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Published in: Cardiovascular Diabetology 1/2010

Open Access 01-12-2010 | Original investigation

Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients C-reactive protein in type 2 diabetic patients

Authors: Emanuela Lapice, Michele Pinelli, Elisabetta Pisu, Antonella Monticelli, Roberto Gambino, Gianfranco Pagano, Silvia Valsecchi, Sergio Cocozza, Gabriele Riccardi, Olga Vaccaro

Published in: Cardiovascular Diabetology | Issue 1/2010

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Abstract

Background

This study evaluated the relationship between the G(-866)A polymorphism of the uncoupling protein 2 (UCP2) gene and high-sensitivity C reactive protein (hs-CRP) plasma levels in diabetic patients.

Methods

We studied 383 unrelated people with type 2 diabetes aged 40-70 years. Anthropometry, fasting lipids, glucose, HbA1c, and hs-CRP were measured. Participants were genotyped for the G (-866)A polymorphism of the uncoupling protein 2 gene.

Results

Hs-CRP (mg/L) increased progressively across the three genotype groups AA, AG, or GG, being respectively 3.0 ± 3.2, 3.6 ± 5.0, and 4.8 ± 5.3 (p for trend = 0.03). Since hs-CRP values were not significantly different between AA and AG genotype, these two groups were pooled for further analyses. Compared to participants with the AA/AG genotypes, homozygotes for the G allele (GG genotype) had significantly higher hs-CRP levels (4.8 ± 5.3 vs 3.5 ± 4.7 mg/L, p = 0.01) and a larger proportion (53.9% vs 46.1%, p = 0.013) of elevated hs-CRP (> 2 mg/L). This was not explained by major confounders such as age, gender, BMI, waist circumference, HbA1c, smoking, or medications use which were comparable in the two genotype groups.

