ABSTRACT
The direct involvement of the human leukocyte antigen class II DR-DQ genes in type 1 diabetes (T1D) is well established, and these genes display a complex hierarchy of risk effects at the genotype and haplotype levels. We investigated, using data from 38 studies, whether the DR-DQ haplotypes and genotypes show the same relative predispositional effects across populations and ethnic groups. Significant differences in risk within a population were considered, as well as comparisons across populations using the patient/control (P/C) ratio. Within a population, the ratio of the P/C ratios for two different genotypes or haplotypes is a function only of the absolute penetrance values, allowing ranking of risk effects. Categories of consistent predisposing, intermediate ('neutral'), and protective haplotypes were identified and found to correlate with disease prevalence and the marked ethnic differences in DRB1-DQB1 frequencies. Specific effects were identified, for example for predisposing haplotypes, there was a statistically significant and consistent hierarchy for DR4 DQB1*0302s: DRB1*0405 =*0401 =*0402 > *0404 > *0403, with DRB1*0301 DQB1*0200 (DR3) being significantly less predisposing than DRB1*0402 and more than DRB1*0404. The predisposing DRB1*0401 DQB1*0302 haplotype was relatively increased compared with the protective haplotype DRB1*0401 DQB1*0301 in heterozygotes with DR3 compared with heterozygotes with DRB1*0101 DQB1*0501 (DR1). Our results show that meta-analyses and use of the P/C ratio and rankings thereof can be valuable in determining T1D risk factors at the haplotype and amino acid residue levels.
Subject(s)
Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Genetic Predisposition to Disease , HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Haplotypes , Europe , Genotype , HLA-DQ beta-Chains , HLA-DRB1 Chains , HumansABSTRACT
OBJECTIVE: To determine incidence, geographic distribution, and seasonal variation of IDDM in children 0-14 years of age living in Puerto Rico. Because these data have been collected through the infrastructure of the World Health Organization's DiaMond project, these results are directly comparable with incidence data from other population worldwide involved in this study. RESEARCH DESIGN AND METHODS: Beginning in 1990, new cases of IDDM were registered retrospectively from 1985 and prospectively to 1994 by review of medical records from island hospitals. Included in the hospital registry are 1,527 cases of IDDM. Validation of the primary source was by three secondary lists of cases obtained through diabetic camps, surveys of schools, and a government registry. Long linear modeling (capture-recapture) was used to correct incidence. RESULTS: Mean incidence of IDDM from 1985-1994 was 18.0 cases/100,000 children per year (95% CI 17.6-18.3). There was a slight female rather than male predominance: 51% of the cases were girls, and 49% were boys. Although Puerto Rico has marked variation in rainfall, altitude, and genetic markers, no significant differences are found in the incidence rates of different areas or seasons of the island. CONCLUSIONS: This registry of Puerto Rican children is the largest IDDM registry of minority children in the U.S. The results of this study indicate that the annual incidence of IDDM of children living in Puerto Rico is higher than the incidence of other multiracial ethnic groups living in the U.S.
