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Made available in DSpace on 2018-12-11T16:52:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-04-01 Objective: The goal of the present work was to use dental conditions that have been independently associated with cleft lip and palate (CL/P) as a tool to identify a broader collection of individuals to be used for gene identification that lead to clefts. Study design: We studied 1573 DNA samples combining individuals that were born with CL/P or had tooth agenesis, supernumerary teeth, molar incisor hypomineralization, or dental caries with the goal to identify genetic associations. We tested 2 single-nucleotide polymorphisms that were located in the vicinity of regions suggested to contribute to supernumerary teeth. Overrepresentation of alleles were determined for combinations of individuals as well as for each individual phenotypic group with an α of.05. Results: We determined that the allele C of rs622260 was overrepresented in all individuals studied compared with a group of unrelated individuals who did not present any of the conditions described earlier. When subgroups were tested, associations were found for individuals with hypomineralization. Conclusions: Although we did not test this hypothesis directly in the present study, based on associations reported previously, we believe that CL/P is actually a syndrome of alterations of the dentition, and considering it that way may allow for the identification of genotype-phenotype correlations that may be useful for clinical care. Department of Pedodontics School of Dentistry Istanbul University Department of Pedodontics School of Dentistry Istanbul Medipol University Department of Oral Biology University of Pittsburgh School of Dental Medicine Department of Pediatric Dentistry UNESP Department of Pediatric Dentistry University of Pittsburgh School of Dental Medicine Department of Pediatric Dentistry UNESP

Caries is a multifactorial disease and little is still known about the host genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified the interval 5q12.1–5q13.3 as linked to low caries susceptibility in Filipino families. Here we fine-mapped this region in order to identify genetic contributors to caries susceptibility. Four hundred and seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. DMFT scores and genotype data of 75 single-nucleotide polymorphisms were evaluated in the Filipino families with the Family-Based Association Test. For replication purposes, a total 1,467 independent subjects from five different populations were analyzed in a case-control format. In the Filipino cohort, statistically significant and borderline associations were found between low caries experience and four genes spanning 13 million base pairs (PART1, ZSWIM6, CCNB1, and BTF3). We were able to replicate these results in some of the populations studied. We detected PART1 and BTF3 expression in whole saliva, and the expression of BTF3 was associated with caries experience. Our results suggest BTF3 may have a functional role in protecting against caries. Fil: Shimizu, T.. Nihon University of Dentistry; Japón Fil: Deeley, K.. University of Pittsburgh; Estados Unidos Fil: Briseño Ruiz, J.. University of Pittsburgh; Estados Unidos Fil: Faraco Junior, I. M.. University of Pittsburgh; Estados Unidos Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Brancher, J. A.. Pontifical Catholic University of Paraná; Brasil Fil: Pecharki, G. D.. Pontifical Catholic University of Paraná; Brasil Fil: Küchler, E. C.. Universidade Federal Fluminense; Brasil Fil: Tannure, P. N.. Universidade Federal do Rio de Janeiro; Brasil Fil: Lips, A.. Universidade Federal do Rio de Janeiro; Brasil Fil: Vieira, T. C. S.. Universidade Federal Fluminense; Brasil Fil: Patir, A.. Istanbul Medipol Universit; Turquía Fil: Yildirim, M.. Istanbul University; Turquía Fil: Mereb, J. C.. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina Fil: Resick, J. M.. University of Pittsburgh; Estados Unidos Fil: Brandon, C. A.. University of Pittsburgh; Estados Unidos Fil: Cooper, M. E.. University of Pittsburgh; Estados Unidos Fil: Seymen, F.. Istanbul University; Turquía Fil: Costa, M. C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Granjeiro, J. M.. Universidade Federal Fluminense; Brasil Fil: Trevilatto, P. C.. Pontifical Catholic University of Paraná; Brasil Fil: Orioli, I. M.. Universidade Federal do Rio de Janeiro; Brasil. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina Fil: Castilla, Eduardo Enrique. Instituto Oswaldo Cruz; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Marazita, M. L.. University of Pittsburgh; Estados Unidos Fil: Vieira, A. R.. University of Pittsburgh; Estados Unidos

