Research Studies
Study Tracker
Possible Association Between Polymorphisms in ESR1, COL1A2, BGLAP, SPARC, VDR, and MMP2 Genes and Dental Fluorosis in a Population from an Endemic Region of West Bengal.Abstract
Dental fluorosis (DF) is the most prevalent form of fluorosis in India affecting millions of people all over the country. As estrogen receptor 1 (ESR1), collagen type 1 alpha 2 (COL1A2), bone ?-carboxyglutamic acid protein (BGLAP), secreted protein acidic and cysteine-rich (SPARC), vitamin D receptor (VDR), and matrix metallopeptidase 2 (MMP2) genes play critical roles in bone metabolism, bone formation, mineral metabolism, and mineralization, variants in these genes could influence susceptibility to DF. The present study was aimed at evaluating the association between 15 single-nucleotide polymorphisms (SNPs) in the six candidate genes (namely, ESR1, COL1A2, BGLAP, SPARC, VDR, and MMP2) and DF among 132 individuals (case = 71 and control = 61) living in a fluoride endemic region of West Bengal, India. No statistically significant association with disease risk was found when the genotypes and allele frequencies of each of the 15 SNPs was analyzed individually using odd’s ratio with 95% confidence interval. “CC” and “AG” haplotypes of the COL1A2 gene showed a borderline association with DF. The present study is the first in India to use multifactor dimensionality reduction (MDR) analysis for identifying gene-gene and gene-environment interactions in fluorosis. The biomarker of serum fluoride showed a significant association with the disease state among the 17 attributes (15 SNPs and 2 biomarkers of urine fluoride and serum fluoride) (P value = 0.011). The best model of MDR analysis with maximized testing accuracy involved two SNPs from the ESR1 gene (rs9340799 and rs2077647) and one SNP from BGLAP gene (rs1543294) (P value < 0.0001).
Keywords: Biomarker; Candidate gene; Dental fluorosis; Genetic association; Haplotype; Multifactor dimensionality reduction.
*Original abstract online at https://link.springer.com/article/10.1007%2Fs12011-021-03072-8
Excerpt:
References
1. Podgorski JE, Labhasetwar P, Saha D, Berg M (2018) Prediction modeling and mapping of groundwater fluoride contamination throughout India. Environ Sci Technol 52. https://doi.org/10.1021/acs.est.8b01679
2. Del Bello L (2020) Fluorosis: an ongoing challenge for India. Lancet Planet Heal 4. https://doi.org/10.1016/S2542-5196(20)30060-7
3. Majumdar KK (2011) Health impact of supplying safe drinking water containing fluoride below permissible level on flourosis patients in a fluoride-endemic rural area of West Bengal. Indian J Public Health 55. https://doi.org/10.4103/0019-557X.92411
4. Ailani V, Gupta RC, Gupta SK, Gupta K (2009) Oxidative stress in cases of chronic fluoride intoxication. Indian J Clin Biochem 24. https://doi.org/10.1007/s12291-009-0076-0
5. Singh N, Verma KG, Verma P et al (2014) A comparative study of fluoride ingestion levels, serum thyroid hormone & TSH level derangements, dental fluorosis status among school children from endemic and non-endemic fluorosis areas. Springerplus 3. https://doi.org/10.1186/2193-1801-3-7
6. Kumar S, Lata S, Yadav J, Yadav JP (2017) Relationship between water, urine and serum fluoride and fluorosis in school children of Jhajjar District, Haryana, India. Appl Water Sci 7. https://doi.org/10.1007/s13201-016-0492-2
7. Pramanik S, Saha D (2017) The genetic influence in fluorosis. Environ Toxicol Pharmacol 56. https://doi.org/10.1016/j.etap.2017.09.008
8. Ba Y, Zhang H, Wang G, et al (2011) Association of dental fluorosis with polymorphisms of estrogen receptor gene in Chinese children. Biol Trace Elem Res 143. https://doi.org/10.1007/s12011-010-8848-1
9. Dalledone M, Cunha AS, Ramazzotto LA et al (2019) Estrogen receptor gene is associated with dental fluorosis in Brazilian children. Clin Oral Investig 23. https://doi.org/10.1007/s00784-018-2778-2
10. Huang H, Ba Y, Cui L, et al (2008) COL1A2 gene polymorphisms (Pvu II and Rsa I), serum calciotropic hormone levels, and dental fluorosis. Community Dent Oral Epidemiol 36. https://doi.org/10.1111/j.1600-0528.2007.00424.x
11. Ibiyemi O, Maguire A, Valentine R et al (2020) Single nucleotide polymorphisms in COL1A2 gene and dental fluorosis among 4 and 8-year-old Nigerian children. J Dent Open Access 2. https://doi.org/10.31487/j.jdoa.2020.02.04
