocrines on tissue cholesterol in rat, Cir Res, 1989,7(3):354.
21 Vik T, Try K, Thelle DS, et al. Tromso heart study: Vitamin D metabolism and myocardial infarction,Br Med I,1979,2 (6183): 176.
1 Ylikomi T, Laaksi I, Rulou Y, et al. Antipoliferative action of vitamin D. Vitamins and Hormones, 2002, 64:357-406.
2 MORRISON NA , YEOMAN R , KELLY PJ , et al. Contribution of transacting factor alleles to normal physiological variability :vitamin D receptor gene polymorphism and circulating osteocalcin [J] . Proc Natl Acad Sci USA , 1992 ,89(15) :6665-6669.
3 MARC J, PREZELI J, KOMEL R,et al. Association of vitamin D receptor gene polymorphism with bone mineral density in Slovenian postmenopausal women [J] .Gynecol Endocrinol , 2000,14(1) : 60- 64.
4 Thakkinstian A, D Este C, Attia J. Haplotype analysis of VDR gene poly- morphisms: a meta-analysis. Osteoporos Int, 2004, 15(9):729-34.
5 Thakkinstian A, D Este C, Eisman J, et al. Meta-analysis of molecular asso- ciation studies: vitamin Dreceptor gene polymorphisms and BMD asacasestudy. J Bone Miner Res, 2004, 19(3):419-428.
6 Fang Y, Rivadeneira F, van Meurs J B, et al. Vitamin D receptor gene BsmI and TaqI polymorphisms and fracture risk: a meta-analysis Bone, 2006, Oct; 39(4):938-945.
7 Marco MP, Craver L, Betriu A, et al. Influence of vitamin D receptor gene polymorphisms on mortality risk in hemodialysis patients. Am J Kidney Dis 2001,38(5):965-974.
8 Ruggiero M, Pacini S, Amato M, et al. Association between vitamin D receptor gene polymorphism and nephrolithiasis. Miner Electrolyte Metab 1999,25(3): 185-190.
9 Ozkaya O, Soylemezoglu O, Misirlioglu M, et al. Polymorphisms in the vitamin D receptor gene and the risk of calcium nephrolithiasis in children. Eur Urol 2003,44(1):150-154.
10 Taylor JA, Hirvonen A, Watson M, et al. Association of prosta-te cancer with vitamin Dreceptor gene polymorphism. Cancer Res 15-9-1996,56(18):4108- 4110.
11 Ntais C, Polycarpou A, Ioannidis JPA. Vitamin D receptor gen-e polymorphisms and risk of prostate cancer: a meta-analysis.Cancer Epidemiol Biomark Prev, 2003,12(12):1395-1402.
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23 Chiu K C ,Chuang L M, Yoon C. The vitamin D receptor polymorphism in the translation initiation codon is a risk factor for insulin resistance in glucosetolerant Caucasians[J] .BMC Med Genet ,2001,2 :2-11.
24 Ban Y, Ban Y, Taniyama M, et al. Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves disease[J] . Thyroid ,2000, 10 :475-480.
25 Ban Y, Taniyama M, Ban Y. Vitamin D receptor gene polymorphism is associated with Graves disease in the Japanese population [J] . J Clin Endocrinol Metab , 2000,85:4639-4643.
26 Fernandez E ,Fibla T,Betriu A ,et al. Association between vitamin D receptor gene polymorphism and relative hypoparathyroidism in patients with chronic renal failure [J] . J A-m Soc Nephrol , 1997,10:1546-1552.
27 Muray S, Parisi E, Cardus A, et al. Vitamin D receptor genotype and 25 hydroxy vitamin D influence on blood pressure inhealthy individuals. Nefrologia, 2003,23:32-36.
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29 Kammerer CM, Dualan AA, Samollow PB, et al. Bone mineraldensity, carotid artery intimal medial thickness and the vitaminD receptor BsmI polymorphism in Mexican American women.Calcif TissueInt, 2004,75(4):292-298.
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31 Simmons JD, Mullighan C, Welsh KI, et al. Vitamin D recept-or gene polymorphism: association with Crohn's diseases uscept-ibility. Gut, 2000,47(2): 211-214.
32 Tajouri L, Ovcaric M, Curtain R, et al. Variation in the vitami-n D receptor geneis associated with multiple sclerosis in an Australian population. J Neurogenet 2005,19(1):25-38.
33 Partridge JM, Weatherby SJM, Woolmore JA, et al. Susceptibi-lity and outcome in MS-associations with polymorphisms in pigmentation related genes. Neurology 22-6-2004,62(12):2323-2325.
2 Kanshi M, Yoshihito T, Minagawa Y, et al. Difference in height associated with a translation start site polymorphism in the vitamin D receptor gene[J]. Pediatric Res , 1998,44(5) :628 - 632.
3 UKPDS group. UK prospective diabetes study 17. A nine-year update of a randomized. controlled trial on the effect of improved metabolic control on complications in non-insulin-dependant diabetes mellitus[J] . Ann Intern Med, 1996,124-134.
4 Chiu K C ,Chuang L M, Yoon C. The vitamin D receptor polymorphism in the translation initiation codon is a risk factor for insulin resistance in glucose tolerant Caucasians[J] .BMC Med Genet,2001,2 :2-11.