Objective Variations in genes that are critical for tooth formation may contribute to the tooth agenesis. MMPs are potential candidate genes for dental alterations based on the roles they play during embryogenesis. The aim of this study was to investigate the possible association between MMP1, MMP3, and MMP20 and tooth agenesis. Methods One hundred sixty-seven nuclear families from two different populations were analysed, 116 from Brazil and 51 from Turkey. Probands had at least one congenitally missing tooth. DNA samples were obtained from blood or saliva samples and genotyping was performed using TaqMan chemistry. In addition, Mmp20 was selected for quantitative real-time polymerase chain reaction analysis with SYBR Green I Dye in mouse tooth development. Results Associations between tooth agenesis and MMP1 (p = 0.007), and MMP20 (p = 0.03) were found in Brazilian families. In the total dataset, MMP20 continued to be associated with tooth agenesis (p = 0.01). Mmp20 was not expressed during the initial stages of tooth development. Conclusion Our findings provide evidence that MMP1 and MMP20 play a role in human tooth agenesis.

Caries is a multifactorial disease, and studies aiming to unravel the factors modulating its etiology must consider all known predisposing factors. One major factor is bacterial colonization, and Streptococcus mutans is the main microorganism associated with the initiation of the disease. In our studies, we have access to DNA samples extracted from human saliva and blood. In this report, we tested a real-time PCR assay developed to detect copies of genomic DNA from Streptococcus mutans in 1,424 DNA samples from humans. Our results suggest that we can determine the presence of genomic DNA copies of Streptococcus mutans in both DNA samples from caries-free and caries-affected individuals. However, we were not able to detect the presence of genomic DNA copies of Streptococcus mutans in any DNA samples extracted from peripheral blood, which suggests the assay may not be sensitive enough for this goal. Values of the threshold cycle of the real-time PCR reaction correlate with higher levels of caries experience in children, but this correlation could not be detected for adults. Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos Fil: Deeley, Kathleen B.. University of Pittsburgh; Estados Unidos Fil: Callahan, Nicholas F.. University of Pittsburgh; Estados Unidos Fil: Noel, Jacqueline B.. University of Pittsburgh; Estados Unidos Fil: Anjomshoaa, Ida. University of Pittsburgh; Estados Unidos Fil: Carricato, Wendy M.. University of Pittsburgh; Estados Unidos Fil: Schulhof, Louise P.. University of Pittsburgh; Estados Unidos Fil: DeSensi, Rebecca S.. University of Pittsburgh; Estados Unidos Fil: Gandhi, Pooja. University of Pittsburgh; Estados Unidos Fil: Resick, Judith M.. University of Pittsburgh; Estados Unidos Fil: Brandon, Carla A.. University of Pittsburgh; Estados Unidos Fil: Rozhon, Christopher. University of Pittsburgh; Estados Unidos Fil: Patir, Asli. Istanbul Medipol University; Turquía Fil: Yildirim, Mine. Istanbul University; Turquía Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Mereb, Juan C.. Hospital de Area El Bolsón; Argentina Fil: Letra, Ariadne. University of Pittsburgh; Estados Unidos Fil: Menezes, Renato. University of Pittsburgh; Estados Unidos Fil: Wendell, Steven. University of Pittsburgh; Estados Unidos Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Orioli, Ieda Maria. Hospital de Area El Bolsón; Argentina Fil: Seymen, Figen. Istanbul Universit; Turquía Fil: Weyant, Robert J.. University of Pittsburgh; Estados Unidos Fil: Crout, Richard. West Virginia University; Estados Unidos Fil: McNeil, Daniel W.. West Virginia University; Estados Unidos Fil: Modesto, Adriana. University of Pittsburgh; Estados Unidos Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos

Tooth agenesis is a common congenital disorder that affects almost 20% of the world's population. A number of different genes have been shown to be associated with cases of tooth agenesis including AXIN2, IRF6, FGFR1, MSX1, PAX9, and TGFA. Of particular interest is AXIN2, which was linked to two families segregating oligodontia and colorectal cancer. We studied two collections of families affected with tooth agenesis and tested them for association with AXIN2. Significant association between tooth agenesis and AXIN2 was found (p = 0.02) in cases with at least one missing incisor. Our work further supports a role of AXIN2 in human tooth agenesis and for the first time suggests AXIN2 is involved in sporadic forms of common incisor agenesis. Future studies should identify which specific tooth agenesis sub-phenotypes are consequence of AXIN2 genetic variations. A sub-set of these cases could have an increased susceptibility for colon cancer or other types of tumours and this knowledge would have significant clinical implications.