Conclusions

The study shows for the first time, in type 2 diabetic patients, a significant association of hs-CRP levels with the G(-866)A polymorphism of UCP2 beyond the effect of major confounders.
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Literature
1.
go back to reference Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005, 352: 1685-95. 10.1056/NEJMra043430.CrossRefPubMed Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005, 352: 1685-95. 10.1056/NEJMra043430.CrossRefPubMed
2.
go back to reference Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J: C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010, 375: 132-40. 10.1016/S0140-6736(09)61717-7.CrossRef Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J: C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010, 375: 132-40. 10.1016/S0140-6736(09)61717-7.CrossRef
3.
go back to reference Festa A, D'Agostino R, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM: The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord. 2001, 25: 1407-15. 10.1038/sj.ijo.0801792.CrossRefPubMed Festa A, D'Agostino R, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM: The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord. 2001, 25: 1407-15. 10.1038/sj.ijo.0801792.CrossRefPubMed
4.
go back to reference Lapice E, Maione S, Patti L, Cipriano P, Rivellese AA, Riccardi G, Vaccaro O: Abdominal adiposity is associated with elevated C-reactive protein independent of BMI in healthy nonobese people. Diabetes Care. 2009, 32: 1734-6. 10.2337/dc09-0176.PubMedCentralCrossRefPubMed Lapice E, Maione S, Patti L, Cipriano P, Rivellese AA, Riccardi G, Vaccaro O: Abdominal adiposity is associated with elevated C-reactive protein independent of BMI in healthy nonobese people. Diabetes Care. 2009, 32: 1734-6. 10.2337/dc09-0176.PubMedCentralCrossRefPubMed
5.
go back to reference Pankow JS, Folsom AR, Cushman M, Borecki IB, Hopkins PN, Eckfeldt JH, Tracy RP: Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis. 2001, 154: 681-9. 10.1016/S0021-9150(00)00586-4.CrossRefPubMed Pankow JS, Folsom AR, Cushman M, Borecki IB, Hopkins PN, Eckfeldt JH, Tracy RP: Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis. 2001, 154: 681-9. 10.1016/S0021-9150(00)00586-4.CrossRefPubMed
6.
go back to reference MacGregor AJ, Gallimore JR, Spector TD, Pepys MB: Genetic effects on baseline values of C-reactive protein and serum amyloid a protein: a comparison of monozygotic and dizygotic twins. Clin Chem. 2004, 50: 130-4. 10.1373/clinchem.2003.028258.CrossRefPubMed MacGregor AJ, Gallimore JR, Spector TD, Pepys MB: Genetic effects on baseline values of C-reactive protein and serum amyloid a protein: a comparison of monozygotic and dizygotic twins. Clin Chem. 2004, 50: 130-4. 10.1373/clinchem.2003.028258.CrossRefPubMed
7.
go back to reference Mattiasson G, Sullivan PG: The emerging functions of UCP2 in health, disease, and therapeutics. Antioxid Redox Signal. 2006, 8: 1-38. 10.1089/ars.2006.8.1.CrossRefPubMed Mattiasson G, Sullivan PG: The emerging functions of UCP2 in health, disease, and therapeutics. Antioxid Redox Signal. 2006, 8: 1-38. 10.1089/ars.2006.8.1.CrossRefPubMed
8.
go back to reference Lum H, Roebuck KA: Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol. 2001, 280: C719-41.PubMed Lum H, Roebuck KA: Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol. 2001, 280: C719-41.PubMed
9.
go back to reference Griendling KK, FitzGerald GA: Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation. 2003, 108: 2034-40. 10.1161/01.CIR.0000093661.90582.c4.CrossRefPubMed Griendling KK, FitzGerald GA: Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation. 2003, 108: 2034-40. 10.1161/01.CIR.0000093661.90582.c4.CrossRefPubMed
10.
