In Africa, the prevalence of
diabetes is escalating and remains a concern due to the numerous complications
it causes. Vascular damage associated with diabetes leads to a prothrombotic
state observed in diabetic individuals. Diabetes is a complex and
multifactorial disease involving genetic components. With the aim of preventing
complications and contributing to an efficient management of diabetes, we
investigated genes likely to lead to a risk of thrombosis, in particular the C677T
of MTHFR, G20210A of prothrombin, and R506Q of factor V Leiden in type 2
diabetics in Abidjan receiving ambulatory care. A descriptive cross-sectional
study was carried out on consenting type 2 diabetic patients. Mutation
detection was carried out using the PCR-RFLP method employing restriction enzymes.
Hemostasis tests (fibrinogen, D-dimers, fibrin monomers, and von Willebrand
factor) were performed using citrate tubes on the Stage? Star Max automated
system. Plasminogen activator inhibitor was assayed by ELISA method, and
biochemical parameters were determined using the COBAS C311. The study
population consisted of 45 diabetic patients, 51.1% of whom presented vascular
complications, mainly neuropathy. Disturbances in hemostasis parameters were
observed, with 15.5% of patients showing an increase in fibrin monomers.
Mutation analysis revealed an absence of factor V mutation (factor V Leiden)
and of G20210A mutation of the prothrombin gene. However, 15.6% of subjects had
a heterozygous C677T mutation of MTHFR, with 57% of them being anemic. The exploration of biological and genetic factors
associated with thrombotic risk is of significant interest in the optimal
management of African type 2 diabetics.
References
[1]
El Hajj Chehadeh, S.W., Jelinek, H.F., Al Mahmeedc, W.A., et al. (2016) Al Safar Relationship between MTHFR C677T and A1298C Gene Polymorphisms and Complications of Type 2 Diabetes Mellitus in an Emirati Population. Meta Gene, 9, 70-75. https://doi.org/10.1016/j.mgene.2016.04.002
[2]
Atlas du diabéte de la FID 9éme édition (2019). 176 p. https://www.diabetesatlas.org
[3]
Atlas du diabète FID (2021). https://idf.org
[4]
Kouakou adjoua yeboua florence, Kamagate adama and Yapo angoue paul (2016) Complications du Diabète en Côte d’Ivoire chez les Patients Diagnostiques Tardivement. European Scientific Journal, 27, 250-262. https://doi.org/10.19044/esj.2016.v12n27p250
[5]
Oga, A.S.S., Tebi, A., Aka, J., et al. (2006) Le diabète sucre diagnostique en Côte d’ivoire: Des particularités épidémiologiques. Médecine Tropicale, 66, 241-246.
[6]
Jean-Claude, M. and Eugene, S. (2003) Diabetes Microvascular and Macrovascular Disease in Africa. European Journal of Cardiovascular Prevention & Rehabilitation, 10, 97-102. https://doi.org/10.1177/174182670301000204
[7]
Baynes, H.W. (2015) Classification, Pathophysiology, Diagnosis and Management of Diabetes Mellitus. Journal of Diabetes & Metabolism, 6, 541-549.
[8]
Vazzana, N., Ranalli, P., Cuccurullo, C. and Davì, G. (2012) Diabetes Mellitus and Thrombosis. Thrombosis Research, 129, 371-377. https://doi.org/10.1016/j.thromres.2011.11.052
[9]
Audelin, M.C. and Genest, J. (2001) Homocysteine and Cardiovascular Disease in Diabetes Mellitus. Atherosclerosis, 159, 497-511. https://doi.org/10.1016/S0021-9150(01)00531-7
[10]
Grundy, S.M., Benjamin, U., Burke, G.L., Chait, A., Eckel, R.H., Howard, B.V., et al. (1999) Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association. Circulation, 100, 1134-1146. https://doi.org/10.1161/01.CIR.100.10.1134
[11]
Bertina, R.M., et al. (2001) Genetic Approach to Thrombophilia. Thrombosis and Haemostasis-Stuttgart, 86, 92-103. https://doi.org/10.1055/s-0037-1616205
[12]
Very, E., Berkane, N. and Magdelaine, A. (1999) Facteur V Leiden Hyperhomocysteinemie Mutation C677T de la MTHFR. Mutation G20210A de la prothrombine et complications obstétricales. Annales de Biologie Clinique, 57, 539-544.
