HLA genotyping was performed in African American type 1 diabetic patients (n = 772) and controls (n = 1,641) in the largest study of African Americans and type 1 diabetes reported to date. Cases were from Children’s Hospital and Research Center Oakland and from existing collections (Type 1 Diabetes Genetics Consortium [T1DGC], Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications [DCCT/EDIC], and Genetics of Kidneys in Diabetes [GoKinD]). Controls were from the T1DGC and from newborn bloodspot cards. The diversity of HLA DRB1-DQA1-DQB1 haplotypes and genotypes is far greater than that found in Europeans and European Americans. Association analyses replicated many type 1 diabetes risk effects of European-derived haplotypes but also revealed novel effects for African-derived haplotypes. Notably, the African-specific “DR3” haplotype DRB1*03:02-DQA1*04:01-DQB1*04:02 is protective for type 1 diabetes, in contrast to the common and highly-susceptible DR3 DRB1*03:01-DQA1*05:01-DQB1*02:01. Both DRB1*07:01 and DRB1*13:03 haplotypes are predisposing when they include DQA1*03:01-DQB1*02:01g but are protective with DQA1*02:01-DQB1*02:01g. The heterozygous DR4/DR9 genotype, containing the African-derived “DR9” haplotype DRB1*09:01-DQA1*03:01-DQB1*02:01g, exhibits extremely high risk (odds ratio = 30.88), approaching that for DR3/DR4 in European populations. Disease risk assessment for African Americans differs greatly from risk assessment in European populations. This has profound implications on risk screening programs and underscores the need for high-resolution genotyping of multiple populations for the rational design of screening programs with tests that will fairly represent the population being screened.

Signaling via Programmed Death Ligand (PD-L)-1 and PD-L2 is crucial for maintaining peripheral tolerance. CD90+ myofibroblasts/fibroblasts (CMFs) are major PD-1 ligands -expressing cells in normal human colonic mucosa. CMFs suppress activated CD4+ T cell proliferation via PD-1 ligands. It is not known whether signaling through TLRs contribute to the regulation PD-1 ligands on CMFs upon colonic mucosal tolerance. Herein, we demonstrated that stimulation of TLR4 on human CMFs upregulates PD-L1, but not PD-L2, and reinforces CMF-mediated suppression of CD4+ T cell proliferation and IFN-γ production. TLR4-mediated upregulation of PD-L1 on CMFs involved NF-κB pathways and was JAK2- and MyD88-dependent. MyD88-dependent stimulation of TLR1/2 and TLR 5 also upregulated PD-L1 expression on CMFs in culture. PD-L1 expression was drastically decreased in vivo in the colonic mucosa of mice devoid of MyD88. Induction of MyD88 deficiency in CMFs in fibroblast-specific MyD88 conditional knockout mice resulted in a strong increase in a mucosal IFN-γ expression concomitantly with the abrogation of PD-L1 expression in CMFs under homeostasis and epithelial injury induced by dextran sodium sulfate. Together these data suggest that MyD88-dependent TLR stimulation of CMFs in the normal colonic mucosa may reinforce these cells' anti-inflammatory capacity, and thus contribute to the maintenance of mucosal tolerance.

Objective To test the hypothesis that closely-related HLA haplotypes containing the DRB1*07:01 gene (“DR7” haplotypes) derived from European and African populations differ in their genetic susceptibility for type 1 diabetes (T1D) depending on the DQ-α molecule present. Research Design and Methods A combined total of ninety-eight African American T1D patients from the Type 1 Diabetes Genetics Consortium and from Children’s Hospital and Research Center Oakland were genotyped for the HLA class II loci DRB1, DQA1, and DQB1. DNA samples extracted from newborn blood spot cards from African Americans born in California (n=947) were used as a population-based control group. Results Among African American cases, the European-derived DRB1*07:01-DQA1*02:01-DQB1*02:01g haplotype was protective for T1D risk (odds ratio (OR)=0.34; 95% CI 0.14 - 0.78; p<0.011), but the African-derived DRB1*07:01-DQA1*03:01-DQB1*02:01g haplotype increased T1D risk (OR=3.96; 95% CI 1.94 - 8.08; p<5.5E-05). Conclusions The effect of DRB1*07:01-DQB1*02:01g on T1D susceptibility depends on the DQA1 allele. DRB1*07:01-DQA1*02:01-DQB1*02:01g is protective for T1D however, the presence of DQA1*03:01 on the DRB1*07:01-DQB1*02:01g haplotype not only renders the DR7 haplotype not protective, it creates a haplotype with significant T1D risk. These data underscore the importance of assessing genetic effects within ethnic context.

ObjectiveTo test the hypothesis that clinical observations made at patient presentation can distinguish type 2 diabetes (T2D) from type 1 diabetes (T1D) in pediatric patients aged 2 to 18.Subjects and MethodsMedical records of 227 African American and 112 Hispanic American pediatric patients diagnosed as T1D or T2D were examined to compare parameters in the two diseases. Age at presentation, BMI z-score, and gender were the variables used in logistic regression analysis to create models for T2D prediction.ResultsThe regression-based model created from African American data had a sensitivity of 92% and a specificity of 89%; testing of a replication cohort showed 91% sensitivity and 93% specificity. A model based on the Hispanic American data showed 92% sensitivity and 90% specificity. Similarities between African American and Hispanic American patients include: (1) age at onset for both T1D and T2D decreased from the 1980s to the 2000s; (2) risk of T2D increased markedly with obesity. Racial/ethnic-specific observations included: (1) in African American patients, the proportion of females was significantly higher than that of males for T2D compared to T1D (p<0.0001); (2) in Hispanic Americans, the level of glycated hemoglobin (HbA1c) was significantly higher in T1D than in T2D (p<0.002) at presentation; (3) the strongest contributor to T2D risk was female gender in African Americans, while the strongest contributor to T2D risk was BMI z-score in Hispanic Americans.ConclusionsDistinction of T2D from T1D at patient presentation was possible with good sensitivity and specificity using only three easily-assessed variables: age, gender, and BMI z-score. In African American pediatric diabetes patients, gender was the strongest predictor of T2D, while in Hispanic patients, BMI z-score was the strongest predictor. This suggests that race/ethnic specific models may be useful to optimize distinction of T1D from T2D at presentation.

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