Irf6 (interferon regulatory factor 6) is expressed in tooth buds and palatine rugae during development in the mouse. Here we report the first study to investigate whether IRF6 variation is associated with palatine rugae patterns in a population with sporadic tooth agenesis. Fifty-two individuals with sporadic tooth agenesis and their parents were studied. Palatine rugae were scored from casts available for a subset of 38 families. DNA samples were obtained from whole blood or saliva samples. Genotyping was performed using TaqMan assays. Linkage disequilibrium and transmission distortion analyses of the marker alleles were performed. Borderline results were obtained for IRF6 genetic variation and having primary rugae larger on the right side than on the left (rs20131633, P = 0.07; rs642961, P = 0.06) and having fewer than eight primary palatine rugae (rs20131623, P = 0.07). However, no specific pattern of tooth agenesis was associated with the palatine rugae patterns studied. Our data suggest that IRF6 may contribute to specific palatine rugae patterns in humans.

Aquaporins (AQP) are water channel proteins and the genes coding for AQP2, AQP5, and AQP6 are clustered in 12q13. Since AQP5 is expressed in serous acinar cells of salivary glands, we investigated its involvement in caries. DNA samples from 1,383 individuals from six groups were studied. Genotypes of eight single nucleotide polymorphisms covering the aquaporin locus were tested for association with caries experience. Interaction with genes involved in enamel formation was tested. The association between enamel microhardness at baseline, after creation of artificial caries lesion, and after exposure to fluoride and the genetic markers in AQP5 was tested. Finally, AQP5 expression in human whole saliva, after exposure to fluoride in a mammary gland cell line, which is known to express AQP5, and in Wistar rats was also verified. Nominal associations were found between caries experience and markers in the AQP5 locus. Since these associations suggested that AQP5 may be inhibited by levels of fluoride in the drinking water that cause fluorosis, we showed that fluoride levels above optimal levels change AQP5 expression in humans, cell lines, and rats. We have shown that AQP5 is involved in the pathogenesis of caries and likely interact with fluoride. Fil: Anjomshoaa, Ida. University of Pittsburgh; Estados Unidos Fil: Briseño Ruiz, Jessica. University of Pittsburgh; Estados Unidos Fil: Deeley, Kathleen. University of Pittsburgh; Estados Unidos Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Mereb, Juan C.. Provincia de Río Negro. Ministerio de Salud. Hospital de Área El Bolsón ; Argentina Fil: Leite, Aline L.. Universidade de Sao Paulo; Brasil Fil: Barreta, Priscila A. T.. Universidade de Sao Paulo; Brasil Fil: Silva, Thelma L.. Universidade de Sao Paulo; Brasil Fil: Dizak, Piper. University of Pittsburgh; Estados Unidos Fil: Ruff, Timothy. University of Pittsburgh; Estados Unidos Fil: Patir, Asli. İstanbul Medipol Üniversitesi; Turquía Fil: Koruyucu, Mine. İstanbul Üniversitesi; Turquía Fil: Abbasoğlu, Zerrin. Yeditepe Üniversitesi; Turquía Fil: Casado, Priscila L.. Universidade Federal Fluminense; Brasil Fil: Brown, Andrew. University of Pittsburgh; Estados Unidos Fil: Zaky, Samer H.. University of Pittsburgh; Estados Unidos Fil: Bayram, Merve. İstanbul Medipol Üniversitesi; Turquía Fil: Küchler, Erika C.. University of Pittsburgh; Estados Unidos Fil: Cooper, Margaret E.. University of Pittsburgh; Estados Unidos Fil: Liu, Kai. University of Pittsburgh; Estados Unidos Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos Fil: Tanboğa, İlknur. Marmara Üniversitesi; Turquía Fil: Granjeiro, José M.. Universidade Federal Fluminense; Brasil. Instituto Nacional de Metrologia, Qualidade e Tecnologia; Brasil Fil: Seymen, Figen. İstanbul Üniversitesi; Turquía Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. Fundación Oswaldo Cruz; Brasil Fil: Orioli, Iêda M.. Universidade Federal do Rio de Janeiro; Brasil Fil: Sfeir, Charles. University of Pittsburgh; Estados Unidos Fil: Owyang, Hongjiao. Marmara Üniversitesi; Turquía Fil: Rabelo Buzalaf, Marilia Afonso. Universidade de Sao Paulo; Brasil Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos

