VITAMIN D RECEPTOR GENE POLYMORPHISMS AND HAPLOTYPE ANALYSIS IN TYPE 2 DIABETES MELLITUS PATIENTS FROM NORTH INDIA

Nancy Taneja; Rajesh Khadgawat; Shalini Mani

doi:10.22159/ajpcr.2017.v10i10.20453

Authors

Nancy Taneja Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
Rajesh Khadgawat Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India.
Shalini Mani Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India

DOI:

https://doi.org/10.22159/ajpcr.2017.v10i10.20453

Keywords:

Type 2 diabetes, Vitamin D, Vitamin D receptor, Polymorphisms, Haplotype

Abstract

Â

Â Objective: Vitamin D receptor (VDR) mediated Vitamin D signaling is important for expression of insulin gene and glucose transporters, which help in glucose uptake by cells. Current evidence suggests that four common polymorphisms (FokI, BsmI, ApaI, TaqI) of VDR gene are associated with Type 2 diabetes mellitus (T2DM) in different populations. However, there is a scarcity of data on VDR polymorphisms from Indian population.

Methods: In the current study, total genomic DNA was isolated from 100 well-characterized T2DM patients and 100 healthy controls. We investigated the prevalence of FokI and ApaI polymorphisms in VDR gene of these patients by polymerase chain reaction-restriction fragment length polymorphism-based method. Taking help of our previous published data on TaqI and BsmI polymorphisms in same patients, the haplotype study was also conducted. Statistical analysis of data was performed using SPSS 21.0 software. Haplotype and linkage disequilibrium analysis was performed by Haploview software.

Results: Both the wild (TT) and mutant (CC) genotype of FokI polymorphism showed a significant difference between patients and controls (p<0.001 and p<0.001, respectively). The frequency of mutant allele (C) was also significantly higher in T2DM patients than the controls (p<0.001). In case of ApaI, frequency of wild (GG) and mutant (CC) genotype was significantly different in patients and controls (p=0.017 and p=0.034). As per haplotype analysis, the CACT haplotype was predicted to be of significance in patients and consists of mutant alleles of three polymorphisms (FokI, BsmI, ApaI).

Conclusion: Our study supports the association of FokI and ApaI polymorphism in T2DM. The haplotype analysis also indicates that the combinations of mutant allele of different VDR polymorphisms are probably responsible for increased susceptibility of these individuals toward T2DM.

Downloads

Download data is not yet available.

References

Chantal M, Conny G, Annapaula G, Roger B. Vitamin D and diabetes. Diabetologia 2005;48:1247-57.

Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinol Metab Clin North Am 2010;39(2):419-46.

Palomer X, GonzÃ¡lez-Clemente JM, Blanco-Vaca F, Mauricio D. Role of vitamin D in the pathogenesis of Type 2 diabetes mellitus. Diabetes Obes Metab 2008;10(3):185-97.

Mitri J, Pittas AG. Vitamin D and diabetes. Endocrinol Metab Clin North Am 2014;43(1):205-32.

Kalsi A, Singh S, Taneja N, Kukal S, Mani S. Current treatment for Type 2 diabetes, their side effects and possible complementary treatments. Int J Pharm Pharm Sci 2015;3:13-8.

Carlberg C. The concept of multiple vitamin D signaling pathways. J Investig Dermatol Symp Proc 1996;1(1):10-4.

Hossein-Nezhad A, Spira A, Holick MF. Influence of vitamin D status

and vitamin D3 supplementation on genome wide expression of white blood cells: A randomized double-blind clinical trial. PLoS One 2013;8(1):e58725.

Montecino M, Stein GS, Stein JL, Lian JB, van Wijnen AJ, Carvallo L, et al. Vitamin D control of gene expression: Temporal and spatial parameters for organization of the regulatory machinery. Crit Rev Eukaryot Gene Expr 2008;18(2):163-72.

Zittermann A. Vitamin D in preventive medicine: Are we ignoring the evidence? Br J Nutr 2003;89(5):552-72.

McCullough ML, Stevens VL, Diver WR, Feigelson HS, Rodriguez C, Bostick RM, et al. Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: A nested case-control study. Breast Cancer Res 2007;9(1):R9.

Cicek MS, Liu X, Schumacher FR, Casey G, Witte JS. Vitamin D receptor genotypes/haplotypes and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2006;15:2549-52.

