Investigation of genetic susceptibility to chronic periodontitis associated with type 2 diabetes mellitus

Author(s)

Thamiris Cirelli

• Document type: Doctoral Thesis
• Press: Araraquara. 2020-10-20.
• Institution: Universidade Estadual Paulista (Unesp). Faculdade de Odontologia. Araraquara
• Defense date: 2020-09-24
• Advisor: Raquel Mantuaneli Scarel Caminaga

Abstract

Periodontitis (P) and Diabetes Mellitus Type 2 (T2DM) are diseases with a high prevalence in the population, and the number of patients affected by both diseases, such as comorbidities, has been increasing. In addition, periodontitis and T2DM are complex diseases that have common pathogenic mechanisms, but the potential genetic component that can be shared between these diseases remains poorly investigated. Genetic risk markers for each of these diseases have been identified, but they must be evaluated in different populations to be validated. In addition, it is important to verify whether such isolated genetic markers would be useful in identifying the joint occurrence of these diseases as comorbidities. The objective of this study in a Brazilian population was divided into 2 publications: (i) To assess whether single nucleotide polymorphisms (SNPs) in the IL10, IL1A, IL1B, IL4, TNFA, IL6, OPG, RANK and RANKL genes, "classically" related to periodontitis, may be associated with susceptibility to T2DM and also with both diseases concomitantly; (ii) evaluate 12 SNPs selected from studies of genome-wide association (GWAS) and bioinformatics previously associated with T2DM or periodontitis alone, as genetic markers for T2DM, or periodontitis, or both diseases as comorbidities. Considering the sample size, 956 patients underwent a complete periodontal examination, in addition to biochemical analysis of their glycemic and lipid profile. Patients with T2DM and P (Group T2DM+P, n=239 patients) were investigated; and for comparison of results, patients without T2DM with severe or moderate P (Periodontitis Group, n = 358) were considered, and also patients without T2DM and without P, being considered healthy (Control Group, n = 356). Thus, the Periodontitis group was considered control for T2DM and the Control Group was considered control for T2DM and P. After a complete periodontal examination and biochemical tests, each patient's mouthwash was obtained for DNA extraction using the Salting- out. The 21 single nucleotide polymorphisms (SNP) were investigated using the OpenArray genotyping system. The associations between SNPs and pathologies were tested by multiple logistic regressions, adjusting for age, sex and smoking. We also investigated whether there was an effect influenced by sex or smoking in each SNP on the occurrence of these phenotypes. Regarding publication 1, it was found that the SNP rs1143634-GA (IL1B) was significantly less likely to develop P+T2DM in the entire population, but mainly in women (adjusted OR = 0.37, 95% CI = 0.16 - 0.88, p = 0.02), while women with the CT rs224320 (IL4) genotype were more susceptible to developing P+T2DM (adjusted OR = 1.81, 95% CI = 1.04-3.15, p = 0.03). Men with the rs1800795-CC (IL6) genotype were less likely to develop T2DM (adjusted OR = 0.12, 95% CI = 0.02 - 0.70, p = 0.01). In publication 2, considering Bonferroni’s correction, it was found that the rs7957197-TA genotype (HNF1A gene) was associated with greater susceptibility to T2DM (Periodontitis versus P+T2DM, OR=1.95; 95% CI=1.26 –3.02; p=0.003) in the entire population and also for men compared to women. Women with the rs77544840-GT genotype (CDKAL1 gene) also showed susceptibility to T2DM (P versus P+T2DM, OR = 2.49; 95% CI = 1.41–4.42; p = 0.002). The patients homozygous for the rarer (GG) allele of rs7018475 (CDKN2B gene) showed susceptibility to develop P+T2DM (all control versus all P + T2DM, OR=3.91; 95% CI=1.76–8, 70; p=0.001), as well as for women and never smokers. Therefore, it can be concluded that SNPs in the IL1B, IL4 and IL6 genes demonstrated an association influenced by sex with periodontitis concomitant with T2DM, increasing the evidence of a common genetic component between these diseases. The genetic variants rs7957197 (HNF1A) and rs77544840 (CDKAL1) have been validated in Brazil as risk markers for T2DM. Rs7018475 (CDKN2B) was associated with an increased risk of developing periodontitis along with T2DM (P + T2DM). As these findings were sex-specific, further studies with similar selection criteria are needed to confirm the observed results and to investigate the functional role of these SNPs in the context of the sex and disease phenotype. (AU)

• FAPESP's process: 16/08070-6 - Investigation of genetic susceptibility to chronic periodontitis associated with Type 2 Diabetes mellitus
• Grantee: Thamiris Cirelli
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)