Journal of Scientific and Technical Research (Sharda University, Noida)

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Genetic Association of a Polymorphic Variant (rs7903146) in TCF7L2 Gene by Allele-Specific Genotyping to Predict the Susceptibility of T2DM


Affiliations
1 Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
2 School of Sciences (Zoology), Maulana Azad Urdu University, Hyderabad, India
3 Department of Statistics and Operations Research, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
4 Rajiv Gandhi Centre for Diabetes and Endocrinology, J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
5 Department of Human Genetics, Guru Nanak Dev University (GNDU), Amritsar, Punjab, India
6 School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu & Kashmir, India
     

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In type 2 diabetes mellitus (T2DM), transcription factor 7- like 2 (TCF7L2) gene has been linked its susceptibility in multiple ethnicities. This case-control study investigates the possible role of TCF7L2 variant; rs7903146 (C/T) along with anthropometric data and clinical profiles in the North Indian population. TCF7L2 polymorphism was genotyped by allele-specific PCR assay. Odds ratio (OR) and 95% Confidence Intervals were used to assess the strength of genetic association. A total of 500 human subjects consisting of 250 T2DM patients together with 250 normoglycemic controls from the region of North India. Out of total T2DM subjects, 64.4% had a family history and 74% were reported to be hypertensive. Most of the anthropometric markers showed a statistically significant (p<0.0001) association with T2DM when compared to normoglycemic controls, specifically in fasting glucose, postprandial glucose, and HbA1c. Further analysis indicates that recessive genetic model of association established that the unadjusted odds ratio of risk homozygous (TT) subjects was 2.6 fold higher (OR=2.63; 95% CI=1.27-5.43) compared to wild homozygous (CC) subjects. Simultaneously, when adjusted with age, sex, and BMI, this risk was increased up to 3.4 fold (OR=3.46; 95% CI=1.63-7.34). Risk alleles (TT subjects) were also found to be statistically significant in BMI and blood sugar parameters. This SNP was also showed significant statistical association with T2DM under dominant and co-dominant models of logistic regression even after adjusting the covariates. This study exposed the positive genetic association of the risk variant rs7903146 (T) SNP of TCF7L2 in T2DM subjects of the North India.

Keywords

rs7903146, Single Nucleotide Polymorphism, TCF7L2, Type 2 Diabetes Mellitus (T2DM).
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  • B. Badaruddoza, B. Barna, K. Matharoo, and A. J. S. Bhanwer, “A case-control association study of K121Q (rs 1044498) and G/T (rs 1225572) variants in ENPP1 and TCF7L2 genes with type 2 diabetes mellitus in north Indian Punjabi population,” Int J Diabetes Dev Ctries, vol. 35, no. 4, pp. 546-553, 2015. Available: https://doi.org/10.1007/s13410-015-0337-9

  • D. Bodhini, V. Radha, M. Dhar, N. Narayani, and V. Mohan, “The rs12255372(G/T) and rs7903146(C/T) polymorphisms of the TCF7L2 gene are associated with type 2 diabetes mellitus in Asian Indians,” Metab Clin Exp., vol. 56, no. 9, pp. 1174-1178, 2007. Available: https://doi.org/10.1016/j.metabol.2007.04.012

  • S. Cauchi, Y. El Achhab, H. Choquet, C. Dina, F. Krempler, R. Weitgasser, C. Nejjari, W. Patsch, M. Chikri, D. Meyre, and P. Froguel, “TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: A global meta-analysis,” J Mol Med., vol. 85, no. 7, pp. 777-782, 2007. Available: https://doi.org/10.1007/s00109-007-0203-4

  • G. R. Chandak, C. S. Janipalli, S. Bhaskar, S. R. Kulkarni, P. Mohankrishna, A. T. Hattersley et al., “Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population,” Diabetologia, vol. 50, no. 1, pp. 63-67, 2007. Available: https://doi.org/10.1007/s00125-006-0502-2