5 WHO专家咨询报告.关于糖尿病的新诊断标准与分型[J].中国糖尿病杂志, 2000, 8 : 5-6.
6 Khoury Z, Schwartz R , Gottlieb S ,et al. Relation of coronary artery disease to atherosclerotic disease in the aorta, carotid, and femoral arteries evaluated by ultrasound. Am J Cardiol ,1997 , 80(11) :1429 - 1433.
7 Kallikazaros I, Tsioufis C, Sideris S , et al. Carotid artery disease as a marker for the presence of severe coronary artery dis2ease in patients evaluated for chest pain. Stroke, 1999, 30(5) :1002 -1007.
8 Mack WJ,La Bree L,Liu C, et al. Correlations between measures of athero- sclerosis change using carotid ultrasongraphy and coronary angiography. Atherosclerosis ,2000 , 150(2) :371- 379.
9 Xing shaoji, Zhou lishe, Xu xiuju. Polymorphism of vitamin D receptor gene FokⅠin Mongolian population of China. Chin J Med Genet , April 2006, Vol . 23 , No. 2,236-237.
10 Bid HK, Mittal RD. Study of vitaminD receptor (VDR) gene start codon polymorphism(Fok1) in healthy individuals from north india. Indian J Hum Genet ,2003,9∶51-54.
11 Minamitani K, Takahashi Y, Minagawa M, et al . Difference in heightassociated with a translation start site polymorphism in the vitamin D receptor gene. Pediatr Res, 1998, 44∶628-632.
12 Sergeev INRhoten W B. 1,25-Dihydroxyvitamin D3 evokes oscillations of intracellular calcium in a pancreatic beta-cell line.Endocnnology 1995,136(7):2852-2861.
13 Bodssova AM, Tankova T, Kirilov G, et a1.The efect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients.Int J Clin Pract 2003,57(4):258-261.
14 Lee S, Clark SA , Gill RK, et al. 1, 25-dihydroxyvitam in D3 and pancreatic B-cell function: vitamin D receptors, gene expression and insulin secretion. Endocrinology, 1994, 134: 1602-1610.
15 Rab inovitch A, Suarez-Pinzon WL, Sooy K,et a1. Expression of Calbindin- D(28k)in a pancreatic islet beta-cell line protects against cytokine- induced apoptosis and necrosis[J].Endocrinology,2001,142(8):3649-4655
16 Arai H, Miyamoto K, Taketani Y, et al. A vitamin D receptor gene poly- morphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J BoneM iner Res, 1997, 12∶915-921.
17李慧敏,缪珩,鲁一兵,等.维生素D受体基因多态性与2型糖尿病易感性的研究[J].中国现代医学杂志, 2005, 15(7):989-992.
18 Duguid JB. Vitamin D sclerosis in the rat,s aorta. J Pathol Bact, 1980,33(4):697.
19 Kamio A, Kummerow FA, Imai H.Degeneration of aortic smooth muscle cell in swine fed excess vitamin D, Arch Pathol Lab Med,1997,101(7):378.
20 Lee Co,Herrmann RG.Effect of vitamin D,sucrose,corn oil and endocrines on tissue cholesterol in rat, Cir Res, 1989,7(3):354.
21 Vik T, Try K, Thelle DS, et al. Tromso heart study: Vitamin D metabolism and myocardial infarction,Br Med I,1979,2 (6183): 176.
1 Ylikomi T, Laaksi I, Rulou Y, et al. Antipoliferative action of vitamin D. Vitamins and Hormones, 2002, 64:357-406.
2 MORRISON NA , YEOMAN R , KELLY PJ , et al. Contribution of transacting factor alleles to normal physiological variability :vitamin D receptor gene polymorphism and circulating osteocalcin [J] . Proc Natl Acad Sci USA , 1992 ,89(15) :6665-6669.
3 MARC J, PREZELI J, KOMEL R,et al. Association of vitamin D receptor gene polymorphism with bone mineral density in Slovenian postmenopausal women [J] .Gynecol Endocrinol , 2000,14(1) : 60- 64.
4 Thakkinstian A, D Este C, Attia J. Haplotype analysis of VDR gene poly- morphisms: a meta-analysis. Osteoporos Int, 2004, 15(9):729-34.
5 Thakkinstian A, D Este C, Eisman J, et al. Meta-analysis of molecular asso- ciation studies: vitamin Dreceptor gene polymorphisms and BMD asacasestudy. J Bone Miner Res, 2004, 19(3):419-428.
6 Fang Y, Rivadeneira F, van Meurs J B, et al. Vitamin D receptor gene BsmI and TaqI polymorphisms and fracture risk: a meta-analysis Bone, 2006, Oct; 39(4):938-945.
7 Marco MP, Craver L, Betriu A, et al. Influence of vitamin D receptor gene polymorphisms on mortality risk in hemodialysis patients. Am J Kidney Dis 2001,38(5):965-974.
8 Ruggiero M, Pacini S, Amato M, et al. Association between vitamin D receptor gene polymorphism and nephrolithiasis. Miner Electrolyte Metab 1999,25(3): 185-190.
9 Ozkaya O, Soylemezoglu O, Misirlioglu M, et al. Polymorphisms in the vitamin D receptor gene and the risk of calcium nephrolithiasis in children. Eur Urol 2003,44(1):150-154.
10 Taylor JA, Hirvonen A, Watson M, et al. Association of prosta-te cancer with vitamin Dreceptor gene polymorphism. Cancer Res 15-9-1996,56(18):4108- 4110.
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