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Influence of ancestry in susceptibility to type 1 Diabetes in a brazilian population

Grant number: 12/14212-7
Support type:Regular Research Grants
Duration: December 01, 2012 - November 30, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Maria Elizabeth Rossi da Silva
Grantee:Maria Elizabeth Rossi da Silva
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The approach used for the investigation of genes associated with disease is the case-control study, in which one seeks to identify the frequency of polymorphic variants differs among the group of patients and controls. One problem with this approach is the population stratification according to the melting pot, which is one of characteristics of the population. It is therefore difficult to use the methodology of case-control in our population for the study of complex diseases, because there is a risk of finding spurious associations due to differences in genetic background of the individual cases and controls. Ancestry informative markers (AIMs) can be applied to estimate biogeographical ancestry at the population level, subgroups (cases and controls) and individual. For information on their high ancestry, these markers increase the power to detect spurious associations between cases and controls. We found that the same susceptibility alleles for type 1 diabetes autoimmune (T1D) present in Caucasians are also prevalent in our population, but less frequently (HLA-DR3-DR4, polymorphisms of the genes PTPN22, CTLA4 and INS-VNTR .) We aim to 1) Identify the individual and ancestral component of the study population, allowing the knowledge of their potential stratification. 2) Redefine the role of the alleles of HLA-DR and DQ polymorphisms of the genes PTPN22, CTLA4 and INS-VNTR, the predisposition to the disease, correcting for the bias introduced by stratification. For so much, 93 ancestry informative markers, as previously described by Nassir and colleagues (Nassir R, et al. 2009). Will evaluate the influence of ancestry on the frequency of alleles of HLA-DR and DQ genes and polymorphisms of PTPN22, CTLA4 and INS-VNTR in the predisposition to disease. Thus, try to correct the results obtained from analysis of these genes for the bias introduced by the stratification of our population. Will use the DNA extracted from peripheral leukocytes of the DNA bank of 500 T1D patients and 500 normal controls of the Hospital das Clínicas. T1D patients selected by clinical criteria of severe hyperglycemia or ketoacidosis at diagnosis and early need for insulin therapy less than 6 months of diagnosis were recruited from the Diabetes Outpatient Hospital das Clínicas. The control group includes individuals with no family history of diabetes, blood glucose and glycosylated hemoglobin normal. Genotyping of ancestry informative SNPS will be performed by BeadXpress platform (Illumina, USA). The composition ancestor of individuals will be characterized by the program 2.3.3 Structure (Pritchard JK, et al. 2000), and SNPs contained in the candidate gene will be tested by means of structured association analysis using the program STRAT (Pritchard et al. 2000). (AU)