  • Y. C. Chang, T. J. Chang, Y. D. Jiang, S. S. Kuo, K. C. Lee, K. C. Chiu, and L. M. Chuang, “Association study of the genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population,” Diabetes, vol. 56, no. 10, pp. 2631-2637, 2007. Available: https://doi.org/10.2337/db07-0421

  • G. Chauhan, C. J. Spurgeon, R. Tabassum, S. Bhaskar, S. R. Kulkarni, A. Mahajan et al., “The risk of type 2 diabetes in 5,164 Indians,” Diabetes, vol. 59, no. 8, pp. 2068-2074, 2010. Available: https://doi.org/10.2337/db09-1386.G.C.

  • S. Cuschieri, “The genetic side of type 2 diabetes - A review,” Diabetes Metab Syndr, vol. 13, no. 4, pp. 2503-2506, 2019. Available: https://doi.org/10.1016/j.dsx.2019.07.012

  • S. S. Deeb, L. Fajas, M. Nemoto, J. Pihlajamäki, L. Mykkänen, J. Kuusisto et al., “A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity,” Nat Genet, vol. 20, no. 3, pp. 284-287, 1998. Available: https://doi.org/10.1038/3099

  • W. Ding, L. Xu, L. Zhang, Z. Han, Q. Jiang, Z. Wang, and S. Jin, “Meta-analysis of association between TCF7L2 polymorphism rs7903146 and type 2 diabetes mellitus,” BMC Med Genet, vol. 19, no. 1, pp. 1-12, 2018. Available: https://doi.org/10.1186/s12881-018-0553-5

  • Z. Doddigarla, I. Parwez, and J. Ahmad, “A hospital based study on correlation between hyperglycemia, glycated hemoglobin, lipid and oxidative stress variables in type 2 diabetes mellitus subjects: A cross sectional analysis,” World J Pharm Res, vol. 5, no. 8, pp. 729-736, 2016. Available: https://doi.org/10.20959/wjpr20168-6701

  • L. A. S. Dutra, P. G. G. Costa, L. F. R. Velasco, A. A. Amato, and G. B. Barra, “Allele-specific PCR assay to genotype SNP rs7903146 in TCF7L2 gene for rapid screening of diabetes susceptibility,” Arq Bras Endocrinol Metabol, vol. 52, no. 8, pp. 1362-1366, 2008. Available: https://doi.org/10.1590/S0004-27302008000800026

  • D. El-Lebedy, and I. Ashmawy, “Common variants in TCF7L2 and CDKAL1 genes and risk of type 2 diabetes mellitus in Egyptians,” J Genet Eng Biotechnol, vol. 14, no. 2, pp. 247-251, 2016. Available: https://doi.org/10.1016/j.jgeb.2016.10.004

  • S. Ereqat, A. Nasereddin, S. Cauchi, K. Azmi, Z. Abdeen, and R. Amin, “Association of a common variant in TCF7L2 gene with type 2 diabetes mellitus in the Palestinian population,” Acta Diabetol, vol. 47, no. suppl. 1, pp. 195-198, 2010. Available: https://doi.org/10.1007/s00592-009-0161-0

  • K. Faerch, K. Pilgaard, F. K. Knop, T. Hansen, O. Pedersen, T. Jørgensen, and J. J. Holst, “Incretin and pancreatic hormone secretion in Caucasian non-diabetic carriers of the TCF7L2 rs7903146 risk T allele,” Diabetes Obes Metab, vol. 15, no. 1, pp. 91-95, 2013. Available: https://doi.org/10.1111/j.1463-1326.2012.01675.x

  • A. L. Gloyn, M. N. Weedon, K. R. Owen, M. J. Turner, B. A. Knight, G. Hitman et al., “Large-scale association studies of variants in genes encoding the pancreatic β-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes,” Diabetes, vol. 52, no. 2, pp. 568-572, 2003. Available: https://doi.org/10.2337/diabetes.52.2.568