Mittal RD, Mishra DK, Srivastava P, Manchanda P, Bid HK, Kapoor R. Polymorphisms in the vitamin D receptor and the androgen receptor gene associated with the risk of urolithiasis. Indian J Clin Biochem 2010;25(2):119-26.

GyÃ¶rffy B, VÃ¡sÃ¡rhelyi B, Krikovszky D, MadÃ¡csy L, Tordai A, Tulassay T, et al. Gender-specific association of vitamin D receptor polymorphism combinations with Type 1 diabetes mellitus. Eur J Endocrinol 2002;147(6):803-8.

Li HM, Miao H, Lu YB, Gen HF, Jiang XQ. Association between DNA polymorphism of human vitamin D receptor gene and Type 2 diabetes mellitus. China J Mod Med 2005;15:989-92.

Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, et al. Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol 1997;11(8):1165-79.

Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, et al. Prediction of bone density from vitamin D receptor alleles. Nature 1994;367(6460):284-7.

Cyganek K, Mirkiewicz-Sieradzka B, Malecki MT, Wolkow P, Skupien J, Bobrek J, et al. Clinical risk factors and the role of VDR gene polymorphisms in diabetic retinopathy in Polish Type 2 diabetes patients. Acta Diabetol 2006;43(4):114-9.

Malecki MT, Frey J, Moczulski D, Klupa T, Kozek E, Sieradzki J. Vitamin D receptor gene polymorphisms and association with Type 2 diabetes mellitus in a Polish population. Exp Clin Endocrinol Diabetes 2003;111(8):505-9.

Ye WZ, Reis AF, Dubois-Laforgue D, BellannÃ©-Chantelot C, Timsit J, Velho G. Vitamin D receptor gene polymorphisms are associated with obesity in Type 2 diabetic subjects with early age of onset. Eur J Endocrinol 2001;145(2):181-6.

Al-Daghri NM, Al-Attas OS, Alkharfy KM, Khan N, Mohammed AK, Vinodson B, et al. Association of VDR-gene variants with factors related to the metabolic syndrome, Type 2 diabetes and vitamin D deficiency. Gene 2014;542(2):129-33.

Bid HK, Konwar R, Aggarwal CG, Gautam S, Saxena M, Nayak VL, et al. Vitamin D receptor (FokI, BsmI and TaqI) gene polymorphisms and Type 2 diabetes mellitus: A North Indian study. Indian J Med Sci 2009;63(5):187-94.

Taneja N, Khadgawat R, Mani S. BsmI and TaqI polymorphisms in Vitamin D receptor gene of Type 2 diabetes mellitus patients from north India. Asian J Pharm Clin Res 2016;9:186-9.

Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of Vitamin D receptor polymorphisms. Gene 2004;338(2):143-56.

Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16(3):1215.

Naito M, Miyaki K, Naito T, Zhang L, Hoshi K, Hara A, et al. Association between Vitamin D receptor gene haplotypes and chronic periodontitis among Japanese men. Int J Med Sci 2007;4(4):216-22.

Harris SS, Eccleshall TR, Gross C, Dawson-Hughes B, Feldman D. The Vitamin D receptor start codon polymorphism (FokI) and bone mineral density in premenopausal American black and white women. J Bone Miner Res 1997;12(7):1043-8.

Ogunkolade BW, Boucher BJ, Prahl JM, Bustin SA, Burrin JM, Noonan K, et al. Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to Vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. Diabetes 2002;51(7):2294-300.

Reis AF, Hauache OM, Velho G. Vitamin D endocrine system and the genetic susceptibility to diabetes, obesity and vascular disease. A review of evidence. Diabetes Metab 2005;31:318-25.

McDermott MF, Ramachandran A, Ogunkolade BW, Aganna E, Curtis D, Boucher BJ, et al. Allelic variation in the Vitamin D receptor influences susceptibility to IDDM in Indian Asians. Diabetologia 1997;40(8):971-5.

Hitman GA, Mannan N, McDermott MF, Aganna E, Ogunkolade BW, Hales CN, et al. Vitamin D receptor gene polymorphisms influence insulin secretion in Bangladeshi Asians. Diabetes 1998;47(4):688-90.

