Analysis of genetic component of type 2 Diabetes Mellitus

Author(s)

Diogo Maciel Duarte da Mota

• Document type: Doctoral Thesis
• Press: São Carlos.
• Institution: Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT)
• Defense date: 2024-01-22

Examining board members

João Carlos Setubal; Milena Gurgel Teles Bezerra; Ilana Lopes Baratella da Cunha Camargo; Lygia da Veiga Pereira Carramaschi; Michel Satya Naslavsky

• Advisor: João Carlos Setubal; Alexander Augusto de Lima Jorge

Abstract

Type 2 Diabetes Mellitus (T2D) represents a set of complex metabolic conditions characterized by hyperglycemia due to defects in insulin secretion or its action. The chronic hyperglycemia associated with T2D has long-term detrimental effects on various organs and is among the top causes of mortality in adults. In its multifactorial nature, the genetic complexity of T2D, involving multiple gene loci and their interaction with the environment, plays a relevant role in disease manifestation. Through Genome-Wide Association Studies (GWAS), more than 800 single nucleotide polymorphisms (SNPs) distributed across over 500 susceptibility loci for T2D have been described. This study aims to investigate the high prevalence of T2D based on structural and evolutionary characteristics of the genomic regions that present SNPs associated with the phenotype, in addition to carrying out a study of these SNPs in a brazilian population (SABE), from the Brazilian Online Mutation Archive ABraOM, to identify variants with specific characteristics. The results reveal that genes with SNPs associated with T2D are concentrated in regions with lower tissue specificity, lower expression variation, suggesting more stable expression profiles, characteristic of housekeeping genes. Furthermore, the study identified an enrichment of rare variants in 41 genes, with 24 genes having synonymous variants and 17 with non-synonymous variants related to loss of function and potential deleterious effects. 63 SNPs with statistically significant odds ratios (OR) were also validated, in which 11 of them had a protective effect in the brazilian population, in contrast to the results of the original GWAS. The heterogeneity in variants suggests the existence of population specific genetic effects in the SABE population. However, the need for larger data samples to obtain more accurate results is emphasized, with an ideal sample size in the order of hundreds of thousands to one million individuals. The performance of Polygenic Risk Score (PGS) models for T2D in the brazilian population was evaluated, with models showing varied performance. These results represent a significant step forward for T2D risk analysis studies in the brazilian population. In conclusion, this study contributes to understanding the genetic complexity of T2D and the importance of studying specific populations, emphasizing the need for larger sample sizes to obtain more robust results, and highlighting the potential of PGS models in identifying genetic risks associated with T2D in the brazilian population. (AU)

• FAPESP's process: 18/11907-0 - Evolutionary and structural analysis of genes associated with Type 2 Diabetes Mellitus
• Grantee: Diogo Maciel Duarte da Mota
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)