HLA-DR4 SUBTYPE AND -B ALLELES IN DQB1*0302- POSITIVE HAPLOTYPES ASSOCIATED WITH IDDM H. R EIJONEN ,*† S. N EJENTSEV ,† J. T UOKKO ,‡ S. K OSKINEN ,† E. T UOMILEHTO -WOLF ,§ H. K. Å KERBLOM ,¶ J. I LONEN † & THE C HILDHOOD D IABETES IN F INLAND S TUDY G ROUP Turku Immunology Centre and †Departments of Virology and ‡Medical Microbiology, University of Turku, Turku, §National Public Health Institute, Helsinki, and the ¶Children’s Hospital, University of Helsinki, Helsinki, Finland (Received 10 April 1997; revised 1 July 1997; accepted 10 July 1997) SUMMARY We determined the distribution of DR4 subtypes in 309 DQB1*0302-positive haplotypes found in insulin-dependent diabetes mellitus (IDDM) patients and 70 control haplotypes present only in healthy family members. An increased frequency of DRB1*0401 allele (74.4% vs. 55.7%, P = 0.003) and a decrease of DRB1*0404 allele (23.6% vs. 40.0%, P = 0.0064) was revealed. A further analysis of extended haplotypes demonstrated strong linkages between various B alleles and DRB1*04 subtypes. HLA-B39 was more frequent in DRB1*0404–DQB1*0302-positive IDDM haplotypes compared with control ones (37.0% vs. 14.3%, P = 0.049), suggesting an involvement of the region telomeric to HLA- DRB1 in the susceptibility to IDDM. INTRODUCTION HLA-DQ alleles represent the predominant but not exclusive class II gene associated with insulin- dependent diabetes mellitus (IDDM) in Caucasian populations (Thorsby & Rønningen, 1993). Although numerous studies have emphasized the primary role of DQ in the predisposition to IDDM, the involvement of DR loci is likely in some cases. This conclusion is supported by analysis of the linkage between DR and DQ genes, which carry the DQB1*0302 allele (She, 1996). DR4- DQB1*0302 is associated with the susceptibility to develop IDDM in most populations studied, but only certain DR4-associated DRB1 alleles (DR4 subtypes) are prevalent among IDDM patients. DRB1*0401 is positively associated with IDDM but DRB1*0403 is not, although they both carry DQB1*0302. In addition, DRB1*0402 has been reported to be associated with a high risk in French Caucasians, Mexican Americans and Jewish populations (Caillat-Zucman et al., 1992; Sheehy, 1992; Erlich et al., 1993), but in the multipopulation study of the 11th HLA workshop there was no differ- ence in the frequency of DRB1*0402 between IDDM patients and control subjects (Rønningen et al., European Journal of Immunogenetics (1997), 24, 357–363 © 1997 Blackwell Science Ltd 357 *Present address: Virginia Mason Research Centre, 1000 Seneca St, Seattle, WA 98101, USA. Correspondence: Dr J. Ilonen, Department of Virology, University of Turku, Kiinamyllynkatu 13, FIN-20520 Turku, Finland.