Genetic Susceptibility to Periodontal Disease in Down Syndrome: A Case-Control Study

Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the “Axiom Spanish Biobank” array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10−5, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10−5, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10−5, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10−5, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10−5, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10−2, p = 5.1 × 10−3, p = 1.2 × 10−2, respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory responseThe genotyping service was carried out at CeGen-PRB3-ISCIII; it is supported by grant PT13/0001, ISCIII-SGEFI/FEDERS

A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci

Aim:Few genome-wide association studies (GWAS) have been conducted for severe forms of periodontitis (stage III/IV grade C), and the number of known risk genes is scarce. To identify further genetic risk variants to improve the understanding of the disease aetiology, a GWAS meta-analysis in cases with a diagnosis at <= 35 years of age was performed.Materials and Methods:Genotypes from German, Dutch and Spanish GWAS studies of III/IV-C periodontitis diagnosed at age <= 35 years were imputed using TopMed. After quality control, a meta-analysis was conducted on 8,666,460 variants in 1306 cases and 7817 controls with METAL. Variants were prioritized using FUMA for gene-based tests, functional annotation and a transcriptome-wide association study integrating eQTL data.Results:The study identified a novel genome-wide significant association in the FCER1G gene (p = 1.0 x 10(-9)), which was previously suggestively associated with III/IV-C periodontitis. Six additional genes showed suggestive association with p < 10(-5), including the known risk gene SIGLEC5. HMCN2 showed the second strongest association in this study (p = 6.1 x 10(-8)).Conclusions:This study expands the set of known genetic loci for severe periodontitis with an age of onset <= 35 years. The putative functions ascribed to the associated genes highlight the significance of oral barrier tissue stability, wound healing and tissue regeneration in the aetiology of these periodontitis forms and suggest the importance of tissue regeneration in maintaining oral health

A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci

Aim:Few genome-wide association studies (GWAS) have been conducted for severe forms of periodontitis (stage III/IV grade C), and the number of known risk genes is scarce. To identify further genetic risk variants to improve the understanding of the disease aetiology, a GWAS meta-analysis in cases with a diagnosis at <= 35 years of age was performed.Materials and Methods:Genotypes from German, Dutch and Spanish GWAS studies of III/IV-C periodontitis diagnosed at age <= 35 years were imputed using TopMed. After quality control, a meta-analysis was conducted on 8,666,460 variants in 1306 cases and 7817 controls with METAL. Variants were prioritized using FUMA for gene-based tests, functional annotation and a transcriptome-wide association study integrating eQTL data.Results:The study identified a novel genome-wide significant association in the FCER1G gene (p = 1.0 x 10(-9)), which was previously suggestively associated with III/IV-C periodontitis. Six additional genes showed suggestive association with p < 10(-5), including the known risk gene SIGLEC5. HMCN2 showed the second strongest association in this study (p = 6.1 x 10(-8)).Conclusions:This study expands the set of known genetic loci for severe periodontitis with an age of onset <= 35 years. The putative functions ascribed to the associated genes highlight the significance of oral barrier tissue stability, wound healing and tissue regeneration in the aetiology of these periodontitis forms and suggest the importance of tissue regeneration in maintaining oral health

Susceptibilidad genética y periodontitis

La periodontitis es una de las enfermedades inflamatorias más comunes, con una prevalencia mundial del 11% para su forma más severa y una heredabilidad estimada de aproximadamente el 30%. La periodontitis tiene un impacto negativo en la salud general, siendo asociada con otras enfermedades sistémicas. A pesar de la evidencia de la contribución de factores genéticos en el desarrollo de la periodontitis, la base genética de esta enfermedad es aún desconocida. El objetivo de la presenta tesis es obtener conocimientos novedosos sobre la etiología genética de la forma más severa de periodontitis, periodontitis grado C estadios III/IV (PIII/IV-C), y de los mecanismos moleculares subyacentes a la asociación de la periodontitis con la diabetes mellitus de tipo 2 (DM2), la enfermedad de las arterias coronarias (CAD) y la enfermedad de Alzheimer (EA). Para ello, en primer lugar, se realizó un estudio de asociación de genoma completo (GWAS) en una población española en el que se identificaron 8 nuevos loci asociados con la PIII/IV-C y se confirmó la asociación del gen SIGLEC5 con la periodontitis. En segundo lugar, se llevó a cabo un análisis a nivel de gen y de vías, incluyendo variantes comunes y raras, que resultó en la identificación de 7 genes y de 38 vías asociados con la PIII/IV-C. Finalmente se generaron puntuaciones de riesgo poligénico (PRS), en cuyo análisis no se apreció que la DM2, la EA y la CAD compartan riesgo genético con la periodontitis.2023-02-0

Assessment of genotyping tools applied in genetic susceptibility studies of periodontal disease: A systematic review

This is the accepted manuscript of the following article: de Coo, A., Quintela, I., Blanco, J., Diz, P., & Carracedo, Á. (2018). Assessment of genotyping tools applied in genetic susceptibility studies of periodontal disease: A systematic review. Archives Of Oral Biology, 92, 38-50. doi: 10.1016/j.archoralbio.2018.04.012. © Elsevier 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 licenseObjective: A systematic review to evaluate the various genotyping tools and study strategies employed to define genetic susceptibility to periodontitis. Methods: The review was performed in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. The search for publications referring to the genetic bases of periodontal disease was performed on the MEDLINE-PubMed and Cochrane Library databases, on trials registers, and on the web pages of regulatory agencies. Results: We found 2439 potentially eligible articles, of which only 25 satisfied the established inclusion criteria and were processed for data extraction. The review revealed marked heterogeneity between studies, caused in part by the lack of a universally accepted definition for periodontitis phenotypes and by the variety of genotyping tools available. The most commonly used technique was genotyping candidate genes. Conclusion: The few rigorous studies that have been published on genetic susceptibility to periodontitis are subject to severe methodological bias due to their design and the genotyping tools employed. Despite their limitations, candidate gene studies continue to be the predominant methodological approach, rather than genome-wide association studies. Further studies must be designed using a universally accepted, validated diagnostic criterion for periodontitis, analysing multiple genes and polymorphisms in combination with rare variantsThis review was supported in part by University f Santiago de Composela and by the Spanish Ministry of Education, Culture and Sport by a FPU grant (FPU15/05974)S