Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
BMC Oral Health. 2012 Dec 21;12:57. doi: 10.1186/1472-6831-12-57.
Over 90% of adults aged 20 years or older with permanent teeth have suffered from dental caries leading to pain, infection, or even tooth loss. Although caries prevalence has decreased over the past decade, there are still about 23% of dentate adults who have untreated carious lesions in the US. Dental caries is a complex disorder affected by both individual susceptibility and environmental factors. Approximately 35-55% of caries phenotypic variation in the permanent dentition is attributable to genes, though few specific caries genes have been identified. Therefore, we conducted the first genome-wide association study (GWAS) to identify genes affecting susceptibility to caries in adults.
Five independent cohorts were included in this study, totaling more than 7000 participants. For each participant, dental caries was assessed and genetic markers (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Due to the heterogeneity among the five cohorts regarding age, genotyping platform, quality of dental caries assessment, and study design, we first conducted genome-wide association (GWA) analyses on each of the five independent cohorts separately. We then performed three meta-analyses to combine results for: (i) the comparatively younger, Appalachian cohorts (N = 1483) with well-assessed caries phenotype, (ii) the comparatively older, non-Appalachian cohorts (N = 5960) with inferior caries phenotypes, and (iii) all five cohorts (N = 7443). Top ranking genetic loci within and across meta-analyses were scrutinized for biologically plausible roles on caries.
Different sets of genes were nominated across the three meta-analyses, especially between the younger and older age cohorts. In general, we identified several suggestive loci (P-value ≤ 10E-05) within or near genes with plausible biological roles for dental caries, including RPS6KA2 and PTK2B, involved in p38-depenedent MAPK signaling, and RHOU and FZD1, involved in the Wnt signaling cascade. Both of these pathways have been implicated in dental caries. ADMTS3 and ISL1 are involved in tooth development, and TLR2 is involved in immune response to oral pathogens.
As the first GWAS for dental caries in adults, this study nominated several novel caries genes for future study, which may lead to better understanding of cariogenesis, and ultimately, to improved disease predictions, prevention, and/or treatment.
超过 90%的 20 岁及以上成年人的恒牙患有导致疼痛、感染甚至牙齿缺失的龋齿。尽管在过去十年中龋齿的患病率有所下降，但在美国仍有约 23%的有牙成年人患有未经治疗的龋损。龋齿是一种复杂的疾病，受个体易感性和环境因素的影响。大约 35-55%的恒牙龋病表型变异归因于基因，尽管已经确定了少数特定的龋齿基因。因此，我们进行了首次全基因组关联研究（GWAS），以确定影响成年人龋齿易感性的基因。
本研究纳入了五个独立的队列，总人数超过 7000 人。对每个参与者，评估了龋齿，并对整个基因组的遗传标记（单核苷酸多态性，SNP）进行了基因分型或推断。由于五个队列在年龄、基因分型平台、龋齿评估质量和研究设计方面存在异质性，我们首先对五个独立队列分别进行了全基因组关联（GWA）分析。然后，我们进行了三项荟萃分析，以合并以下结果：（i）年龄较小、阿巴拉契亚地区（N=1483）的评估较好的龋齿表型队列，（ii）年龄较大、非阿巴拉契亚地区（N=5960）的龋齿表型较差的队列，以及（iii）所有五个队列（N=7443）。对荟萃分析中内在和跨内在的排名最高的遗传位点进行了深入研究，以探讨其在龋齿方面的生物学作用。
在三项荟萃分析中，特别是在年龄较小和较大的队列之间，提名了不同的基因。总的来说，我们在参与 p38 依赖的 MAPK 信号的 RPS6KA2 和 PTK2B 等与龋齿有合理生物学作用的基因内或附近，以及参与 Wnt 信号级联的 RHOU 和 FZD1 等基因内或附近，确定了几个提示性位点（P 值≤10E-05）。这两个途径都与龋齿有关。ADMTS3 和 ISL1 参与牙齿发育，TLR2 参与对口腔病原体的免疫反应。
作为成人龋齿的首次 GWAS，本研究为未来的研究提名了几个新的龋齿基因，这可能有助于更好地了解龋病的发生机制，并最终实现更好的疾病预测、预防和/或治疗。
