ABSTRACT
Ethnic admixtures may interfere with the definition of type 1 diabetes (T1D) risk determinants. The role of HLA, PTPN22, INS-VNTR, and CTLA4 in T1D predisposition was analyzed in Brazilian T1D patients (n = 915), with 81.7% self-reporting as white and 789 controls (65.6% white). The results were corrected for population stratification by genotyping 93 ancestry informative markers (AIMs) (BeadXpress platform). Ancestry composition and structural association were characterized using Structure 2.3 and STRAT. Ethnic diversity resulted in T1D determinants that were partially discordant from those reported in Caucasians and Africans. The greatest contributor to T1D was the HLA-DR3/DR4 genotype (OR = 16.5) in 23.9% of the patients, followed by -DR3/DR3 (OR = 8.9) in 8.7%, -DR4/DR4 (OR = 4.7) in 6.0% and -DR3/DR9 (OR = 4.9) in 2.6%. Correction by ancestry also confirmed that the DRB1*09-DQB1*0202 haplotype conferred susceptibility, whereas the DRB1*07-DQB1*0202 and DRB1*11-DQB1*0602 haplotypes were protective, which is similar to reports in African-American patients. By contrast, the DRB1*07-DQB1*0201 haplotype was protective in our population and in Europeans, despite conferring susceptibility to Africans. The DRB1*10-DQB1*0501 haplotype was only protective in the Brazilian population. Predisposition to T1D conferred by PTPN22 and INS-VNTR and protection against T1D conferred by the DRB1*16 allele were confirmed. Correcting for population structure is important to clarify the particular genetic variants that confer susceptibility/protection for T1D in populations with ethnic admixtures.
Subject(s)
Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/genetics , Genetic Association Studies , Genetic Markers , Genetic Predisposition to Disease , Adolescent , Adult , Alleles , Case-Control Studies , Child , Diabetes Mellitus, Type 1/diagnosis , Female , Gene Frequency , Genotype , HLA Antigens/genetics , Humans , Male , Odds Ratio , Population Surveillance , Young AdultABSTRACT
There is a scarcity of data of zinc transporter-8 autoantibody (ZnT8A) on mixed populations such as Brazilian. Therefore, we evaluated the relevance of ZnT8A for type 1 diabetes (T1D) diagnosis and the role of ZnT8 coding gene (SLC30A8) in T1D predisposition. Patients with T1D (n = 629; diabetes duration = 11 (6-16) years) and 651 controls were genotyped for SLC30A8 rs16889462 and rs2466295 variants (BeadXpress platform). ZnT8 triple antibody was measured by ELISA; glutamic acid decarboxylase (GAD65A) and protein tyrosine phosphatase (IA-2A) autoantibodies by radioimmunoassay. RESULTS: Znt8A was detected in 68.7% of recent-onset T1D patients and 48.9% of the entire patient cohort, similar to GAD65A (68.3% and 47.2%) and IA-2A (64.8% and 42.4%) positivities respectively. ZnT8A was the only antibody in 8.4% of patients. Znt8A and IA2A frequencies and titers were independent of gender and ethnicity, whereas GAD65A titers were greater in females. The diabetes duration-dependent decline in ZnT8A frequency was similar to GAD65A and IA-2A. The SLC30A8 rs2466293 AG + GG genotypes were associated with T1D risk in non-European descents (56.2% × 42.9%; p = 0.018), and the GG genotype with higher ZnT8A titers in recent-onset T1D: 834.5 IU/mL (711.3-2190.0) × 281 IU/mL (10.7-726.8); p = 0.027. Conclusion ZnT8A detection increases T1D diagnosis rate even in mixed populations. SLC30A8 rs2466293 was associated with T1D predisposition in non-European descents.
