Determinación del polimorfismo pro12ala en el receptor activado por proliferadores de peroxisomas gamma-2 en pacientes que padecen diabetes mellitus tipo 2

Evelyn Visuete; Tomás A. Diez; Edgardo Castro; Magaly de Chial; Ana E. Tejada; Carlos W. Ramos D.

doi:10.48204/j.tecno.v27n1.a6641

Enviado diciembre 27, 2024

Publicado 2025-01-03

Artículos

Vol. 27 Núm. 1 (2025): Tecnociencia

Determinación del polimorfismo pro12ala en el receptor activado por proliferadores de peroxisomas gamma-2 en pacientes que padecen diabetes mellitus tipo 2

Evelyn Visuete ⁺⁻
Tomás A. Diez ⁺⁻
Edgardo Castro⁺⁻
Magaly de Chial⁺⁻
Ana E. Tejada ⁺⁻
Carlos W. Ramos D.⁺⁻

DOI https://doi.org/10.48204/j.tecno.v27n1.a6641

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DOI: 10.48204/j.tecno.v27n1.a6641

Publicado: 2025-01-03

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Visuete , E., Diez , T. A., Castro, E., de Chial, M., Tejada , A. E. y Ramos D., C. W. (2025) «Determinación del polimorfismo pro12ala en el receptor activado por proliferadores de peroxisomas gamma-2 en pacientes que padecen diabetes mellitus tipo 2», Tecnociencia, 27(1), pp. 125–144. doi: 10.48204/j.tecno.v27n1.a6641.

Derechos de autor 2024 Tecnociencia

Esta obra está bajo una licencia internacional Creative Commons Atribución-NoComercial-CompartirIgual 4.0.

Resumen

La diabetes mellitus es un grupo de trastornos metabólicos comunes que comparten el fenotipo de hiperglucemia. El polimorfismo Pro12Ala en el exón B del gen que codifica para PPARg2 ha sido asociado en algunas poblaciones con diabetes tipo 2. El objetivo de este estudio fue determinar si existe asociación del polimorfismo Pro12Ala de PPARg2 y la diabetes mellitus tipo 2 en una muestra de la población panameña. Se evaluó la posible asociación del polimorfismo Pro12Ala en una muestra de 195 individuos (99 controles y 96 experimentales) de la población panameña. El polimorfismo Pro12Ala se detectó mediante análisis de reacción en cadena de la polimerasa y polimorfismo de longitud de fragmentos de restricción (PCR-RFLP). Se observó una mayor frecuencia del genotipo Pro12Ala en el grupo experimental (DM2) con respecto al grupo control (0.114 vs 0.010). La frecuencia del alelo Ala12 (alelo de menor frecuencia) en nuestro estudio fue de 2.8%. Este trabajo representa el primer estudio sobre asociación entre diabetes mellitus tipo 2 y el polimorfismo Pro12Ala (rs18012829) en una muestra de casos y controles. La razón de momios (OR) evidenció asociación con un riesgo relativo de 1.9735 en aquellos con genotipo Pro12Ala. La frecuencia del genotipo Pro12Ala fue mayor en mujeres lo cual sugiere que éstas pueden estar más predispuestas a desarrollar esta condición.

