Summary HLA-associated relative risks of type 1 (insulin-depen- dent) diabetes mellitus were analysed in population- based Swedish patients and controls aged 0–34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201- A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB1*0602- A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype other than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplo- types other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604- A1*0102 (DQ6.4) and that the peak risk for the nega- tively associated DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-posi- tive individuals. Introduction Type 1 diabetes mellitus may develop at any age. Clinical onset is more abrupt at younger than older ages (Karjalainen et al., 1989) and the frequency of immune markers at onset also varies with age (Landin-Olsson et al., 1992b; Vandewalle et al., 1993; Gorus et al., 1994). Epidemiological studies show age-dependent variation in incidence rates (Nyström et al., 1992), with a male predominance among older patients (Blohmé et al., 1992; Palmer 1993). These variations are not under- stood. Sensitivity to environmental factors may play a role, but it is also possible that the age at onset of type 1 diabetes is influenced by genetic susceptibility factors and gender. Indeed, age gradients in the HLA frequen- cies of type 1 diabetic patients have been demonstrated in analyses in several studies (Schernthaner et al., 1976; Mustonen et al., 1985; Ludvigsson et al., 1986; Svejgaard et al., 1986; Deschamps et al., 1988; Karjalainen et al., 1989; Caillat-Zucman et al., 1992, 1997; Awata et al., 1995; Chan et al., 1995; Tait et al., 1995; Mizota et al., 1996; Lohmann et al., 1997), sug- gesting heterogeneity in the age at onset of type 1 dia- betes associated with HLA alleles. Heterogeneity in age at onset related to the well-known positively associated HLA genotype DR3-DQB1*0201-DQA1*0501/DR4- DQB1*0302-DQA1*0301 (DQ2/8) and negatively associated HLA haplotype DR15-DQB1*0602 (DQ6.2) is of particular interest (for recent HLA nomenclature, see Bodmer et al., 1997). Previous studies have shown that the positive population association between type 1 © 1999 Blackwell Science Ltd, European Journal of Immunogenetics 26, 117–127 Negative association between type 1 diabetes and HLA DQB1*0602- DQA1*0102 is attenuated with age at onset Jinko Graham, 1 Ingrid Kockum, 2 Carani B. Sanjeevi, 2 Mona Landin-Olsson, 3, * Lennarth Nyström, 4,* Göran Sundkvist, 5, * Hans Arnqvist, 6, * Göran Blohmé, 7, * Folke Lithner, 8, * Bengt Littorin, 9, * Bengt Scherstén, 9, * Lars Wibell, 10,* Jan Östman, 11, * Åke Lernmark, 12 Norman Breslow, 1 Gisela Dahlquist 13 and the Swedish Childhood Diabetes Study Group † 117 1 Department of Biostatistics, University of Washington, Seattle, USA, 2 Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, 3 Department of Medicine, University of Lund, Lund, Sweden, 4 Department of Epidemiology and Public Health, Umeå University, Umeå, Sweden, 5 Department of Endocrinology, Malmö University Hospital, Malmö, Sweden, 6 Department of Internal Medicine, University of Linköping, Linköping, Sweden, 7 Sahlgrenska Hospital, University of Göteborg, Göteborg, Sweden, 8 Department of Medicine, Umeå University, Umeå, Sweden, 9 Department of Community Health Sciences, Dahlby/Lund, University of Lund, Sweden, 10 Department of Medicine, University Hospital, Uppsala, Sweden, 11 Centre for Metabolism and Endocrinology, Huddinge University Hospital, Stockholm, Sweden, 12 Department of Medicine, University of Washington, Seattle, USA and 13 Department of Paediatrics, Umeå University, Umeå, Sweden. *Members of the Diabetes Incidence in Sweden Study Group. †Listed in the Acknowledgements. Received 17 March 1998; revised 15 May 1998; re-revised 29 June 1998; accepted 9 July 1998 Correspondence: Prof. Åke Lernmark, Department of Medicine, University of Washington, R. H. Williams Laboratory, Box 357710, Seattle, WA 98195-7710, USA. Short Communication