  • S. F. A. Grant, G. Thorleifsson, I. Reynisdottir, R. Benediktsson, A. Manolescu, J. Sainz J. et al., “Variant risk of type 2 diabetes,” Nat Genet, vol. 38, no. 3, pp. 320-323, 2006. Available: https://doi.org/10.1038/ng1732

  • C. J. Groves, E. Zeggini, J. Minton, T. M. Frayling, M. N. Weedon, N. W. Rayner et al., “Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk,” Diabetes, vol. 55, no. 9, pp. 2640-2644, 2006. Available: https://doi.org/10.2337/db06-0355

  • R. Gupta, and A. Misra, “Type 2 diabetes in India: Regional disparities,” Br J Diabetes Vasc Dis, vol. 7, no. 1, pp. 12-16, 2007. Available: https://doi.org/10.1177/14746514070070010301

  • T. Hayashi, Y. Iwamoto, K. Kaku, H. Hirose, and S. Maeda, “Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population,” Diabetologia, vol. 50, no. 5, pp. 980-984, 2007. Available: https://doi.org/10.1007/s00125-007-0618-z

  • A. Helgason, S. Pálsson, G. Thorleifsson, S. F. A. Grant, V. Emilsson, S. Gunnarsdottir et al., “Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution,” Nat Genet, vol. 39, no. 2, pp. 218-225, 2007. Available: https://doi.org/10.1038/ng1960

  • S. E. Humphries, D. Gable, J. A. Cooper, H. Ireland, J. W. Stephens, S. J. Hurel et al., “Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and AfroCaribbean men and women,” J Mol Med, vol. 84, no. 12, pp. 1-10, 2006. Available: https://doi.org/10.1007/s00109-006-0108-7

  • W. Ip, Y-T. A. Chiang, and T. Jin, “The involvement of the wnt signaling pathway and TCF7L2 in diabetes mellitus: The current understanding, dispute, and perspective,” Cell and Bioscience, vol. 2, no. 1, pp. 1-12, 2012. Available: https://doi.org/10.1186/2045-3701-2-28

  • I. A. Khan, P. Jahan, Q. Hasan, and P. Rao, “Genetic confirmation of T2DM meta-analysis variants studied in gestational diabetes mellitus in an Indian population,” Diabetes Metab Syndr, vol. 13, no. 1, pp. 688-694, 2019. Available: https://doi.org/10.1016/j.dsx.2018.11.035

  • K. Kirchhoff, F. Machicao, A. Haupt, S. A. Schäfer, O. Tschritter, H. Staiger et al., “Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion,” Diabetologia, vol. 51, no. 4, pp. 597-601, 2008. Available: https://doi.org/10.1007/s00125-008-0926-yAvailable: https://doi.org/10.1073/pnas.0701509104

  • L. Li., J. Wang, Z. Ping, Y. Li, C. Wang, Y. Shi et al., “Interaction analysis of gene variants of TCF7L2 and body mass index and waist circumference on type 2 diabetes,” Clin Nutr, vol. 39, no. 1, pp. 192-197, 2019. Available: https://doi.org/10.1016/j.clnu.2019.01.014

  • V. Lyssenko, R. Lupi, P. Marchetti, S. D. Guerra, M. Orho-Melander, P. Almgren et al., “Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes,” J Clin Investig, vol. 117, no. 8, pp. 2155-2163, 2007. Available: https://doi.org/10.1172/JCI30706

  • S. A. Miller, D. D. Dykes, and H. F. Polesky, “A simple salting out procedure for extracting DNA from human nucleated cells,” Nucleic Acids Res, vol. 16, no. 3, pp. 12-15, 1988. Available: https://doi.org/10.1093/nar/16.3.1215

  • V. Mohan, and R. Deepa, “Adipocytokines and the expanding Asian Indian phenotype,” J Assoc Physicians India, vol. 54, no. 9, pp. 685-686, 2006.