go back to reference Vogler S, Goedde R, Miterski B, Gold R, Kroner A, Koczan D, Zettl UK, Rieckmann P, Epplen JT, Ibrahim SM: Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis. J Mol Med. 2005, 83: 806-11. 10.1007/s00109-005-0661-5.CrossRefPubMed Vogler S, Goedde R, Miterski B, Gold R, Kroner A, Koczan D, Zettl UK, Rieckmann P, Epplen JT, Ibrahim SM: Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis. J Mol Med. 2005, 83: 806-11. 10.1007/s00109-005-0661-5.CrossRefPubMed
11.
go back to reference Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F, Ladurner G, Hell E, Strosberg AD, Patsch JR, Krempler F, Patsch W: A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nat Genet. 2001, 28: 178-83. 10.1038/88911.CrossRefPubMed Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F, Ladurner G, Hell E, Strosberg AD, Patsch JR, Krempler F, Patsch W: A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nat Genet. 2001, 28: 178-83. 10.1038/88911.CrossRefPubMed
12.
go back to reference Sasahara M, Nishi M, Kawashima H, Ueda K, Sakagashira S, Furuta H, Matsumoto E, Hanabusa T, Sasaki H, Nanjo K: Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes. 2004, 53: 482-5. 10.2337/diabetes.53.2.482.CrossRefPubMed Sasahara M, Nishi M, Kawashima H, Ueda K, Sakagashira S, Furuta H, Matsumoto E, Hanabusa T, Sasaki H, Nanjo K: Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes. 2004, 53: 482-5. 10.2337/diabetes.53.2.482.CrossRefPubMed
13.
go back to reference Oberkofler H, Iglseder B, Klein K, Unger J, Haltmayer M, Krempler F, Paulweber B, Patsch W: Associations of the UCP2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol. 2005, 25: 604-10. 10.1161/01.ATV.0000153141.42033.22.CrossRefPubMed Oberkofler H, Iglseder B, Klein K, Unger J, Haltmayer M, Krempler F, Paulweber B, Patsch W: Associations of the UCP2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol. 2005, 25: 604-10. 10.1161/01.ATV.0000153141.42033.22.CrossRefPubMed
14.
go back to reference Krempler F, Esterbauer H, Weitgasser R, Ebenbichler C, Patsch JR, Miller K, Xie M, Linnemayr V, Oberkofler H, Patsch W: A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes. 2002, 51: 3331-5. 10.2337/diabetes.51.11.3331.CrossRefPubMed Krempler F, Esterbauer H, Weitgasser R, Ebenbichler C, Patsch JR, Miller K, Xie M, Linnemayr V, Oberkofler H, Patsch W: A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes. 2002, 51: 3331-5. 10.2337/diabetes.51.11.3331.CrossRefPubMed
15.
go back to reference Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, Couplan E, Alves-Guerra MC, Goubern M, Surwit R, Bouillaud F, Richard D, Collins S, Ricquier D: Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet. 2000, 26: 435-9. 10.1038/82565.CrossRefPubMed Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, Couplan E, Alves-Guerra MC, Goubern M, Surwit R, Bouillaud F, Richard D, Collins S, Ricquier D: Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet. 2000, 26: 435-9. 10.1038/82565.CrossRefPubMed
16.
go back to reference Yu X, Wieczorek S, Franke A, Yin H, Pierer M, Sina C, Karlsen TH, Boberg KM, Bergquist A, Kunz M, Witte T, Gross WL, Epplen JT, Alarcón-Riquelme ME, Schreiber S, Ibrahim SM: Association of UCP2 -866 G/A polymorphism with chronic inflammatory diseases. Genes Immun. 2009, 10: 601-5. 10.1038/gene.2009.29.CrossRefPubMed Yu X, Wieczorek S, Franke A, Yin H, Pierer M, Sina C, Karlsen TH, Boberg KM, Bergquist A, Kunz M, Witte T, Gross WL, Epplen JT, Alarcón-Riquelme ME, Schreiber S, Ibrahim SM: Association of UCP2 -866 G/A polymorphism with chronic inflammatory diseases. Genes Immun. 2009, 10: 601-5. 10.1038/gene.2009.29.CrossRefPubMed
17.
go back to reference Cheurfa N, Dubois-Laforgue D, Ferrarezi DA, Reis AF, Brenner GM, Bouché C, Le Feuvre C, Fumeron F, Timsit J, Marre M, Velho G: The common -866G > A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men. Diabetes. 2008, 57: 1063-8. 10.2337/db07-1292.CrossRefPubMed Cheurfa N, Dubois-Laforgue D, Ferrarezi DA, Reis AF, Brenner GM, Bouché C, Le Feuvre C, Fumeron F, Timsit J, Marre M, Velho G: The common -866G > A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men. Diabetes. 2008, 57: 1063-8. 10.2337/db07-1292.CrossRefPubMed