BACKGROUND: Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans. METHODS: We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice. RESULTS: Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience. CONCLUSIONS: The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy. Fil: Weber, Megan L.. University of Pittsburgh; Estados Unidos Fil: Hsin, Hong Yuan. University of Pittsburgh; Estados Unidos Fil: Kalay, Ersan. Karadeniz Technical University; Turquía Fil: Brožková, Dana Š. Charles University; República Checa. University Hospital Motol; República Checa Fil: Shimizu, Takehiko. Nihon University. School of Dentistry; Japón Fil: Bayram, Merve. Medipol Istanbul University; Turquía Fil: Deeley, Kathleen. University of Pittsburgh; Estados Unidos Fil: Küchler, Erika C.. University of Pittsburgh; Estados Unidos Fil: Forella, Jessalyn. University of Pittsburgh; Estados Unidos Fil: Ruff, Timothy D.. University of Pittsburgh; Estados Unidos Fil: Trombetta, Vanessa M.. University of Pittsburgh; Estados Unidos Fil: Sencak, Regina C.. University of Pittsburgh; Estados Unidos Fil: Hummel, Michael. University of Pittsburgh; Estados Unidos Fil: Briseño Ruiz, Jessica. University of Pittsburgh; Estados Unidos Fil: Revu, Shankar K.. University of Pittsburgh; Estados Unidos Fil: Granjeiro, José M.. Universidade Federal Fluminense; Brasil Fil: Antunes, Leonardo S.. Universidade Federal Fluminense; Brasil Fil: Antunes, Livia A.. Universidade Federal Fluminense; Brasil Fil: Abreu, Fernanda V.. Universidade Federal Fluminense; Brasil Fil: Costabel, Marcelo C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Tannure, Patricia N.. Veiga de Almeida University; Brasil. Salgado de Oliveira University; Brasil Fil: Koruyucu, Mine. Istanbul University; Turquía Fil: Patir, Asli. Medipol Istanbul University; Turquía Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mereb, Juan C.. Estudio Colaborativo Latino Americano de Malformaciones Congénitas; Argentina Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Orioli, Iêda M.. Universidade Federal do Rio de Janeiro; Brasil Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos Fil: Ouyang, Hongjiao. University of Pittsburgh; Estados Unidos Fil: Jayaraman, Thottala. University of Pittsburgh; Estados Unidos Fil: Seymen, Figen. Istanbul University; Turquía Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos

Objective: The purpose of this study was to fine map the locus Xq25.1-27-2 in order to identify genetic contributors involved in low caries experience. Design: Seventy-two families from the Philippines were studied. Caries experience was recorded and genomic DNA extracted from peripheral blood was obtained from all subjects. One hundred and twenty-eight polymorphisms in the locus Xq25.1-27-2, a region that contains 24 genes, were genotyped. Association between caries experience and alleles was tested using the transmission disequilibrium test (TOT). This initial analysis was followed by experiments with DNA samples from 1481 subjects from Pittsburgh, 918 children from Brazil, and 275 children from Turkey in order to follow up the results found in the Filipino families. Chi-square or Fisher's exact tests were used. Sequencing of the coding regions and exon-intron boundaries of MST4 and FGF13 were also performed on 91 women from Pittsburgh. Results: Statistically significant association with low caries experience was found for 11 markers in Xq25.1-27-2 in the Filipino families. One marker was in MST4, another marker was in FGF13, and the remaining markers were in intergenic regions. Haplotype analysis also confirmed these results, but the follow up studies with DNA samples from Pittsburgh, Brazil, and Turkey showed associations for a subset of the 11 markers. No coding mutations were identified by sequencing. Conclusions: Our study failed to conclusively demonstrate that genetic factors in Xq25.1-27-2 contribute to caries experience in multiple populations. (C) 2014 Elsevier Ltd. All rights reserved. NIH/NIDCR Grant

