Interactions Between BMP2/BMP4 Gene Polymorphisms and Fluoride Exposure on Essential Hypertension: A Cross-Sectional Study in China.

Fluorine, the thirteenth most abundant element on Earth, is highly accessible to the human body due to its chemical properties and geographic mobility [18]. Prior research suggests a potential link between fluoride exposure and an increased likelihood of vascular dysfunction and hypertension [19]. Previous studies investigating the correlation between fluoride exposure and blood pressure have faced several limitations, including small sample sizes, inadequate case numbers, diverse types of fluoride exposure, numerous confounding factors, and inconsistent inclusion criteria for hypertension cases. These issues have resulted in conflicting findings, with reports of positive, negative, and null associations. In our study, we addressed these limitations by investigating residents of Wenshui County, Lüliang City, Shanxi Province, who had lived in the area for at least 10 years, were of Han ethnicity, were aged 16 years or older, and had no other forms of hypertension. Potential confounding factors were rigorously controlled. Moreover, there were no statistically significant differences in the general characteristics between the included and excluded populations in this study, indicating that the study population is representative and can accurately reflect the target population. For this study, we selected urinary fluoride levels as an indicator of fluoride exposure. Regardless of whether urinary fluoride is analyzed as a continuous variable, a categorical variable, or analyzed for trend, the findings consistently demonstrate a statistically significant positive association between urinary fluoride concentration and hypertension prevalence. Notably, after adjusting for confounding factors, each 1 mg/L increase in urinary fluoride was associated with a 21% increase in hypertension risk. Additionally, urinary fluoride concentrations above 1.25 mg/L were linked to an elevated risk of hypertension, suggesting a dose-dependent effect with a potential threshold beyond which fluoride exposure may significantly raise blood pressure. This finding aligns with multiple animal studies supporting fluoride’s impact on hypertension [20,21].

Bone morphogenetic proteins (BMPs), part of the TGF-? family, play key roles in regulating cell proliferation, differentiation [22], and apoptosis [23]. Dysregulated BMP signaling contributes to skeletal and cardiovascular diseases, including hypertension [24]. BMP2 and BMP4 are particularly important in vascular smooth muscle cell (VSMC) trans-differentiation, a process that leads to the loss of muscle characteristics, increased expression of bone-related proteins, and vascular calcification, all of which are linked to hypertension [25]. Polymorphisms in BMP2 and BMP4 genes, such as rs235756 (BMP2) and rs17563 (BMP4), have been associated with cardiovascular and skeletal diseases. A study on middle-aged Finnish men found a significant association between the BMP2 gene variant (rs235756) and the BMP4 gene variant (rs4901417) were associated with hypertension [14].

This study focused on the rs17563 of the BMP4 gene and the rs1005464 of the BMP2 gene. The rs1005464 SNP is located in the non-coding region of BMP2 and is classified as an intronic variant. Its molecular and metabolic pathways have not yet been fully elucidated, but it may influence splicing patterns or affect the rate, efficiency, and accuracy of gene transcription [26]. In this study, the rs1005464 was found to be associated with hypertension. Specifically, the GG genotype increases the risk of hypertension in women, non-elderly individuals, and alcohol drinkers. On the other hand, rs17563 of BMP4 is a missense variant that causes an amino acid substitution (V152A) [27], potentially affecting mRNA stability, protein expression, and receptor binding affinity [28], thereby altering BMP4 signaling [29]. Our study demonstrated that interactions between rs17563 (BMP4) and rs235756 (BMP2) influence hypertension risk. BMP2 and BMP4 proteins share similar signaling pathways, activating Smad proteins that regulate gene expression [30]. Their combined effects in VSMCs and endothelial cells may enhance cell proliferation and contractility, increase vascular resistance [31], and promote hypertension [32]. This synergistic interaction highlights the role of BMP-related genetic variations in hypertension pathogenesis.

Diseases are influenced by the combined effects of genetic and environmental factors. In this study, an interaction between the rs17563 polymorphism of the BMP4 gene and fluoride exposure was identified. Individuals with the AG + GG genotype and high fluoride exposure had over twice the risk of hypertension compared to those with the AA genotype and low fluoride exposure, suggesting a synergistic effect. The rs17563 polymorphism is associated with elevated serum BMP4 levels [33], which contribute to vascular calcification [34], endothelial dysfunction, and inflammation, all linked to hypertension [35,36]. Previous research shows that fluoride upregulates the BMP/Smad pathway [37], stimulating BMP gene expression and increasing serum BMP levels [38], which may enhance vascular calcification. Consistent with these findings, our study identified significant interactions between urinary fluoride concentration and the rs17563 polymorphism. We hypothesize that high fluoride exposure influences vascular calcification through the BMP pathway, providing new insights into the mechanisms underlying hypertension caused by fluoride exposure.

This study identified high fluoride exposure as a significant risk factor for hypertension. The rs1005464 (G > A) polymorphism of the BMP2 gene was associated with an increased risk of hypertension. Additionally, an interaction was discovered between the BMP2 rs1005464 polymorphism and the BMP4 rs17563 polymorphism in relation to hypertension. Furthermore, UF and the BMP4 rs17563 polymorphism have an interaction on hypertension.