In addition to apolipoprotein E (APOE), recent large genome-wide association studies (GWASs) have identified nine other genes/loci (CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7) for late-onset Alzheimer's disease (LOAD). However, the genetic effect attributable to known loci is about 50%, indicating that additional risk genes for LOAD remain to be identified. In this study, we have used a new GWAS data set from the University of Pittsburgh (1291 cases and 938 controls) to examine in detail the recently implicated nine new regions with Alzheimer's disease (AD) risk, and also performed a meta-analysis utilizing the top 1% GWAS single-nucleotide polymorphisms (SNPs) with P<0.01 along with four independent data sets (2727 cases and 3336 controls) for these SNPs in an effort to identify new AD loci. The new GWAS data were generated on the Illumina Omni1-Quad chip and imputed at ∼2.5 million markers. As expected, several markers in the APOE regions showed genome-wide significant associations in the Pittsburg sample. While we observed nominal significant associations (P<0.05) either within or adjacent to five genes (PICALM, BIN1, ABCA7, MS4A4/MS4A6E and EPHA1), significant signals were observed 69–180 kb outside of the remaining four genes (CD33, CLU, CD2AP and CR1). Meta-analysis on the top 1% SNPs revealed a suggestive novel association in the PPP1R3B gene (top SNP rs3848140 with P=3.05E–07). The association of this SNP with AD risk was consistent in all five samples with a meta-analysis odds ratio of 2.43. This is a potential candidate gene for AD as this is expressed in the brain and is involved in lipid metabolism. These findings need to be confirmed in additional samples.

Dental caries is influenced by a complex interplay of genetic and environmental factors including dietary habits. Previous reports have characterized the influence of genetic variation on taste preferences and dietary habits. We therefore hypothesized that genetic variation in taste pathway genes (TAS2R38, TAS1R2, GNAT3) may be associated with dental caries risk and/or protection. Families were recruited by the Center for Oral Health Research in Appalachia (COHRA) for collection of biological samples, demographic data and clinical assessment of oral health including caries scores. Multiple single nucleotide polymorphism (SNP) assays for each gene were performed and analyzed using transmission disequilibrium test (TDT) analysis (FBAT software) for three dentition groups: primary, mixed, and permanent. Statistically significant associations were seen in TAS2R38 and TAS1R2 for caries risk and/or protection.

The importance of genetic factors in the genesis of dental caries of both primary and permanent dentitions is well established; however, the degree to which genes contribute to the development of dental caries, and whether these genes differ between primary and permanent dentitions, is largely unknown. Using family-based likelihood methods, we assessed the heritability of caries-related phenotypes for both children and adults in 2,600 participants from 740 families. We found that caries phenotypes in the primary dentition were highly heritable, with genes accounting for 54–70% of variation in caries scores. The heritability of caries scores in the permanent dentition was also substantial (35–55%, all p < 0.01), although this was lower than analogous phenotypes in the primary dentition. Assessment of the genetic correlation between primary and permanent caries scores indicated that 18% of the covariation in these traits was due to common genetic factors (p < 0.01). Therefore, dental caries in primary and permanent teeth may be partly attributable to different suites of genes or genes with differential effects. Sex and age explained much of the phenotypic variation in permanent, but not primary, dentition. Further, including pre-cavitated white-spot lesions in the phenotype definition substantially increased the heritability estimates for dental caries. In conclusion, our results show that dental caries are heritable, and suggest that genes affecting susceptibility to caries in the primary dentition may differ from those in permanent teeth. Moreover, metrics for quantifying caries that incorporate white-spot lesions may serve as better phenotypes in genetic studies of the causes of tooth decay.

A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental.

The importance of susceptibility genes in the risk for dental caries has been clearly established. While many candidate caries genes have been proposed, to date, few of them have been rigorously validated through observational and experimental studies. Moreover, most genetic epidemiological studies have analyzed global caries phenotypes that ignore the possibility that genes may exert differential effects across tooth surfaces of the dentition. Therefore, we performed genome-wide association studies (GWAS) of 5 novel dental caries phenotypes (developed by clustering the permanent dentition into categories of tooth surfaces based on co-occurrence of caries) to nominate new candidate caries genes. GWAS was performed in 920 self-reported white participants, aged 18 to 75 years, with genotype data on 518,997 genetic variants. We identified a significant genetic association between dental caries of the anterior mandibular teeth and LYZL2 (p value = 9e-9), which codes a bacteriolytic agent thought to be involved in host defense. We also identified a significant genetic association between caries of the mid- dentition tooth surfaces and AJAP1 (p value = 2e-8), a gene possibly involved in tooth development. Suggestive genetic associations were also observed for ABCG2, PKD2, the dentin/bone SCPP sub-family, EDNRA, TJFBR1, NKX2-3, IFT88, TWSG1, IL17D, and SMAD7 (p values < 7e-6). We nominate these novel genes for future study.