Background: Our previous genome-wide linkage scan mapped five loci for caries experience. The purpose of this study was to fine map one of these loci, the locus 13q31.1, in order to identify genetic contributors to caries. Methods: Seventy-two pedigrees from the Philippines were studied. Caries experience was recorded and DNA was extracted from blood samples obtained from all subjects. Sixty-one single nucleotide polymorphisms (SNPs) in 13q31.1 were genotyped. Association between caries experience and alleles was tested. We also studied 1,481 DNA samples obtained from saliva of subjects from the USA, 918 children from Brazil, and 275 children from Turkey, in order to follow up the results found in the Filipino families. We used the AliBaba2.1 software to determine if the nucleotide changes of the associated SNPs changed the prediction of the presence of transcription-binding site sequences and we also analyzed the gene expression of the genes selected based on binding predictions. Mutation analysis was also performed in 33 Filipino individuals of a segment of 13q31.1 that is highly conserved in mammals. Results: Statistically significant association with high caries experience was found for 11 markers in 13q31.1 in the Filipino families. Haplotype analysis also confirmed these results. In the populations used for follow-up purposes, associations were found between high caries experience and a subset of these markers. Regarding the prediction of the transcription-binding site, the base change of the SNP rs17074565 was found to change the predicted-binding of genes that could be involved in the pathogenesis of caries. When the sequence has the allele C of rs17074565, the potential transcription factors binding the sequence are GR and GATA1. When the subject carries the G allele of rs17074565, the potential transcription factor predicted to bind to the sequence is GATA3. The expression of GR in whole saliva was higher in individuals with low caries experience when compared to individuals with high caries experience (p = 0.046). No mutations were found in the highly conserved sequence. Conclusions: Genetic factors contributing to caries experience may exist in 13q31.1. The rs17074565 is located in an intergenic region and is predicted to disrupt the binding sites of two different transcription factors that might be involved with caries experience. GR expression in saliva may be a biomarker for caries risk and should be further explored. Fil: Küchler, Erika C.. University of Pittsburgh; Estados Unidos Fil: Deeley, Kathleen. University of Pittsburgh; Estados Unidos Fil: Ho, Bao. University of Pittsburgh; Estados Unidos Fil: Linkowski, Samantha. University of Pittsburgh; Estados Unidos Fil: Meyer, Chelsea. University of Pittsburgh; Estados Unidos Fil: Noel, Jacqueline. University of Pittsburgh; Estados Unidos Fil: Kouzbari, M. Zahir. University of Pittsburgh; Estados Unidos Fil: Bezamat, Mariana. University of Pittsburgh; Estados Unidos Fil: Granjeiro, José M.. Universidade Federal Fluminense; Brasil Fil: Antunes, Leonardo S.. Universidade Federal Fluminense; Brasil Fil: Antunes, Livia Azeredo. Universidade Federal Fluminense; Brasil Fil: Abreu, Fernanda Volpe de. Universidade Federal Fluminense; Brasil Fil: Costa, Marcelo C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Tannure, Patricia N.. Veiga de Almeida; Brasil. Salgado de Oliveira University; Brasil Fil: Seymen, Figen. Istanbul University; Turquía Fil: Koruyucu, Mine. Istanbul University; Turquía Fil: Patir, Asli. Istanbul University; Turquía Fil: Mereb, Juan C.. Estudio Colaborativo Latinoamericano de Malformaciones Congénitas; Argentina. Hospital de Área El Boóon; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. Oswaldo Cruz Foundation; Brasil Fil: Castilla, Eduardo Enrique. Oswaldo Cruz Foundation; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Orioli, Ieda M.. Universidade Federal do Rio de Janeiro; Brasil Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos

