Fluoride Action Network


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



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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).


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.

Author information



Arijit Chakraborty: investigation, data curation, and validation.

Sreemanta Pramanik: conceptualization, investigation, resources, writing—original draft, writing—review and editing, visualization, supervision, project administration, and funding acquisition.

Kallol Datta: formal analysis and writing—review and editing.

Rakesh Goswami: investigation, data curation, and validation.

Depanwita Saha: investigation, data curation, and validation.

Kunal Kanti Majumdar: investigation and writing—review and editing.

Nilabja Sikdar: formal analysis and writing—review and editing.

Corresponding author

Correspondence to Sreemanta Pramanik.

*Original abstract online at https://link.springer.com/article/10.1007%2Fs12011-021-03072-8