Interaction between fluoride exposure and bone metabolism-related gene polymorphisms in the susceptibility to essential hypertension.

BACKGROUND

Groundwater contaminated with high fluoride levels poses a global public health concern. While fluoride exposure has been linked to hypertension, the role of genetic polymorphisms in bone metabolism-related genes in modulating this relationship remains unclear.

OBJECTIVE

This study aimed to investigate the associations between fluoride exposure, polymorphisms in bone metabolism-related genes, and susceptibility to essential hypertension in a Han Chinese population.

METHODS

A cross-sectional study was conducted involving 837 participants (424 hypertension cases and 413 controls) from endemic fluorosis areas in China. Bayesian benchmark dose (BBMD) modeling was applied to estimate the dose-response relationship between fluoride exposure and hypertension. Multivariable logistic regression was used to evaluate associations between hypertension and single nucleotide polymorphisms (SNPs) in four genes: COL11A1 (rs2615977), LRP5 (rs3736228), SMAD3 (rs12901499), and ANP32A (rs7164503). Generalized multifactor dimensionality reduction (GMDR) was employed to assess gene-gene and gene-environment interactions.

RESULTS

Urinary fluoride (UF) was significantly associated with increased risk of hypertension (OR = 1.371, 95% CI: 1.164-1.614). BBMD analysis yielded BMD and BMDL values of 0.36 mg/L and 0.21 mg/L, respectively, at a BMR level of 5%. Certain SNPs showed significant associations in stratified subgroups. The rs2615977 AC+CC genotype was associated with increased hypertension risk in older, male, high-fluoride, and lean individuals, whereas LRP5 rs3736228 TC+TT and SMAD3 rs12901499 AG+GG genotypes conferred protective effects in specific exposure and demographic subgroups. Additionally, the ANP32A rs7164503 TC genotype was linked to reduced risk among females, high-fluoride, and lean participants. Notably, a four-locus gene-gene interaction model (COL11A1 × LRP5 × SMAD3 × ANP32A) demonstrated significant effects on hypertension susceptibility (testing balanced accuracy = 0.5931; cross-validation consistency = 10/10; P = 0.0107).

CONCLUSIONS

This study suggests an association between fluoride exposure and hypertension, and indicates that bone metabolism-related genetic polymorphisms may modify this association. These findings provide novel insights into the gene-environment interplay in fluoride-induced hypertension and highlight potential targets for precision prevention.