  • J. Munoz, K. H. Lok, B. A. Gower, J. R. Fernandez, G. R. Hunter, C. Lara-Castro et al., “Polymorphism in the transcription factor 7-Like 2 (TCF7L2) gene is associated with reduced insulin secretion in nondiabetic women,” Diabetes, vol. 55, no. 12, pp. 3630-3634, 2006. Available: https://doi.org/10.2337/db06-0574

  • A. Palizban, M. Nikpour, R. Salehi, and M. R. Maracy, “Association of a common variant in TCF7L2 gene with type 2 diabetes mellitus in a Persian population,” Clin Exp Med, vol. 12, no. 2, pp. 115-119, 2012. Available: https://doi.org/10.1007/s10238-011-0144-7

  • S. Peng, Y. Zhu, B. Lü, F. Xu, X. Li, and M. Lai, “TCF7L2 gene polymorphisms and type 2 diabetes risk: A comprehensive and updated meta-analysis involving 121,174 subjects,” Mutagenesis, vol. 28, no. 1, pp. 2537, 2013. Available: https://doi.org/10.1093/mutage/ges048

  • S. D. Rees, S. Bellary, A. C. Britten, J. P. O’Hare, S. Kumar, A. H. Barnett, and M. A. Kelly, “Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population,” BMC Med Genet, vol. 9, pp. 2-7, 2008. Available: https://doi.org/10.1186/1471-2350-9-8

  • M. Ridderstråle, and L. Groop, “Genetic dissection of type 2 diabetes,” Mol Cell Endocrinol, vol. 297, no. 1-2, pp. 10-17, 2009. Available: https://doi.org/10.1016/j.mce.2008.10.002

  • I. C. Rulifson, S. K. Karnik, P. W. Heiser, D. Ten Berge, H. Chen, X. Gu et al., “Wnt signaling regulates pancreatic β cell proliferation,” Proceedings of the National Academy of Sciences of the United States

  • H. Saadi, N. Nagelkerke, S. G. Carruthers, S. Benedict, S. Abdulkhalek, R. Reed et al., “Association of TCF7L2 polymorphism with diabetes mellitus, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects,” Diabetes Res Clin Pract, vol. 80, no. 3, pp. 392-398, 2008. Available: https://doi.org/10.1016/j.diabres.2008.01.008

  • P. Saeedi, I. Petersohn, P. Salpea, B. Malanda, S. Karuranga, N. Unwin et al. “Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition,” Diabetes Res Clin Pract, vol. 157, 2019, Art. no. 107843. Available: https://doi.org/10.1016/j.diabres.2019.107843

  • D. K. Sanghera, L. Ortega, S. Han, J. Singh, S. K. Ralhanl, G. S. Wander et al., “Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk,” BMC Med. Genet, vol. 9, no. 101, pp. 1-9, 2008. Available: https://doi.org/10.1186/1471-2350-9-59

  • S. A. Schäfer, O. Tschritter, F. Machicao, C. Thamer, N. Stefan, B. Gallwitz et al. “Impaired glucagonlike peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms,” Diabetologia, vol. 50, no. 12, pp. 2443-2450, 2007. Available: https://doi.org/10.1007/s00125-007-0753-6

  • R. Sladek, G. Rocheleau, J. Rung, C. Dina, J. Shen, D. Serre et al. “A genome-wide association study identifies novel risk loci for type 2 diabetes,” Nature, vol. 445, no. 7130, pp. 881-885, 2007. Available: https://doi.org/10.1038/nature05616

  • F. J. Tsai, C. F. Yang, C. C. Chen, L. M. Chuang, C. H. Lu, C. T. Chang et al. “A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese,” PLoS Genet, vol. 6, no. 2, 2010. Available: https://doi.org/10.1371/journal.pgen.1000847

  • A. Turki, G. S. Al-Zaben, N. Mtiraoui, H. Marmmuoch, T. Mahjoub, and W. Y. Almawi, “Transcription factor7-like 2 gene variants are strongly associated with type 2 diabetes in Tunisian Arab subjects,” Gene, vol. 513, no. 2, pp. 244-248, 2013. Available: https://doi.org/10.1016/j.gene.2012.10.086