12. Kuchler EC, Tannure PN, Oliveira DS, Charone S, Nelson-Filho P, Silva RA, Costa MC, Antunes LS, Calasans Maia MD, Antunes LA (2017) Polymorphisms in genes involved in enamel development are associated with dental fluorosis. Arch Oral Biol 76. https://doi.org/10.1016/j.archoralbio.2017.01.009
13. Kuchler EC, Bruzamolin CD, Omori MA et al (2018) Polymorphisms in nonamelogenin enamel matrix genes are associated with dental fluorosis. Caries Res 52. https://doi.org/10.1159/000479826
14. Romualdo PC, Pucinelli CM, Tannure PN et al (2019) Evaluation of genetic polymorphisms in MMP2, MMP9 and MMP20 in Brazilian children with dental fluorosis. Environ Toxicol Pharmacol 66. https://doi.org/10.1016/j.etap.2018.12.016
15. Shu J, Li J, Fu Y et al (2020) Association of ESR1 polymorphism rs2234693 and rs9340799 with postmenopausal osteoporosis in a Chinese population. BMC Musculoskelet Disord 21. https://doi.org/10.1186/s12891-020-03359-2
16. Garcia-Giralt N, Nogués X, Enjuanes A et al (2002) Two new single-nucleotide polymorphisms in the COL1A1 upstream regulatory region and their relationship to bone mineral density. J Bone Miner Res 17. https://doi.org/10.1359/jbmr.2002.17.3.384
17. Korostishevsky M, Malkin I, Trofimov S et al (2012) Significant association between body composition phenotypes and the osteocalcin genomic region in normative human population. Bone 51. https://doi.org/10.1016/j.bone.2012.07.010
18. Ling Y, Gao X, Lin H et al (2016) A common polymorphism rs1800247 in osteocalcin gene was associated with serum osteocalcin levels, bone mineral density, and fracture: the Shanghai Changfeng Study. Osteoporos Int 27. https://doi.org/10.1007/s00198-015-3244-5
19. Delany AM, McMahon DJ, Powell JS et al (2008) Osteonectin/SPARC polymorphisms in Caucasian men with idiopathic osteoporosis. Osteoporos Int 19. https://doi.org/10.1007/s00198-007-0523-9
20. Yang XL, Hu ZD, Wu Q et al (2016) Association of polymorphisms in SPARC and NLRP2 genes with rheumatoid arthritis in a Chinese Han population. Mod Rheumatol 25. https://doi.org/10.3109/14397595.2014.903595
21. Pike JW, Meyer MB, Lee SM et al (2017) The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. J Clin Invest 127. https://doi.org/10.1172/JCI88887
22. Wu J, Shang DE, Yang S et al (2016) Association between the vitamin D receptor gene polymorphism and osteoporosis. Biomed Rep 5. https://doi.org/10.3892/br.2016.697
23. Biczo A, Szita J, McCall I et al (2020) Association of vitamin D receptor gene polymorphisms with disc degeneration. Eur Spine J 29. https://doi.org/10.1007/s00586-019-06215-7
24. Zhang Y, Gu Z, Qiu G (2013) Association of the polymorphism of MMP2 with the risk and severity of lumbar disc degeneration in the Chinese Han population. Eur Rev Med Pharmacol Sci 17:1830–1834
25. Yu Y, Xie Z, Wang J et al (2016) Single-nucleotide polymorphisms of MMP2 in MMP/TIMP pathways associated with the risk of alcohol-induced osteonecrosis of the femoral head in Chinese males A case-control study. Medicine (United States) 95. https://doi.org/10.1097/MD.0000000000005407
26. Akey J, Jin L, Xiong M (2001) Haplotypes vs single marker linkage disequilibrium tests: what do we gain? Eur J Hum Genet 9. https://doi.org/10.1038/sj.ejhg.5200619
27. Ritchie MD, Hahn LW, Roodi N et al (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69. https://doi.org/10.1086/321276
28. Cho YM, Ritchie MD, Moore JH, et al (2004) Multifactor-dimensionality reduction shows a two-locus interaction associated with type 2 diabetes mellitus. Diabetologia 47. https://doi.org/10.1007/s00125-003-1321-3
29. Tsai CT, Lai LP, Lin JL et al (2004) Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation 109. https://doi.org/10.1161/01.CIR.0000124487.36586.26
30. Zhao L, Yu C, Lv J, et al (2021) Fluoride exposure, dopamine relative gene polymorphism and intelligence: a cross-sectional study in China. Ecotoxicol Environ Saf 209. https://doi.org/10.1016/j.ecoenv.2020.111826
31. Majumder PP (1998) People of India: biological diversity and affinities. Evol Anthropol 6. https://doi.org/10.1002/(SICI)1520-6505(1998)6:3<100::AID-EVAN4>3.0.CO;2-I