[13]
Maeda, M., Yamamoto, I., Fukuda, M., et al. (2003) MTHFR Gene Polymorphism as a Risk Factor for Diabetic Retinopathy in Type 2 Diabetic Patients without Serum Creatinine Elevation. Diabetes Care, 26, 547-548. https://doi.org/10.2337/diacare.26.2.547-a
[14]
Mehri, S., Koubaa, N., Nakbi, A., et al. (2010) Relationship between Genetic Polymorphisms of Angiotensin-Converting Enzyme and Methylenetetrahydrofolate Reductase as Risk Factors for Type 2 Diabetes in Tunisian Patients. Clinical Biochemistry, 43, 259-266. https://doi.org/10.1016/j.clinbiochem.2009.10.008
[15]
Sun, J., Xu, Y., Xue, J., Zhu, Y. and Lu, H. (2005) Methylenetetrahydrofolate Reductase Polymorphism Associated with Susceptibility to Coronary Heart Disease in Chinese Type 2 Diabetic Patients. Molecular and Cellular Endocrinology, 229, 95-101. https://doi.org/10.1016/j.mce.2004.09.003
[16]
Weisberg, I., Tran, P., Christensen, B., et al. (1998) A Second Genetic Polymorphism in Methylenetetrahydrofolate Reductase (MTHFR) Associated with Decreased Enzyme Activity. Molecular Genetics and Metabolism, 64, 169-172. https://doi.org/10.1006/mgme.1998.2714
[17]
Ksiazek, P., Bednarek-Skublewsk, A. and Buraczynska, M. (2004) The C677T Methylenetetrahydrofolate Reductase Gene Mutation and Nephropathy in Type 2 Diabetes Mellitus. Medical Science Monitor, 10, BR47-BR51.
[18]
Sun, J., Xu, Y., Zhu, Y., et al. (2004) Genetic Polymorphism of Methylenetetrahydrofolate Reductase as a Risk Factor for Diabetic Nephropathy in Chinese Type 2 Diabetic Patients. Diabetes Research and Clinical Practice, 64, 185-190. https://doi.org/10.1016/j.diabres.2003.10.022
[19]
Lee, R. and Frenkel, E.P. (2003) Hyperhomocysteinemia and Thrombosis. Hematology/Oncology Clinics of North America, 17, 85-102. https://doi.org/10.1016/S0889-8588(02)00090-4
[20]
Whayne, T.F. (2015) Methylenetetrahydrofolate Reductase C677T Polymorphism, Venous Thrombosis, Cardiovascular Risk and Other Effects. Angiology, 66, 401-404. https://doi.org/10.1177/0003319714548871
[21]
Saeedi, P., Petersohn, I., Salpea, P., et al. (2019) Global and Regional Diabetes Prevalence Estimates for 2019 and Projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas. Diabetes Research and Clinical Practice, 157, Article ID: 107843. https://doi.org/10.1016/j.diabres.2019.107843
[22]
Bell, E.J., Folsom, A.R., Lutsey, P.L., Selvin, E., Zakai, N.A., Cushman, M. and Alonso, A. (2016) Diabetes Mellitus and Venous Thromboembolism: A Systematic Review and Meta-Analysis. Diabetes Research and Clinical Practice, 111, 10-18. https://doi.org/10.1016/j.diabres.2015.10.019
[23]
Behnam Rassouli, M., Ghayour, M.B. and Ghayour, N. (2010) Microvascular Complication of Diabetes. Journal of Biological Science, 10, 411-423. https://doi.org/10.3923/jbs.2010.411.423
[24]
Djiby, S.O.W., Diedhiou, D., Diallo, I.M., et al. (2018) Etude des facteurs de risque cardiovasculaire chez les patients diabétiques de type 2 au Centre Marc Sankalé de Dakar. Revue Africaine de Médecine Interne, 5, 43-44.