Caries is the most common chronic, multifactorial disease in the world today; and little is still known about the genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified five loci related to caries susceptibility: 5q13.3, 13q31.1, 14q11.2, 14q 24.3, and Xq27. In the present study, we fine mapped the 14q11.2 locus to identify genetic contributors to caries susceptibility. Four hundred seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. An additional 387 DNA samples from unrelated individuals were used to determine allele frequencies. For replication purposes, a total of 1,446 independent subjects from four different populations were analyzed based on their caries experience (low versus high). Forty-eight markers in 14q11.2 were genotyped using TaqMan chemistry. Transmission disequilibrium test was used to detect over transmission of alleles in the Filipino families, and Chi-square, Fisher’s exact and logistic regression were used to test for association between low caries experience and variant alleles in the replication data sets. We finally assessed the mRNA expression of TRAV4 in the saliva of 143 study subjects. In the Filipino families, statistically significant associations were found between low caries experience and markers in TRAV4. We were able to replicate these results in the populations studied that were characteristically from underserved areas. Direct sequencing of 22 subjects carrying the associated alleles detects one missense mutation (Y30R) that is predicted to be probably damaging. Finally, we observed higher expression in children and teenagers with low caries experience, correlating with specific alleles in TRAV4. Our results suggest that TRAV4 may have a role in protecting against caries. Fil: Briseño Ruiz, Jessica. University of Pittsburgh; Estados Unidos Fil: Shimizu, Takehiko. Nihon University of Dentistry at Matsudo; Japón Fil: Deeley, Kathleen. University of Pittsburgh; Estados Unidos Fil: Dizak, Piper M.. University of Pittsburgh; Estados Unidos Fil: Ruff, Timothy D. University of Pittsburgh; Estados Unidos Fil: Faraco Jr., Italo M.. University of Pittsburgh; Estados Unidos Fil: Poletta, Fernando Adrián. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina. Estudio Colaborativo Latino Americano de Malformaciones Congénitas. Buenos Aires; Argentina. Instituto de investigación en Porto Alegre; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Brancher, Joao A.. Universidade Federal do Paraná; Brasil Fil: Pecharki, Giovana D.. Universidade Federal do Paraná; Brasil Fil: Kuchler, Erika C. University of Pittsburgh; Estados Unidos Fil: Tannure, Patricia N.. Universidade Federal do Rio de Janeiro; Brasil Fil: Lips, Andrea. Universidade Federal Fluminense; Brasil Fil: Vieira, Thays C. S.. Universidade Federal Fluminense; Brasil Fil: Patir, Asli. Istanbul Medipol University; Turquía Fil: Koruyucu, Mine. Istanbul University; Turquía Fil: Mereb, J. C.. Estudio Colaborativo Latino Americano de Malformaciones Congénita; Argentina Fil: Resick, Judith M.. University of Pittsburgh; Estados Unidos Fil: Brandon, Carla A.. University of Pittsburgh; Estados Unidos Fil: Letra, Ariadme. University of Texas Health Science Center at Houston; Estados Unidos Fil: Silva, Renato M.. University of Texas Health Science Center at Houston; Estados Unidos Fil: Cooper, Margaret E.. University of Pittsburgh; Estados Unidos Fil: Seymen, Figen. Istanbul University; Turquía Fil: Costa, Marcelo C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Granjeiro, Jose M. Universidade Federal Fluminense; Brasil Fil: Trevilatto, Paula C.. Universidade Federal do Paraná; Brasil Fil: Orioli, Eeda M.. Instituto Nacional de Metrologia, Qualidade e Tecnologia; Brasil Fil: Castilla, Eduardo Enrique. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina. Estudio Colaborativo Latino Americano de Malformaciones Congénitas. Buenos Aires; Argentina. Instituto de investigación en Porto Alegre; Brasil Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos

The majority of tooth agenesis cases are mild (hypodontia) and typically not associated with the gene mutations linked to oligodontia. From this, we hypothesise that most cases of tooth agenesis fit a polygenic mode of inheritance, where several genes with small effects cause a variety of varying phenotypes. In this study, we looked at 18 not typically studied genes in this condition, to ascertain their contribution to hypodontia. Our study subjects consisted of 167 patients with hypodontia and their parents from two cohorts (one from Brazil and one from Turkey). An additional 465 DNA samples (93 cases with hypodontia and 372 controls without family history for tooth agenesis or oral clefts) from Brazil were also available for this study. Ninety-three single nucleotide polymorphisms that maximally represent the linkage disequilibrium structure of the genes for the 18 genes were selected and genotyped using Taqman chemistry. Chi square was used to test if genotype distributions were in Hardy–Weinberg equilibrium, and 24 markers that were in Hardy–Weinberg equilibrium and had allele frequencies higher than 5 % in a panel of 50 CEPH samples were further tested. Association between hypodontia and genetic variants was tested with the transmission disequilibrium test within the programme Family-Based Association Test (FBAT) and by using Chi square and Fisher’s exact tests. Alpha at a level of 0.05 was used to report results. Results suggest possible associations between several genes and hypodontia in the three populations. In the Turkish cohort (n = 51 parent–affected child trios) the most significant results were as follows: FGF3 rs1893047, p = 0.08; GLI3 rs929387, p = 0.03; GLI3 haplotype rs929387-rs846266, p = 0.002; and PAX9 rs2073242, p = 0.03. In the Brazilian cohort (n = 116 parent–affected child trios), the results were as follows: DLX1 rs788173, p = 0.07; FGF3 rs12574452, p = 0.03; GLI2 rs1992901, p = 0.03; and PITX2 rs2595110, p = 0.01. The second Brazilian cohort also suggested that FGF3 (rs12574452, p = 0.01) is associated with hypodontia and added EDAR (rs17269487, p = 0.04), LHX6 (rs989798, p = 0.02), and MSX1 (rs12532, p = 0.003). Our results suggest that several genes are potentially associated with hypodontia and their individual contributions may be modest. Hence, these cases may not be explained by inactivating mutations such as many oligodontia cases segregating in a Mendelian fashion but rather are influenced by one or more susceptibility alleles in multiple small effect genes.