While genetics clearly influences dental caries risk, few caries genes have been discovered and validated. Recent studies have suggested differential genetic factors for primary dentition caries and permanent dentition caries, as well as for pit-and-fissure-(PF) and smooth-(SM) surface caries. We performed separate GWAS for caries in permanent-dentition PF surfaces (1,017 participants, adjusted for age, sex, and the presence of Streptococcus mutans) and SM surfaces (1,004 participants, adjusted for age, education group, and the presence of Streptococcus mutans) in self-reported whites (ages 14 to 56 yrs). Caries scores were derived based on visual assessment of each surface of each tooth; more than 1.2 million SNPs were either successfully genotyped or imputed and were tested for association. Two homologous genes were suggestively associated: BCOR (Xp11.4) in PF-surface caries (p value = 1.8E-7), and BCORL1 (Xq26.1) in SM-surface caries (p value = 1.0E-5). BCOR mutations cause oculofaciocardiodental syndrome, a Mendelian disease involving multiple dental anomalies. Associations of other plausible cariogenesis genes were also observed for PF-surface caries (e.g., INHBA, p value = 6.5E-6) and for SM-surface caries (e.g., CXCR1 and CXCR2, p value = 1.9E-6). This study supports the notion that genes differentially affect cariogenesis across the surfaces of the permanent dentition, and nominates several novel genes for investigation.

Estrogen receptor α (ERα) is a master driver of a vast majority of breast cancers. Breast cancer cells often develop resistance to endocrine therapy via restoration of the ERα activity through survival pathways. Thus identifying the epigenetic activator of ERα that can be targeted to block ERα gene expression is a critical topic of endocrine therapy. Here, integrative genomic analysis identified MYST3 as a potential oncogene target that is frequently amplified in breast cancer. MYST3 is involved in histone acetylation via its histone acetyltransferase domain (HAT) and, as a result, activates gene expression by altering chromatin structure. We found that MYST3 was amplified in 11% and/or overexpressed in 15% of breast tumors, and overexpression of MYST3 correlated with worse clinical outcome in estrogen receptor+ (ER+) breast cancers. Interestingly, MYST3 depletion drastically inhibited proliferation in MYST3-high, ER+ breast cancer cells, but not in benign breast epithelial cells or in MYST3-low breast cancer cells. Importantly, we discovered that knocking down MYST3 resulted in profound reduction of ERα expression, while ectopic expression of MYST3 had the reversed effect. Chromatin IP revealed that MYST3 binds to the proximal promoter region of ERα gene, and inactivating mutations in its HAT domain abolished its ability to regulate ERα, suggesting MYST3 functioning as a histone acetyltransferase that activates ERα promoter. Furthermore, MYST3 inhibition with inducible MYST3 shRNAs potently attenuated breast tumor growth in mice. Together, this study identifies the first histone acetyltransferase that activates ERα expression which may be potentially targeted to block ERα at transcriptional level.

A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. AbstrActDental caries affects most adults worldwide; however, the risk factors for dental caries do not necessarily exert their effects uniformly across all tooth surfaces. Instead, the actions of some risk factors may be limited to a subset of teeth/surfaces. Therefore, we used hierarchical clustering on tooth surface-level caries data for 1,068 Appalachian adults (ages 18-75 yrs) to group surfaces based on co-occurrence of caries. Our cluster analysis yielded evidence of 5 distinct groups of tooth surfaces that differ with respect to caries: (C1) pit and fissure molar surfaces, (C2) mandibular anterior surfaces, (C3) posterior nonpit and fissure surfaces, (C4) maxillary anterior surfaces, and (C5) mid-dentition surfaces. These clusters were replicated in a national dataset (NHANES 1999(NHANES -2000. We created new caries outcomes defined as the number of carious tooth surfaces within each cluster. We show that some cluster-based caries outcomes are heritable (i.e., under genetic regulation; p < 0.05), whereas others are not. Likewise, we demonstrate the association between some cluster-based caries outcomes and potential risk factors such as age, sex, educational attainment, and toothbrushing habits. Together, these results suggest that the permanent dentition can be subdivided into groups of tooth surfaces that are useful for understanding the factors influencing cariogenesis. Abbreviations: COHRA, Center for Oral Health in Appalachia, the principal study sample; C1-5, clusters 1-5, groups of similarly behaving tooth surfaces identified through hierarchical clustering; DMFS index, decayed, missing, or filled surfaces, a traditional caries measure representing the number of affected surfaces across the entire dentition; DMFS1-5, partial DMFS indices representing the number of affected surfaces within a hierarchical cluster; and NHANES, National Health and Nutrition Examination Survey, the secondary study sample.