Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study

Abstract

Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10−6; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes.

Bacterial Community Modifies Host Genetics Effect on Early Childhood Caries

“…Taste genes may also affect the microbiome and ECC by changing diets. Our PGS did not contain SNPs in taste genes previously associated with both ECC and the microbiome (i.e., taste 2 receptor member genes) (Cruz de Jesus et al 2022;Orlova et al 2023). While we did not observe a significant association between the PGS and the CST, future research in larger cohorts should investigate these mediating pathways.…”

Role of socioeconomic factors and interkingdom crosstalk in the dental plaque microbiome in early childhood caries

“…Furthermore, the biases introduced by class imbalance for variables selected in the study, sample processing and sequencing at different time points are also inevitable in microbiome studies, however, some biases were minimized using centered log ratio transformation. Some studies have highlighted the association between host taste genetics and the incidence of caries, including ECC (de Jesus et al, 2022;Orlova et al, 2022). Therefore, the inclusion of genetic data, especially in the field of taste genetics, may help to identify the role of nutrition and food intake in the susceptibility to ECC.…”

“…The link between ECC and future caries experiences in permanent dentition highlights its importance as a critical factor in long-term oral health (Jordan et al, 2016;Tsai et al, 2023). Furthermore, ECC can increase the risk of other dental diseases, malocclusion, negative oral health related quality of life (OHRQoL), and nutritional status (Davidson et al, 2016;Khan et al, 2023;J. Lee et al, 2022;Schroth et al, 2022).…”

Interkingdom Detection of Bacterial Quorum-Sensing Molecules by Mammalian Taste Receptors

“…This may extend to other bitter receptors. A meta-analysis of GWAS data suggested that TAS2R43 and TAS2R14 gene expression levels are associated with early childhood dental caries [ 220 ]. Another study showed that variants in TAS2R3 , TAS2R4 , TAS2R5 , and TAS2R60 are also associated with severe early childhood caries [ 221 ], finding that variant taste genes were also correlated with relative abundances of bacteria and fungi [ 221 ].…”