32. Ramesh M, Malathi N, Aruna RM et al (2021) Role of COL2A1 gene variable number of tandem repeats (VNTR) polymorphism in susceptibility to dental fluorosis in Salem District, Tamil Nadu: a cross-sectional study. Fluoride 54:156–168. CAS Google Scholar
33. Saha D, Goswami R, Majumdar KK et al (2021) Evaluating the association between dental fluorosis and polymorphisms in bone development and mineralization genes among population from a fluoride endemic region of Eastern India. Biol Trace Elem Res 199. https://doi.org/10.1007/s12011-020-02116-9
34. Rahila C, Aswath Narayanan MB, Ramesh Kumar SG et al (2019) Association of COL1A2 (PvuII) gene polymorphism with risk and severity of dental fluorosis – a case control study. Saudi Dent J 31. https://doi.org/10.1016/j.sdentj.2019.05.004
35. Susheela AK (1991) Prevention and control of fluorosis: dental fluorosis-symptoms (1st ed) National Technology Mission on Drinking Water, New Delhi, pp 7–9
36. Maral S, Acar M, Balcik OS, et al (2015) Matrix metalloproteinases 2 and 9 polymorphism in patients with myeloproliferative diseases: a STROBE-compliant observational study. Medicine (United States) 94. https://doi.org/10.1097/MD.0000000000000732
37. Hutchinson PE, Osborne JE, Lear JT et al (2000) Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma. Clin Cancer Res 6:498–504. CAS PubMed Google Scholar
38. Beg MK, Srivastav SK, Carranza EJM, de Smeth JB (2011) High fluoride incidence in groundwater and its potential health effects in parts of Raigarh District, Chhattisgarh, India. Curr Sci 100:750–754. CAS Google Scholar
39. Khandare AL, Harikumar R, Sivakumar B (2005) Severe bone deformities in young children from vitamin D deficiency and fluorosis in Bihar-India. Calcif Tissue Int 76. https://doi.org/10.1007/s00223-005-0233-2
40. Duran-Merino D, Molina-Frechero N, Sánchez-Pérez L, et al (2020) ENAM gene variation in students exposed to different fluoride concentrations. Int J Environ Res Public Health 17. https://doi.org/10.3390/ijerph17061832
41. Jarquín-Yñezá L, Alegría-Torres JA, Castillo CG, de Jesús Mejía-Saavedra J (2018) Dental fluorosis and a polymorphism in the COL1A2 gene in Mexican children. Arch Oral Biol 96. https://doi.org/10.1016/j.archoralbio.2018.08.010
42. Tremillo-Maldonado O, Molina-Frechero N, González-González R, et al (2020) DNA sequencing reveals AMELX, ODAM and MMP20 variations in dental fluorosis. Arch Oral Biol 110. https://doi.org/10.1016/j.archoralbio.2019.104626
43. Bhattacharyya NP, Basu P, Das M, et al (1999) Negligible male gene flow across ethnic boundaries in India, revealed by analysis of Y-chromosomal DNA polymorphisms. Genome Res 9. https://doi.org/10.1101/gr.9.8.711
44. Zhao H, Pfeiffer R, Gail MH (2003) Haplotype analysis in population genetics and association studies. Pharmacogenomics 4. https://doi.org/10.1517/phgs.4.2.171.22636
45. Lin DY, Zeng D (2006) Likelihood-based inference on haplotype effects in genetic association studies. J Am Stat Assoc 101. https://doi.org/10.1198/016214505000000808
46. Chu Y, Liu Y, Guo N, et al (2021) Association between ALOX15 gene polymorphism and brick-tea type skeletal fluorosis in Tibetans, Kazaks and Han, China. Int J Environ Health Res 31. https://doi.org/10.1080/09603123.2019.1666972
Acknowledgements
Dr. Samsiddhi Bhattacharjee, Associate Professor, National Institute of Biomedical Genomics, Kalyani, West Bengal, India, is gratefully acknowledged for his help with the statistical analysis of data. Ms. Ishita Debnath and Ms. Sushmita Ghosal of School of Biotechnology and Bioinformatics, D. Y. Patil Deemed to be University, Navi Mumbai, are acknowledged for their help in standardizing the PCR conditions and genotyping of some samples for the VDR and MMP2 SNPs. The authors wish to express their sincere thanks to all the subjects who participated in the study. We are thankful to Mr. Moizul Haq of Rampurhat Paribesh Pariseva, Rampurhat, District-Birbhum, for his help in questionnaire survey, enrollment of subjects, and sample collection. KRC, CSIR-NEERI, is duly acknowledged for checking the manuscript through the anti-plagiarism software, iThenticate (KRC CSIR-NEERI/KRC/2021/NOV/KZC/1).
Funding
This work was financially supported by a grant from the Department of Biotechnology, Government of India (Project No. BT/PR8283/MED/12/619/2013) to Dr. Sreemanta Pramanik.