Alelos de classe II do sistema maior de histocompatibilidade HLA e marcadores INDELs de ancestralidade genômica e sua associação com a retinopatia diabética: estudo multicêntrico de pacientes com diabetes tipo 1 no Brasil

Abstract

This study’s objective is to analyze the class II alleles profile and the genomic ancestry of patients with type 1 diabetes (T1D) in Brazil and its relationship with diabetic retinopathy. Patients belong to a nationwide study involving 1760 individuals from all over the country. Clinical and laboratory data were collected and HLA-class II (DRB1, DQB1, DQA1) genotyped by either the NGS or SSO method. A panel of 46 AIMs was used for the determination of genomic ancestry. All patients had indirect ophthalmoscopy performed and were classified as absent, mild, moderate or severe non-proliferative DR or proliferative DR. This thesis presents the results in the form of scientific articles. The first article analyses the prevalence of HLA alleles in patients with T1D compared to a healthy population from the bone marrow donors’ database of Brazil (REDOME). In addition, evaluation of frequencies of HLA alleles between groups of self-reported color/race was performed. In summary, this article shows that the most frequent alleles associated with risk and protection are, respectively, DRB1*03 and DRB1*07. The second article studies the relationship of HLA class II alleles and severe DR. It compares T1D individuals with and without severe DR matched by the duration of diabetes. After Bonferroni correction, no association was found. The third study shows a positive association of African genomic ancestry and the presence of severe DR even after adjusting for clinical and socio-demographic variables. The fourth (and last) article shows that health-related quality of life in T1D patients is influenced by African genomic ancestry. We can conclude that the Brazilian population that has T1D, although highly admixed, is similar to Caucasian populations in relation to its genetic profile. Evidence pointed out that DR was not associated with class II alleles, but it was associated with African genomic ancestry. This might be explained due to the fact that the pathogenesis of DR is more related to inflammatory pathways linked to oxidative stress, and so, other loci might be responsible for the genetic influence on DR. More studies are needed to better understand the genetic mechanism associated to the development of DR, especially in admixed populations. The results also highlight the importance of a multidisciplinary approach in T1D patients, considering socio-cultural-factors, like ethnicity, to achieve better clinical and psychological control.