Original Paper

Class I and II HLA Genes Are Associated with Susceptibility and Age at Onset in Finnish Families with Type 1 Diabetes
Janne Pitkäniemi^a,b, Timo Hakulinen^a, Jurkka Näsänen^b, Eva Tuomilehto-Wolf^b, Jaakko Tuomilehto^a, and The DiMe Study Group

^aDepartment of Public Health, School of Medicine, University of Helsinki,
^bDivision of Diabetes and Genetic Epidemiology, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland

Address of Corresponding Author

Hum Hered 2004;57:69-79 (DOI: 10.1159/000077544)

  Key Words

• Age at onset
• Susceptibility
• Ascertainment
• T1DM
• HLA

  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.

Copyright © 2004 S. Karger AG, Basel

  Author Contacts

Janne Pitkäniemi, Division of Diabetes and Genetic Epidemiology
Department of Epidemiology and Health Promotion
National Public Health Institute
Mannerheimintie 166, FIN-00300 Helsinki (Finland)
Tel. +358 9 191 27322, Fax +358 9 191 27313, E-Mail janne.pitkaniemi@ktl.fi

  Article Information

Received: September 11, 2003
Accepted after revision: December 31, 2003
Number of Print Pages : 11
Number of Figures : 1, Number of Tables : 6, Number of References : 30