18.
go back to reference Dhamrait SS, Stephens JW, Cooper JA, Acharya J, Mani AR, Moore K, Miller GJ, Humphries SE, Hurel SJ, Montgomery HE: Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2. Eur Heart J. 2004, 25: 468-75. 10.1016/j.ehj.2004.01.007.CrossRefPubMed Dhamrait SS, Stephens JW, Cooper JA, Acharya J, Mani AR, Moore K, Miller GJ, Humphries SE, Hurel SJ, Montgomery HE: Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2. Eur Heart J. 2004, 25: 468-75. 10.1016/j.ehj.2004.01.007.CrossRefPubMed
19.
go back to reference Palmer BR, Devereaux CL, Dhamrait SS, Mocatta TJ, Pilbrow AP, Frampton CM, Skelton L, Yandle TG, Winterbourn CC, Richards AM, Montgomery HE, Cameron VA: The common G-866A polymorphism of the UCP2 gene and survival in diabetic patients following myocardial infarction. Cardiovasc Diabetol. 2009, 15: 8-31. Palmer BR, Devereaux CL, Dhamrait SS, Mocatta TJ, Pilbrow AP, Frampton CM, Skelton L, Yandle TG, Winterbourn CC, Richards AM, Montgomery HE, Cameron VA: The common G-866A polymorphism of the UCP2 gene and survival in diabetic patients following myocardial infarction. Cardiovasc Diabetol. 2009, 15: 8-31.
20.
go back to reference Genest J, McPherson R, Frohlich J, Anderson T, Campbell N, Carpentier A, Couture P, Dufour R, Fodor G, Francis GA, Grover S, Gupta M, Hegele RA, Lau DC, Leiter L, Lewis GF, Lonn E, Mancini GB, Ng D, Pearson GJ, Sniderman A, Stone JA, Ur E: 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 2009 recommendations. Can J Cardiol. 2009, 25: 567-79.PubMedCentralCrossRefPubMed Genest J, McPherson R, Frohlich J, Anderson T, Campbell N, Carpentier A, Couture P, Dufour R, Fodor G, Francis GA, Grover S, Gupta M, Hegele RA, Lau DC, Leiter L, Lewis GF, Lonn E, Mancini GB, Ng D, Pearson GJ, Sniderman A, Stone JA, Ur E: 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 2009 recommendations. Can J Cardiol. 2009, 25: 567-79.PubMedCentralCrossRefPubMed
21.
go back to reference Kim HS, Park KG, Koo TB, Huh S, Lee IK: The modulating effects of the overexpression of uncoupling protein 2 on the formation of reactive oxygen species in vascular cells. Diabetes Res Clin Pract. 2007, 77 (1): S46-8. 10.1016/j.diabres.2007.01.032.CrossRefPubMed Kim HS, Park KG, Koo TB, Huh S, Lee IK: The modulating effects of the overexpression of uncoupling protein 2 on the formation of reactive oxygen species in vascular cells. Diabetes Res Clin Pract. 2007, 77 (1): S46-8. 10.1016/j.diabres.2007.01.032.CrossRefPubMed
22.
go back to reference Harrison D, Griendling KK, Landmesser U, Hornig B, Drexler H: Role of oxidative stress in atherosclerosis. Am J Cardiol. 2003, 91 (3A): 7A-11A. 10.1016/S0002-9149(02)03144-2.CrossRefPubMed Harrison D, Griendling KK, Landmesser U, Hornig B, Drexler H: Role of oxidative stress in atherosclerosis. Am J Cardiol. 2003, 91 (3A): 7A-11A. 10.1016/S0002-9149(02)03144-2.CrossRefPubMed
23.
go back to reference Fialkow L, Wang Y, Downey GP: :Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med. 2007, 42: 153-64. 10.1016/j.freeradbiomed.2006.09.030.CrossRefPubMed Fialkow L, Wang Y, Downey GP: :Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med. 2007, 42: 153-64. 10.1016/j.freeradbiomed.2006.09.030.CrossRefPubMed
24.
go back to reference Blanc J, Alves-Guerra MC, Esposito B, Rousset S, Gourdy P, Ricquier D, Tedgui A, Miroux B, Mallat Z: Protective role of uncoupling protein 2 in atherosclerosis. Circulation. 2003, 107: 388-90. 10.1161/01.CIR.0000051722.66074.60.CrossRefPubMed Blanc J, Alves-Guerra MC, Esposito B, Rousset S, Gourdy P, Ricquier D, Tedgui A, Miroux B, Mallat Z: Protective role of uncoupling protein 2 in atherosclerosis. Circulation. 2003, 107: 388-90. 10.1161/01.CIR.0000051722.66074.60.CrossRefPubMed
25.
