Class I and II HLA Genes Are Associated with Susceptibility and Age at Onset in Finnish Families with Type 1 Diabetes

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Abstract
Objectives: We explored the properties of the long-term survivor model (LTS) in the genetic association studies and studied allelic and haplotypic associations between the age at onset and partially latent susceptibility of type 1 diabetes (T1DM) and Human Leucocyte Antigen (HLA) A, B and DR loci. Methods: The authors applied the long-term survivor model (LTS) for sibships collected in a population-based registry during a calendar time period. The method uses sibs that could not become probands and includes the proband’s age at onset during the recruitment period. Association between the candidate gene and the partially latent susceptibility is modeled with logistic regression and the age at onset with a two-parameter gamma distribution, where a scale parameter depends on the candidate genotypes. We also performed a simulation study of nuclear families to compare the power of the likelihood ratio tests of the genetic association based on the LTS model with those obtained using family-based association method (FBAT) and bias of the case-pseudo control design. In addition, we analysed allele and haplotype associations between HLA A, B and DR loci (IDDM1) with T1DM, using population-based ascertainment of 705 sibships with complete HLA information. Results: A simulation study showed that the estimates of the genetic association using an ascertainment-corrected LTS model are virtually unbiased and that the relative risk estimates obtained from case-pseudo control design (TDT) are negatively biased. In the analysis of the Finnish T1DM families we found that only B62 (p < 0.05) is positively significantly associated with susceptibility after adjusting for the haplotype effects. Five alleles were significantly associated with age at onset (B8 and DR3, p < 0.01; A2, B60 and DR6, p < 0.05). No significant three-locus haplotype associations with the susceptibility were found, but A3B18DR4 (p < 0.001) haplotype was associated with older age at onset than average. Conclusions: Estimates of genetic relative risk obtained from the case-pseudo control design are negatively biased and the prospective LTS model is an appropriate choice, when there are non-susceptible subjects in the population with variable age at onset. Based on the analysis of T1DM, we conclude that there are gene(s) in the HLA region that are associated with susceptibility and/or age at onset of T1DM, and this should be taken into account in future studies.