Speer G, Cseh K, Winkler G, Vargha P, Braun E, TakÃ¡cs I, et al. Vitamin D and estrogen receptor gene polymorphisms in Type 2 diabetes mellitus and in android type obesity. Eur J Endocrinol 2001;144(4):385-9.

Filus A, Trzmiel A, Kuliczkowska-Plaksej J, Tworowska U, Jedrzejuk D, Milewicz A, et al. Relationship between Vitamin D receptor BsmI and FokI polymorphisms and anthropometric and biochemical parameters describing metabolic syndrome. Aging Male 2008;11(3):134-9.

Ortlepp JR, Lauscher J, Hoffmann R, Hanrath P, Joost HG. The Vitamin D receptor gene variant is associated with the prevalence of Type 2 diabetes mellitus and coronary artery disease. Diabet Med 2001;18(10):842-5.

Oh J, Barrett-Connor E. Association between VDR polymorphism and Type 2 diabetes or metabolic syndrome in community-dwelling older adults: The Rancho Bernardo study. Metabolism 2002;5:356-9.

Leandro AC, Rocha MA, Cardoso CS, Bonecini-Almeida MG. Genetic polymorphisms in Vitamin D receptor, Vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-gamma genes and its association with susceptibility to tuberculosis. Braz J Med Biol Res 2009;42(4):312-22.

Wang H, Craig RL, Schay J, Chu W, Das SK, Zhang Z, et al. Alpha-endosulfine, a positional and functional candidate gene for Type 2 diabetes: Molecular screening, association studies, and role in reduced insulin secretion. Mol Genet Metab 2004;81:9-15.

Li L, Wu B, Liu JY, Yang LB. Vitamin D receptor gene polymorphisms and Type 2 diabetes: A meta-analysis. Arch Med Res 2013;44(3):235-41.

VÃ©layoudom-CÃ©phise FL, Larifla L, Donnet JP, Maimaitiming S, Deloumeaux J, Blanchet A, et al. Vitamin D deficiency, vitamin D receptor gene polymorphisms and cardiovascular risk factors in Caribbean patients with Type 2 diabetes. Diabetes Metab 2011;37(6):540-5.

Howard G, Nguyen T, Morrison N, Watanabe T, Sambrook P, Eisman J, et al. Genetic influences on bone density: Physiological correlates of vitamin D receptor gene alleles in premenopausal women. J Clin Endocrinol Metab 1995;80(9):2800-5.

Mocharla H, Butch AW, Pappas AA, Flick JT, Weinstein RS, de Togni P, et al. Quantification of vitamin D receptor mRNA by competitive polymerase chain reaction in PBMC: Lack of correspondence with common allelic variants. J Bone Miner Res 1997;12:726-33.

Yu F, Cui LL, Li X, Wang CJ, Ba Y, Wang L, et al. The genetic polymorphisms in vitamin D receptor and the risk of Type 2 diabetes mellitus: An updated meta-analysis. Asia Pac J Clin Nutr 2016;25(3):614-24.

Wang Q, Xi B, Reilly KH, Liu M, Fu M. Quantitative assessment of the associations between four polymorphisms (FokI, ApaI, BsmI, TaqI) of vitamin D receptor gene and risk of diabetes mellitus. Mol Biol Rep 2012;39(10):9405-14.

Zhong X, Du Y, Lei Y, Liu N, Guo Y, Pan T. Effects of vitamin D receptor gene polymorphism and clinical characteristics on risk of diabetic retinopathy in Han Chinese Type 2 diabetes patients. Gene 2015;566(2):212-6.

Selvaraj P, Prabhu Anand S, Harishankar M, Alagarasu K. Plasma 1,25 dihydroxy vitamin D3 level and expression of vitamin D receptor and cathelicidin in pulmonary tuberculosis. J Clin Immunol 2009;29(4):470-8.

Mallayasamy M, David HA, Pandian PR. Comparison of angiotensin receptor blocker alone and in combination with vitamin D analogue in reducing proteinuria in diabetic nephropathy patients. Int J Pharm Pharm Sci 2014;6:201-4.

Morrison NA, Yeoman R, Kelly PJ, Eisman JA. Contribution of trans-acting factor alleles to normal physiological variability: Vitamin D receptor gene polymorphism and circulating osteocalcin. Proc Natl Acad Sci U S A 1992;89(15):6665-9.