Genome Scan of Early Childhood Caries Again Implicates Beta-Defensins

Objectives: Early childhood caries (ECC) displays a high prevalence (affecting 23-90% of children) and involvement of genetic risk factors, yet few studies have systematically investigated its genetics. Here we perform a genome-wide association study (GWAS) of ECC in 785 non-Hispanic, Caucasian children from Northern Appalachia (COHRA2 cohort).
Methods: ECC was defined as one or more primary teeth being decayed, missing (due to decay), or filled before age 6. Our study included 159 ECC-affected and 626 unaffected children aged 0.5-5 years. We tested 5 million common genetic variants for association with the binary ECC phenotype while adjusting for age, sex, and study site.
Results: 18 loci reached suggestive significance (P < 1e-5). rs2645455 (P = 7.57e-7) is downstream of a DEFB gene cluster encoding members of the defensin family (DEFB136, DEFB135, DEFB134, DEFB130). Beta-defensins are small antimicrobial proteins widely expressed in oral tissues; previous studies have found associations between other defensins and ECC/primary tooth caries. However, there was no other overlap with published caries associations.

Although we did not detect significant enrichment for particular gene sets or biological pathways among our results, additional suggestive associations were near genes with plausibly relevant functions. These include submandibular gland development (NFIB/rs56371878), wound healing in oral tissues (AQP9/rs12905748 and SIAH3/rs3014919), dental pulp stem cell aging (PSAT1/rs1505638), and tooth or craniofacial development (KCTD15/rs17227267 and RSPO4/rs78802022).
Conclusions: No regions were associated with ECC at genome-wide significance (P<5e-8), but we highlight several regions related to plausible biological mechanisms of ECC, including a cluster of the antimicrobial beta-defensins. Hypothesis-free genetics studies of caries susceptibility hold promise for identifying etiological factors of ECC.