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Ahmed, S. A. H., Ansari, S. A., Mensah-Brown, E. P. K. & Emerald, B. S. (2020). Clinical Epigenetics. 12:104 https://doi.org/10.1186/s13148-020-00896-4
Altshuler, D., Hirschhorn, J., Klannemark, M. et al. (2000). The common PPAR? Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26, 76–80. https://doi.org/10.1038/79216
Andrulionyté, L., Zacharova, J., Chiasson, J. et al. (2004). Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial. Diabetologia, 47(12), 2176–2184. https://doi.org/10.1007/s00125-004-1577-2
AsocMexDiabetes. (2021, 30 junio). TRANSPORTADORES DE GLUCOSA (GLUTS). Asociación Mexicana. https://www.amdiabetes.org/post/transportadores-de-glucosa-gluts
Badii, R., Bener, A., Zirie, M. et al. (2008). Lack of association between the Pro12ALA polymorphism of the PPAR-?2 gene and Type 2 diabetes mellitus in the Qatari consanguineous population. Acta Diabetologica, 45(1), 15-21. https://doi.org/10.1007/s00592-007-0013-8
Bouassida, K., Chouchane, L., Jellouli, K. et al. (2005). The peroxisome proliferator activated receptorgamma2 (PPARgamma2) Pro12Ala variant: lack of association with type 2 diabetes in obese and non obese Tunisian patients. Diabetes Metab; 31(2):119-23. doi: 10.1016/s1262-3636(07)70177-5.
Cañizales-Quinteros, Aguilar-Salinas, C., Ortiz-López, M G. et al. (2007). Association of PPARG2 Pro12Ala variant with larger body mass index in Mestizo and Amerindian populations of Mexico. Hum Biol. 79(1):111-9. doi: 10.1353/hub.2007.0022.
Castro, E., Trejos, D., Hrbek, T. et al. (2016). Genetic Ancestry of the Panamanian Population: Polymorphic Structure, Chibchan Amerindian Genes; and Biological Perspectives on Diseases. The Internet Journal of Biological Anthropology. Volume 9 Number 1. Doi: 10.5580/IJBA.44045
Chistiakov, D. A., Potapov, V. A., Nosikov, V. V. et al. (2010) The PPARgamma Pro12Ala variant is associated with insulin sensitivity in Russian normoglycaemic and type 2 diabetic subjects. Diab. Vasc. Dis. Res. 7, 56–62. https://doi.org/10.1177/1479164109347689
Christiansen, C., Arathimos, R., Pain, O. et al. (2023). Stratified genome-wide association análisis of type2 diabetes reveals subgroups with genetic and environmental heterogeneity. Human Molecular Genetics 32 (16): 2638-2645.
Cohen, A. M., Bavly, S. & Poznanski, R. (1961). Change of diet of Yemenite Jews in relation to diabetes and ischemic heart disease. Lancet 21399-1401.
Danawati, C. W., Nagata, M., Moriyama, H. et al. (2005). A possible association of Pro12ALA polymorphism in peroxisome proliferator-activated receptor ?2 gene with obesity in native Javanese in Indonesia. Diabetes/Metabolism Research and Reviews, 21(5), 465-469. https://doi.org/10.1002/dmrr.543
Doney, A., Fischer, B., Cecil, J. et al. (2004). Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes. Diabetologia 47, 555–558.
EpI InfoTM | CDC. (s. f.). https://www.cdc.gov/epiinfo/index.html
Evans, D. et al. (2001). Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor gamma (PPAR gamma) gene and type 2 diabetes. Exp. Clin. Endocrinol. Diabetes109, 151–154, 10.1055/s-2001-14838.
Florez, J. et al.( 2007). Diabetes Prevention Program Research Group. Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. J Clin Endocrinol Metab. 2007 Apr;92(4):1502-9. doi: 10.1210/jc.2006-2275.
Fornage, M. et al. (2005). Inverse effects of the PPARc2 Pro12Ala polymorphism on measures of adiposity over 15 years in African Americans and whites The CARDIA study. Metabolism Clinical and Experimental, 54, 910 – 917
Frederiksen, L. et al. (2002). Comentario: estudios del polimorfismo Pro12Ala del gen PPAR-gamma en la cohorte danesa MONICA: la homocigosidad del alelo Ala confiere un menor riesgo de síndrome de resistencia a la insulina. J Clin Endocrinol Metab. 87: 3989–3992.
Gardner, L. I. et al. (1984). Prevalence of diabetes in Mexican Americans: relationship to percent of gene pool derived from Native American genetic admixture. Diabetes 3336-92.
Ghoussaini, M. et al. (2005). Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population. BMC Med Genet. 22;6:11.doi:10.1186/1471-2350-6-11.
Gouda, H. et al. (2010). The Association Between the Peroxisome Proliferator-Activated Receptor-g2 (PPARG2) Pro12Ala Gene Variant and Type 2 Diabetes Mellitus: A HuGE Review and Meta-Analysis. Am. J. Epidemiol 171:645-655. doi: 10.1093/aje/kwp450
Hara, K. et al. (2000). The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun. 29;271(1):212-6 doi: 10.1006/bbrc.2000.2605.
Hamman, R. (1992). Genetics and environmental determinants of Non-Insulin Dependent Diabetes Mellitus (NIDDM). DiabetesIMetabolism Reviews, Vol. 8, No. 4, 287-338
Hegele, R. A. et al. (2000). Peroxisome Proliferator-Activated Receptor-?2 P12A and Type 2 diabetes in Canadian Oji-Cree. The Journal of Clinical Endocrinology & Metabolism, 85(5), 2014-2019. https://doi.org/10.1210/jcem.85.5.6610
Hur, H. et al. (2022). Association of Polygenic Variants with Type 2 Diabetes Risk and Their Interaction with Lifestyles in Asians. Nutrients, 14, 3222. https:// doi.org/10.3390/ nu141 53222
Irgam, K. et al. (2021). The genetic susceptibility profile of type 2 diabetes and reflection of its possible role related to reproductive dysfunctions in the southern Indian population of Hyderabad. BMC Medical Genomics. 14:272
Iyengar, S. et al. (1991). Amerindian admixture among the Anglo and Hispanic ethnic groups in the San Luis Valley, Colorado. Am f Phys Anthropol Suppl. 12:97-98.
Janani, C., & Ranjitha Kumari, B. (2014). PPAR gamma gene – A review. Diab Met Syndr: Clin Res Rev, http://dx.doi.org/10.1016/j.dsx.2014.09.015
Jaziri, R. et al. (2006). The PPARG Pro12Ala polymorphism is associated with a decreased risk of developing hyperglycemia over 6 years and combines with the effect of the APM1 G-11391A single nucleotide polymorphism: the Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Diabetes 55 1157–1162
Kawate, R. et al. (1979) Diabetes mellitus and its vascular complications in Japanese migrants and on the island of Hawaii. Diabetes Cure 2:161-170.
Kilpelainen, T. et al. (2008). SNPs in PPARG associate with type 2 diabetes and interact with physical activity. Med Sci Sports Exerc. 40(1):25-33. doi: 10.1249/mss.0b013e318159d1cd.
Kirk, B. et al. (2002). Single Nucleotide Polymorphism seeking long term association with complex disease. Nucleic Acid Research. Vol 30 No 15 3295-3311
Klimentidis, Y., Miller, G., & Shriver, M. (2009). The Relationship Between European Genetic Admixture and Body Composition Among Hispanics and Native Americans. Am. J. Hum. Biol. 21:377–382.
Ling, C., Bacos, K. & Rönn, T. (2022). Epigenetics of type 2 diabetes mellitus and weight change — a tool for precision medicine?. Nat Rev Endocrinol 18, 433–448. https://doi.org/10.1038/s41574-022-00671-w
Lucier, J., Weinstock RS. Type 1 Diabetes. (2023) Mar 3. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 29939535.
Majid, M. et al. (2017) Association of Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) gene with type 2 diabetes mellitus in ethnic Kashmiri population. Biochem Genet. 55, 10–21, https://doi.org/10.1007/s10528-016-9765-6
Malecki, M. et al. (2003). The Pro12Ala polymorphism of PPARgamma2 gene and susceptibility to type 2 diabetes mellitus in a Polish population. Diabetes Res Clin Pract 62(2):105-11. doi: 10.1016/s0168-8227(03)00164-5.
Mancini, F. et al. (1999). Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes. Diabetes;48(7):1466-8. doi: 10.2337/diabetes.48.7.1466.
Memisoglu, A. et al. (2003). Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. Hum Mol Genet. 12(22):2923-9. doi: 10.1093/hmg/ddg318. Epub 2003 Sep 23. PMID: 14506127.
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[1] Ahmed, S. A. H., Ansari, S. A., Mensah-Brown, E. P. K. & Emerald, B. S. (2020). Clinical Epigenetics. 12:104 https://doi.org/10.1186/s13148-020-00896-4

