Genomic Determinants and Shared Genetic Pathways of Periodontal Disease

Exploring Genomic Determinants of Periodontal Disease Via Shared Genetic Pathways With Cardiovascular Disease, Diabetes, and Bone Density

Despite significant improvement in treating periodontal disease (PD) and the identification of multiple risk factors, little is known about the specific contribution of genetics to PD pathogenesis. Several genomewide association studies (GWAS) of PD have been published, but only one reported locus has reached the threshold for genome-wide significance. Epidemiological studies and biological experiments established associations and suggested common pathogenetic pathways between PD and cardiovascular disease (CVD), diabetes (DM), and osteoporosis. The overall objective is to identify genetic loci for PD as a first step toward a better understanding of PD pathogenesis. In a preliminary study in the Women's Genome Health Study (WGHS), new-onset cases of PD were associated with a family history of myocardial infarction (MI). Further preliminary analyses presented shared phenotypic variation of PD/CVD, PD/DM, or PD/osteoporosis that could be accounted by the whole-genome genetic matrices. Several variants from the GWAS catalog of bone density and family history of MI were found correlated with PD in the WGHS. Based on these findings and the literature, the central hypothesis is that there are common pathogenetic links between PD and these other diseases and that GWAS using the comorbidity case definitions will help identify potential common loci.

Study Overview

• Status: Completed
• Conditions: Diabetes; Periodontal Diseases; Osteoporosis; Cardiovascular Risk Factor
• Intervention / Treatment: Other: Disease status

Detailed Description

Three specific aims are proposed to refine and validate the PD status in the Women's Health Study (WHS/WGHS) to improve the phenotypic characterization of GWAS of PD: (1) Addition of CDC-AAP (Centers for Disease Control - American Academy of Periodontology) periodontal disease instrument to the WHS annual follow-up survey. (2) Validate existing Periodontal Disease (PD) status in the WHS/WGHS (subset). Request of dental records for 180 women sampled from the WHS who had reported diagnosis of PD in the past. (3) Correlation and validation analysis of new periodontal disease information with requested dental record (most recently dated). Phone interviews and request of dental records for 180 women sampled from the WHS/WGHS who visited a dentist within recent 36 months.

In addition, the investigators propose to identify genetic determinants of PD shared with CVD, DM, or osteoporosis via an integrative computational biological networks approach. Although the systemic links between PD vs. DM, CVD or osteoporosis have been established in clinical genetics as well as in experimental models, high-throughput investigations for gene-gene interplays between the associated conditions (CVD vs. PD; DM vs. PD; osteoporosis vs. PD) have not been explored yet. The investigators propose to approach this using an integrative in silico method, combining existing diverse biological information including genomic, epigenetic, expression and protein data. To our knowledge, this is the first time that hierarchical levels of integrative precision medicine will be tested for PD vs. CVD/DM/osteoporosis to generate plausible hypotheses and experimental targets.

• Study Type: Observational
• Enrollment (Actual): 81

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The participants in this protocol are women in the Women's Health Study that agreed to be contacted for follow-up after the clinical trial ended in 2004~2005.

Description

Inclusion Criteria:

• Women who are willing to consent for requesting dental records;
• Outcome 1 - Women who reported periodontal disease diagnosis at any time point up to the 2006 follow up;
• Outcome 1 - Women whose dental records will be retrievable and usable (retrospectively 2 years and prospectively 1 year at the time of report of periodontal disease diagnosis)
• Outcome 2 - Women who are willing to complete and turn-in the WHS 2018 Annual Follow-up Questionnaire with CDC-AAP oral health questions
• Outcome 2 - Women whose dental records will be retrievable and usable (retrospectively 3 years at the time of 2018 Annual Follow-up Questionnaire turn-in)
• The definition of usable dental records consist of but not exclusive to clinical note, complete periodontal charting, and full-mouth radiographs series (FMX) or panoramic, bite-wing radiographs that could derive a PD diagnosis based on the American Academy of Periodontology 1999 definitions.

Exclusion Criteria:

- Women whose dental records are not retrievable or incomplete.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Validity of self-reported periodontal disease	Cronbach's alpha correlation coefficients will be calculated	Dental records will be requested retrospectively around the time of questionnaire turned-in that self-reported periodontal disease was reported. The record will be traced back 2 years and prospectively 1 years at the date of report (total 3 years)
Correlation of CDC-AAP periodontal condition questions vs. periodontal disease diagnosis	Correlation coefficients will be calculated	Dental records will be requested retrospectively (3 years) for participants who will return 2018 annual follow-up questionnaire with CDC-AAP questions

Collaborators and Investigators

• Sponsor: Tufts University
• Collaborators: Brigham and Women's Hospital; National Institute of Dental and Craniofacial Research (NIDCR)
• Investigators: Study Director: Kathleen Benoit, Tufts University; Principal Investigator: Yau-Hua Yu, DDS, DMSc, Tufts University School of Dental Medicine

Publications and helpful links

General Publications

• Yu YH, Doucette-Stamm L, Rogus J, Moss K, Zee RYL, Steffensen B, Ridker PM, Buring JE, Offenbacher S, Kornman K, Chasman DI. Family History of MI, Smoking, and Risk of Periodontal Disease. J Dent Res. 2018 Sep;97(10):1106-1113. doi: 10.1177/0022034518782189. Epub 2018 Jun 21.
• Shungin D, Haworth S, Divaris K, Agler CS, Kamatani Y, Keun Lee M, Grinde K, Hindy G, Alaraudanjoki V, Pesonen P, Teumer A, Holtfreter B, Sakaue S, Hirata J, Yu YH, Ridker PM, Giulianini F, Chasman DI, Magnusson PKE, Sudo T, Okada Y, Volker U, Kocher T, Anttonen V, Laitala ML, Orho-Melander M, Sofer T, Shaffer JR, Vieira A, Marazita ML, Kubo M, Furuichi Y, North KE, Offenbacher S, Ingelsson E, Franks PW, Timpson NJ, Johansson I. Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data. Nat Commun. 2019 Jun 24;10(1):2773. doi: 10.1038/s41467-019-10630-1.

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2018
• Primary Completion (Actual): May 31, 2022
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: January 2, 2018
• First Submitted That Met QC Criteria: February 12, 2018
• First Posted (Actual): February 19, 2018

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Diabetes; Osteoporosis; Genomic; Cardiovascular Risk Factor; Periodontal Disease
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Stomatognathic Diseases; Mouth Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Periodontal Diseases
• Other Study ID Numbers: HH1804; 1K23DE026804-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No