go back to reference Chevillotte E, Giralt M, Miroux B, Ricquier D, Villarroya F: Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes. 2007, 56: 1042-50. 10.2337/db06-1300.CrossRefPubMed Chevillotte E, Giralt M, Miroux B, Ricquier D, Villarroya F: Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes. 2007, 56: 1042-50. 10.2337/db06-1300.CrossRefPubMed
26.
go back to reference Labayen I, Ortega FB, Sjöström M, Nilsson TK, Olsson LA, Ruiz JR: Association of common variants of UCP2 gene with low-grade inflammation in Swedish children and adolescents; the European Youth Heart Study. Pediatr Res. 2009, 66: 350-4. 10.1203/PDR.0b013e3181b1bd35.CrossRefPubMed Labayen I, Ortega FB, Sjöström M, Nilsson TK, Olsson LA, Ruiz JR: Association of common variants of UCP2 gene with low-grade inflammation in Swedish children and adolescents; the European Youth Heart Study. Pediatr Res. 2009, 66: 350-4. 10.1203/PDR.0b013e3181b1bd35.CrossRefPubMed
27.
go back to reference Giuffrida FM, Furuzawa GK, Kasamatsu TS, Oliveira MM, Reis AF, Dib SA: HNF1A gene polymorphisms and cardiovascular risk factors in individuals with late-onset autosomal dominant diabetes: a cross-sectional study. Cardiovasc Diabetol. 2009, 2 (8): 28-10.1186/1475-2840-8-28.CrossRef Giuffrida FM, Furuzawa GK, Kasamatsu TS, Oliveira MM, Reis AF, Dib SA: HNF1A gene polymorphisms and cardiovascular risk factors in individuals with late-onset autosomal dominant diabetes: a cross-sectional study. Cardiovasc Diabetol. 2009, 2 (8): 28-10.1186/1475-2840-8-28.CrossRef
28.
go back to reference Taghavi SM, Fatemi SS, Rafatpanah H, Ganjali R, Tavakolafshari J, Valizadeh N: Mutations in the coding regions of the hepatocyte nuclear factor 4 alpha in Iranian families with maturity onset diabetes of the young. Cardiovasc Diabetol. 2009, 10 (8): 63-10.1186/1475-2840-8-63.CrossRef Taghavi SM, Fatemi SS, Rafatpanah H, Ganjali R, Tavakolafshari J, Valizadeh N: Mutations in the coding regions of the hepatocyte nuclear factor 4 alpha in Iranian families with maturity onset diabetes of the young. Cardiovasc Diabetol. 2009, 10 (8): 63-10.1186/1475-2840-8-63.CrossRef
29.
go back to reference Reiner AP, Barber MJ, Guan Y, Ridker PM, Lange LA, Chasman DI, Walston JD, Cooper GM, Jenny NS, Rieder MJ, Durda JP, Smith JD, Novembre J, Tracy RP, Rotter JI, Stephens M, Nickerson DA, Krauss RM: Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet. 2008, 82: 1193-201. 10.1016/j.ajhg.2008.03.017.PubMedCentralCrossRefPubMed Reiner AP, Barber MJ, Guan Y, Ridker PM, Lange LA, Chasman DI, Walston JD, Cooper GM, Jenny NS, Rieder MJ, Durda JP, Smith JD, Novembre J, Tracy RP, Rotter JI, Stephens M, Nickerson DA, Krauss RM: Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet. 2008, 82: 1193-201. 10.1016/j.ajhg.2008.03.017.PubMedCentralCrossRefPubMed
30.
go back to reference Carlson CS, Aldred SF, Lee PK, Tracy RP, Schwartz SM, Rieder M, Liu K, Williams OD, Iribarren C, Lewis EC, Fornage M, Boerwinkle E, Gross M, Jaquish C, Nickerson DA, Myers RM, Siscovick DS, Reiner AP: Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet. 2005, 77: 64-77. 10.1086/431366.PubMedCentralCrossRefPubMed Carlson CS, Aldred SF, Lee PK, Tracy RP, Schwartz SM, Rieder M, Liu K, Williams OD, Iribarren C, Lewis EC, Fornage M, Boerwinkle E, Gross M, Jaquish C, Nickerson DA, Myers RM, Siscovick DS, Reiner AP: Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet. 2005, 77: 64-77. 10.1086/431366.PubMedCentralCrossRefPubMed
Metadata
Title
Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients C-reactive protein in type 2 diabetic patients
Authors
Emanuela Lapice
Michele Pinelli
Elisabetta Pisu
Antonella Monticelli
Roberto Gambino
Gianfranco Pagano
Silvia Valsecchi
Sergio Cocozza
Gabriele Riccardi
Olga Vaccaro
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2010
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/1475-2840-9-68

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