[2] Altshuler, D., Hirschhorn, J., Klannemark, M. et al. (2000). The common PPAR? Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26, 76–80. https://doi.org/10.1038/79216

[3] Andrulionyté, L., Zacharova, J., Chiasson, J. et al. (2004). Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial. Diabetologia, 47(12), 2176–2184. https://doi.org/10.1007/s00125-004-1577-2

[4] AsocMexDiabetes. (2021, 30 junio). TRANSPORTADORES DE GLUCOSA (GLUTS). Asociación Mexicana. https://www.amdiabetes.org/post/transportadores-de-glucosa-gluts

[5] Badii, R., Bener, A., Zirie, M. et al. (2008). Lack of association between the Pro12ALA polymorphism of the PPAR-?2 gene and Type 2 diabetes mellitus in the Qatari consanguineous population. Acta Diabetologica, 45(1), 15-21. https://doi.org/10.1007/s00592-007-0013-8

[6] Bouassida, K., Chouchane, L., Jellouli, K. et al. (2005). The peroxisome proliferator activated receptorgamma2 (PPARgamma2) Pro12Ala variant: lack of association with type 2 diabetes in obese and non obese Tunisian patients. Diabetes Metab; 31(2):119-23. doi: 10.1016/s1262-3636(07)70177-5.