  • L. Ugozzoli, and R. B. Wallace, “Allele-specific polymerase chain reaction,” Methods, vol. 2, no. 1, pp. 42-48, 1991. Available: https://doi.org/10.1016/S1046-2023(05)80124-0

  • R. Q. Wang, D. H. Zhou, B. Xi, X. S. Ge, P. Zhu, B. Wang et al. “ENPP1/PC-1 gene K121Q polymorphism is associated with obesity in european adult populations: Evidence from a meta-analysis involving 24,324 subjects,” Biomed Environ. Sci, vol. 24, no. 2, pp. 200-206, 2011. Available: https://doi.org/10.3967/0895-3988.2011.02.015

  • K. V. Yazdi, S. M. Kalantar, M. Houshmand, M. Rahmanian, M. R. Manaviat, M. R. Jahani et al., are associated with type 2 diabetes mellitus in Iranian patients,” Diabetes Metab Syndr Obes, vol. 13, pp. 897-906, 2020. Available: https://doi.org/10.2147/DMSO. S225968

  • E. Zeggini, M. N. Weedon, C. M. Lindgren, T. M. Frayling, K. S. Elliott, H. Lango et al., “Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes,” Science, vol. 316, no. 5829, pp. 1336-1341, 2007. Available: https://doi.org/10.1126/science.1142364


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  • Genetic Association of a Polymorphic Variant (rs7903146) in TCF7L2 Gene by Allele-Specific Genotyping to Predict the Susceptibility of T2DM

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Authors

Monika Sharma
Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
Arif Ahmad
School of Sciences (Zoology), Maulana Azad Urdu University, Hyderabad, India
Arti Sharma
Department of Statistics and Operations Research, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
Jamal Ahmad
Rajiv Gandhi Centre for Diabetes and Endocrinology, J. N. Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
Badaruddoza
Department of Human Genetics, Guru Nanak Dev University (GNDU), Amritsar, Punjab, India
Riaz Ahmad
Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
Iqbal Parwez
School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu & Kashmir, India

Abstract


In type 2 diabetes mellitus (T2DM), transcription factor 7- like 2 (TCF7L2) gene has been linked its susceptibility in multiple ethnicities. This case-control study investigates the possible role of TCF7L2 variant; rs7903146 (C/T) along with anthropometric data and clinical profiles in the North Indian population. TCF7L2 polymorphism was genotyped by allele-specific PCR assay. Odds ratio (OR) and 95% Confidence Intervals were used to assess the strength of genetic association. A total of 500 human subjects consisting of 250 T2DM patients together with 250 normoglycemic controls from the region of North India. Out of total T2DM subjects, 64.4% had a family history and 74% were reported to be hypertensive. Most of the anthropometric markers showed a statistically significant (p<0.0001) association with T2DM when compared to normoglycemic controls, specifically in fasting glucose, postprandial glucose, and HbA1c. Further analysis indicates that recessive genetic model of association established that the unadjusted odds ratio of risk homozygous (TT) subjects was 2.6 fold higher (OR=2.63; 95% CI=1.27-5.43) compared to wild homozygous (CC) subjects. Simultaneously, when adjusted with age, sex, and BMI, this risk was increased up to 3.4 fold (OR=3.46; 95% CI=1.63-7.34). Risk alleles (TT subjects) were also found to be statistically significant in BMI and blood sugar parameters. This SNP was also showed significant statistical association with T2DM under dominant and co-dominant models of logistic regression even after adjusting the covariates. This study exposed the positive genetic association of the risk variant rs7903146 (T) SNP of TCF7L2 in T2DM subjects of the North India.

Keywords


rs7903146, Single Nucleotide Polymorphism, TCF7L2, Type 2 Diabetes Mellitus (T2DM).

References