[25]
Mbaye, M., Niang, K., Sarr, A., et al. (2011) Aspects épidémiologiques du diabète au Sénégal: Résultats d’une enquête sur les facteurs de risque cardio-vasculaires dans la ville de Saint-Louis. Médecine des Maladies Métaboliques, 5, 659-654. https://doi.org/10.1016/S1957-2557(11)70343-1
[26]
Diouf, N.N., Boye, O., Soumboundou, M., et al. (2015) La corrélation entre la variation des paramètres biologiques prothrombotiques et le diabète et ses complications vasculaires. La Revue Médicale de Madagascar, 5, 557-561.
[27]
Ondze-Kafata, L.I., Kouala Landa, C., Traore-Kissima, A., Loumouamou, M., Bani, M., Amounya-Zobo, S., et al. (2012) La thrombose veineuse des membres inférieurs à brazzaville: A propos de 44 cas. Cardiologie Tropicale, 135, 1-11.
[28]
Zhou, X., et al. (2015) Prévalence et sensibilisation au diabète sucré au sein d’une population rurale en Chine: Résultats de la province du Liaoning. Diabetic Medicine, 32, 332-342.
[29]
Ntyintyane, L.M., Panz, V.R., Raal, F.J. and Gill, G.V. (2006) Metabolic Syndrome, Undiagnosed Diabetes Mellitus and Insulin Resistance Are Highly Prevalent in Urbanised South African Blacks with Coronary Artery Disease. Cardiovascular Journal of South Africa, 17, 50-55.
[30]
Scheen, A.J. and Van Gaal, L.F. (2014) Combating the Dual Burden: Therapeutic Targeting of Common Pathways in Obesity and Type 2 Diabetes. The Lancet Diabetes & Endocrinology, 2, 911-922. https://doi.org/10.1016/S2213-8587(14)70004-X
[31]
Alzahrani, S.H. and Ajjan, R.A. (2010) Coagulation and Fibrinolysis in Diabetes. Diabetes and Vascular Disease Research, 7, 260-273. https://doi.org/10.1177/1479164110383723
[32]
Fox, K.M., Gerber, P.R.A., Bolinder, B., Chen, J. and Kumar, S. (2006) Prevalence of Inadequate Glycemic Control among Patients with Type 2 Diabetes in the United Kingdom General Practice Research Database: A Series of Retrospective Analyses of Data from 1998 through 2002. Clinical Therapeutics, 28, 388-395.
[33]
Lodigiani, C., Ferrazzi, P., Di Micco, P., et al. (2009) Is There a Relationship between Factor V Leiden and Type 2 Diabetes? Journal of Translational Medicine, 7, Article No. 52. https://doi.org/10.1186/1479-5876-7-52
[34]
Hou, H.C., Ge, Z.J., Ying, P., et al. (2012) Biomarkers of Deep Venous Thrombosis. Journal of Thrombosis and Thrombolysis, 34, 335-346. https://doi.org/10.1007/s11239-012-0721-y
[35]
Agarwal, C., Bansal, K., Pujani, M., et al. (2019) Association of Coagulation Profile with Microvascular Complications and Glycemic Control in Type 2 Diabetes Mellitus—A Study at a Tertiary Care Center in Delhi. Hematology, Transfusion and Cell Therapy, 41, 31-36. https://doi.org/10.1016/j.htct.2018.05.002
[36]
El Haouari, M. and Rosado, J.A. (2008) Platelet Signalling Abnormalities in Patients with Type 2 Diabetes Mellitus: A Review. Blood Cells, Molecules and Diseases, 41, 119-123. https://doi.org/10.1016/j.bcmd.2008.02.010
[37]
Rahimy, M.C., Krishnamoorthy, R., Ahouignan, G., et al. (1998) The 20210A Allele of Prothrombin Is Not Found among Sickle Cell Disease Patients from West Africa. Thrombosis and Haemostasis, 79, 444-445. https://doi.org/10.1055/s-0037-1615011
[38]
Ferraresi, P., Marchetti, G., Legnani, C., et al. (1997) The Heterozygous 20210 G/A Prothrombin Genotype Is Associated with Early Venous Thrombosis in Inherited Thrombophilias and Is Not Increased in Frequency in Artery Disease. Arteriosclerosis, Thrombosis and Vascular Biology, 17, 2418-2422. https://doi.org/10.1161/01.ATV.17.11.2418