Amelogenesis imperfecta (AI) is a genetically and phenotypically heterogeneous genetic disorder affecting tooth enamel without other non-oral syndromic conditions. Based on a review of the literature, the authors constructed a candidate-gene-based mutational analysis strategy. To test the strategy, they identified two Turkish families with hypoplastic enamel without any other non-oral syndromic phenotype. The authors analyzed all exons and exon/intron boundaries of the enamelin ( ENAM) gene for family 1 and the DLX3 and ENAM genes for family 2, to identify the underlying genetic etiology. The analysis revealed 2 ENAM mutations (autosomal-dominant g.14917delT and autosomal-recessive g.13185–13186insAG mutations). A single T deletion in exon 10 is a novel deletional mutation (g.14917delT, c.2991delT), which is predicted to result in a frameshift with a premature termination codon (p.L998fsX1062). This result supports the use of a candidate-gene-based strategy to study the genetic basis for AI.

There is evidence for a genetic component in caries susceptibility, and studies in humans have suggested that variation in enamel formation genes and their interaction with Streptococcus mutans levels may contribute to caries. For the present study, we used DNA samples collected from 173 unrelated children from Istanbul: 91 children with 4 or more affected tooth surfaces and 82 caries-free children. Six single-nucleotide polymorphism markers were genotyped in selected candidate genes (ameloblastin, amelogenin, enamelin, tuftelin 1 and tuftelin interacting protein 11) that influence enamel formation. Allele and genotype frequencies were compared between groups with distinct caries experience. Regression analysis was used for the evaluation of individual gene effects, environmental effects and gene-environment interactions. Overrepresentation of the C allele of the amelogenin marker was seen in cases with dmft scores higher than 8 (p = 0.01) when compared to controls. Also, overrepresentation of the T allele of the ameloblastin marker was seen in cases with dmfs scores higher than 10 (p = 0.05) when compared to controls. In addition, the CT genotype of the tuftelin rs3790506 marker was overrepresented in cases with dmft scores higher than 5 (p = 0.05) and dmfs scores higher than 6 (p = 0.05) compared to controls. The best-fitting model showed that dmfs is increased when the following factors are present: (1) females and both the anterior and posterior teeth are affected simultaneously, (2) when the T allele of the tuftelin rs3790506 is involved, and (3) the C allele of the amelogenin rs17878486 is involved. Our study provides support that genes involved in enamel formation modify caries susceptibility in humans.

WOS: 000309554700021 PubMed ID: 23028741 There is evidence for a genetic component in caries susceptibility, and studies in humans have suggested that variation in enamel formation genes may contribute to caries. For the present study, we used DNA samples collected from 1,831 individuals from various population data sets. Single nucleotide polymorphism markers were genotyped in selected genes (ameloblastin, amelogenin, enamelin, tuftelin, and tuftelin interacting protein 11) that influence enamel formation. Allele and genotype frequencies were compared between groups with distinct caries experience. Associations with caries experience can be detected but they are not necessarily replicated in all population groups and the most expressive results was for a marker in AMELX (p = 0.0007). To help interpret these results, we evaluated if enamel microhardness changes under simulated cariogenic challenges are associated with genetic variations in these same genes. After creating an artificial caries lesion, associations could be seen between genetic variation in TUFT1 (p = 0.006) and TUIP11 (p = 0.0006) with enamel microhardness. Our results suggest that the influence of genetic variation of enamel formation genes may influence the dynamic interactions between the enamel surface and the oral cavity. National Institutes of Health [R01-DE018914, R01-DE016148] This research is supported by National Institutes of Health grants R01-DE018914 and R01-DE016148. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.