[7] Cañizales-Quinteros, Aguilar-Salinas, C., Ortiz-López, M G. et al. (2007). Association of PPARG2 Pro12Ala variant with larger body mass index in Mestizo and Amerindian populations of Mexico. Hum Biol. 79(1):111-9. doi: 10.1353/hub.2007.0022.

[8] Castro, E., Trejos, D., Hrbek, T. et al. (2016). Genetic Ancestry of the Panamanian Population: Polymorphic Structure, Chibchan Amerindian Genes; and Biological Perspectives on Diseases. The Internet Journal of Biological Anthropology. Volume 9 Number 1. Doi: 10.5580/IJBA.44045

[9] Chistiakov, D. A., Potapov, V. A., Nosikov, V. V. et al. (2010) The PPARgamma Pro12Ala variant is associated with insulin sensitivity in Russian normoglycaemic and type 2 diabetic subjects. Diab. Vasc. Dis. Res. 7, 56–62. https://doi.org/10.1177/1479164109347689

[10] Christiansen, C., Arathimos, R., Pain, O. et al. (2023). Stratified genome-wide association análisis of type2 diabetes reveals subgroups with genetic and environmental heterogeneity. Human Molecular Genetics 32 (16): 2638-2645.

[11] Cohen, A. M., Bavly, S. & Poznanski, R. (1961). Change of diet of Yemenite Jews in relation to diabetes and ischemic heart disease. Lancet 21399-1401.

[12] Danawati, C. W., Nagata, M., Moriyama, H. et al. (2005). A possible association of Pro12ALA polymorphism in peroxisome proliferator-activated receptor ?2 gene with obesity in native Javanese in Indonesia. Diabetes/Metabolism Research and Reviews, 21(5), 465-469. https://doi.org/10.1002/dmrr.543

[13] Doney, A., Fischer, B., Cecil, J. et al. (2004). Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes. Diabetologia 47, 555–558.

[14] EpI InfoTM | CDC. (s. f.). https://www.cdc.gov/epiinfo/index.html

[15] Evans, D. et al. (2001). Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor gamma (PPAR gamma) gene and type 2 diabetes. Exp. Clin. Endocrinol. Diabetes109, 151–154, 10.1055/s-2001-14838.

[16] Florez, J. et al.( 2007). Diabetes Prevention Program Research Group. Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. J Clin Endocrinol Metab. 2007 Apr;92(4):1502-9. doi: 10.1210/jc.2006-2275.

[17] Fornage, M. et al. (2005). Inverse effects of the PPARc2 Pro12Ala polymorphism on measures of adiposity over 15 years in African Americans and whites The CARDIA study. Metabolism Clinical and Experimental, 54, 910 – 917

[18] Frederiksen, L. et al. (2002). Comentario: estudios del polimorfismo Pro12Ala del gen PPAR-gamma en la cohorte danesa MONICA: la homocigosidad del alelo Ala confiere un menor riesgo de síndrome de resistencia a la insulina. J Clin Endocrinol Metab. 87: 3989–3992.

[19] Gardner, L. I. et al. (1984). Prevalence of diabetes in Mexican Americans: relationship to percent of gene pool derived from Native American genetic admixture. Diabetes 3336-92.

[20] Ghoussaini, M. et al. (2005). Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population. BMC Med Genet. 22;6:11.doi:10.1186/1471-2350-6-11.

[21] Gouda, H. et al. (2010). The Association Between the Peroxisome Proliferator-Activated Receptor-g2 (PPARG2) Pro12Ala Gene Variant and Type 2 Diabetes Mellitus: A HuGE Review and Meta-Analysis. Am. J. Epidemiol 171:645-655. doi: 10.1093/aje/kwp450

[22] Hara, K. et al. (2000). The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun. 29;271(1):212-6 doi: 10.1006/bbrc.2000.2605.