[39]
Bourouba, R., Houcher, B., Djabi, F., et al. (2009) The Prevalence of Methylenetetrahydrofolate Reductase 677 C-T, Factor V 1691 G-A, and Prothrombin 20210 G-A Mutations in Healthy Populations in Sétif, Algeria. Clinical and Applied Thrombosis/Hemostasis, 15, 529-534. https://doi.org/10.1177/1076029608319944
[40]
They-They, T.P., Battas, O., Slassi, I., et al. (2012) Prothrombin G20210A and Factor V Leiden Polymorphisms in Stroke. Journal of Molecular Neuroscience, 46, 210-216. https://doi.org/10.1007/s12031-011-9580-9
[41]
Williamson, D., Brown, K., Luddington, R., Baglin, C., Baglin, T. and Factor, V. (1998) Cambridge: A New Mutation (Arg306→Thr) Associated with Resistance to Activated Protein C. Blood, 91, 1140-1144. https://doi.org/10.1182/blood.V91.4.1140
[42]
Chan, W.P., Lee, C.K., Kwong, Y.L., Lam, C.K. and Liang, R. (1998) A Novel Mutation of Arg306 of Factor V Gene in Hong Kong Chinese. Blood, 91, 1135-1139. https://doi.org/10.1182/blood.V91.4.1135
[43]
Alhenc-Gelas, M., Aillaud, M.F., Delahousse, B., Freyburger, G., Le Querrec, A. and Reber, G. (2009) La recherche des facteurs biologiques de risque établis de maladie thromboembolique veineuse: état des connaissances et conséquences pour la pratique en biologie clinique. Sang Thrombose Vaisseaux, 21, 12-39. https://doi.org/10.1684/stv.2009.0404
[44]
Freyburger, G. and Labrouche, S. (2007) Facteur V Leiden (VL) et résistance à la protéine C activée (PCA), facteur II Leiden (G20210 G>A), Aspects physiopathologiques et stratégies diagnostiques. Spectra Biologie, 162, 60-74.
[45]
Nabil, M., Molka, C., Martine, V., Wassim, W.A., et al. (2007) MTHFRC677T and A1298C Gene Polymorphisms and Hyperhomocysteinemia as Risk Factors of Diabetic Nephropathy in Type 2 Diabetes Patients. Diabetes Research and Clinical Practice, 75, 99-106. https://doi.org/10.1016/j.diabres.2006.05.018
[46]
Oudi, M.E., Aouni, Z., Mazigh, C., et al. (2008) C677T Polymorphism of MTHFR Gene in Tunisian Type 2 Diabetic Population. Immunoanalyse et Biologie Spécialisée, 23, 220-223. https://doi.org/10.1016/j.immbio.2008.02.005
[47]
Pandey, S.K., Pandey, S., Mishra, R.M., et al. (2017) Prevalence of Factor V Leiden-G1691A and MTHFR-C677T Thrombosis Gene Modifier in Iron Deficiency Anemia: A Pathophysiological Effect in Indian Isolates. Indian Journal of Clinical Biochemistry, 32, 103-105. https://doi.org/10.1007/s12291-016-0577-6
[48]
Benrahma, H., Abidi, O., Melouk, L., et al. (2012) Association of the C677T Polymorphism in the Human Methylenetetrahydrofolate Reductase (MTHFR) Gene with the Genetic Predisposition for Type 2 Diabetes Mellitus in a Moroccan Population. Genetic Testing and Molecular Biomarkers, 16, 383-387. https://doi.org/10.1089/gtmb.2011.0179
[49]
Eroglu, Z., Erdogan, M., Tetik, A., et al. (2007) The Relationship of the Methylenetetrahydrofolate Reductase C677T Gene Polymorphism in Turkish Type 2 Diabetic Patients with and without Nephropathy. Diabetes/Metabolism Research and Reviews, 23, 621-624. https://doi.org/10.1002/dmrr.735
[50]
Ndrepepa, G., Kastrati, A., Braun, S., et al. (2008) Circulating Homocysteine Levels in Patients with Type 2 Diabetes Mellitus. Nutrition, Metabolism and Cardiovascular Diseases, 18, 66-73. https://doi.org/10.1016/j.numecd.2006.03.007