[23] Hamman, R. (1992). Genetics and environmental determinants of Non-Insulin Dependent Diabetes Mellitus (NIDDM). DiabetesIMetabolism Reviews, Vol. 8, No. 4, 287-338

[24] Hegele, R. A. et al. (2000). Peroxisome Proliferator-Activated Receptor-?2 P12A and Type 2 diabetes in Canadian Oji-Cree. The Journal of Clinical Endocrinology & Metabolism, 85(5), 2014-2019. https://doi.org/10.1210/jcem.85.5.6610

[25] Hur, H. et al. (2022). Association of Polygenic Variants with Type 2 Diabetes Risk and Their Interaction with Lifestyles in Asians. Nutrients, 14, 3222. https:// doi.org/10.3390/ nu141 53222

[26] Irgam, K. et al. (2021). The genetic susceptibility profile of type 2 diabetes and reflection of its possible role related to reproductive dysfunctions in the southern Indian population of Hyderabad. BMC Medical Genomics. 14:272

[27] Iyengar, S. et al. (1991). Amerindian admixture among the Anglo and Hispanic ethnic groups in the San Luis Valley, Colorado. Am f Phys Anthropol Suppl. 12:97-98.

[28] Janani, C., & Ranjitha Kumari, B. (2014). PPAR gamma gene – A review. Diab Met Syndr: Clin Res Rev, http://dx.doi.org/10.1016/j.dsx.2014.09.015

[29] Jaziri, R. et al. (2006). The PPARG Pro12Ala polymorphism is associated with a decreased risk of developing hyperglycemia over 6 years and combines with the effect of the APM1 G-11391A single nucleotide polymorphism: the Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Diabetes 55 1157–1162

[30] Kawate, R. et al. (1979) Diabetes mellitus and its vascular complications in Japanese migrants and on the island of Hawaii. Diabetes Cure 2:161-170.

[31] Kilpelainen, T. et al. (2008). SNPs in PPARG associate with type 2 diabetes and interact with physical activity. Med Sci Sports Exerc. 40(1):25-33. doi: 10.1249/mss.0b013e318159d1cd.

[32] Kirk, B. et al. (2002). Single Nucleotide Polymorphism seeking long term association with complex disease. Nucleic Acid Research. Vol 30 No 15 3295-3311

[33] Klimentidis, Y., Miller, G., & Shriver, M. (2009). The Relationship Between European Genetic Admixture and Body Composition Among Hispanics and Native Americans. Am. J. Hum. Biol. 21:377–382.

[34] Ling, C., Bacos, K. & Rönn, T. (2022). Epigenetics of type 2 diabetes mellitus and weight change — a tool for precision medicine?. Nat Rev Endocrinol 18, 433–448. https://doi.org/10.1038/s41574-022-00671-w

[35] Lucier, J., Weinstock RS. Type 1 Diabetes. (2023) Mar 3. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 29939535.

[36] Majid, M. et al. (2017) Association of Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) gene with type 2 diabetes mellitus in ethnic Kashmiri population. Biochem Genet. 55, 10–21, https://doi.org/10.1007/s10528-016-9765-6

[37] Malecki, M. et al. (2003). The Pro12Ala polymorphism of PPARgamma2 gene and susceptibility to type 2 diabetes mellitus in a Polish population. Diabetes Res Clin Pract 62(2):105-11. doi: 10.1016/s0168-8227(03)00164-5.

[38] Mancini, F. et al. (1999). Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes. Diabetes;48(7):1466-8. doi: 10.2337/diabetes.48.7.1466.

[39] Memisoglu, A. et al. (2003). Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. Hum Mol Genet. 12(22):2923-9. doi: 10.1093/hmg/ddg318. Epub 2003 Sep 23. PMID: 14506127.

[40] Meshkani, R. et al. (2007). Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPARgamma-2) gene is associated with greater insulin sensitivity and decreased risk of type 2 diabetes in an Iranian population. Clin Chem Lab Med. 45(4):477-82. doi: 10.1515/CCLM.2007.095.

[41] Moffett, S. et al. (2005). The C161 —>?T polymorphism in peroxisome proliferator-activated receptor gamma, but not P12A, is associated with insulin resistance in Hispanic and non-Hispanic white women: evidence for another functional variant in peroxisome proliferator-activated receptor gamma. Metabolism 54:1552–1556

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