LINKAGE AND ASSOCIATION OF THE HLA GENE-COMPLEX WITH IDDM IN 81 DANISH FAMILIES - STRONG LINKAGE BETWEEN DR-BETA-1(LYS71+) AND IDDM

Many studies have shown an association of IDDM. with polymorphisms in the HLA region on chromosome 6p21. Previously our case-control study i n the Belgian population showed significant association between IDDM a nd certain HLA class II alleles, in particular Lys(71+), encoding DRB1 alleles. In the present study, 81 Danish multiplex IDDM families and 82 healthy Danish controls were examined for polymorphisms in the HLA- DRB genes and 54 of the 81 families for polymorphisms in HLA-B, -DQA1, -DQB1, -TNFA, and -TNFB genes. The results confirm our previous studi es in the Belgian population and show that DRB1(Lys71+/+) homozygotes have a relative risk (RR) of 103.5. Linkage between IDDM and DRB1 alle les that encode Lys(71+) was shown by affected sib pair analysis which showed strong linkage (p<1 x 10(-6)). By family based association stu dies, the DRB1(Lys71+) was identified as the allele which increased su sceptibility to develop IDDM most in the HLA region (haplotype relativ e risk = 8.38). Haplotype analysis confirmed the increased risk contri buted by DRB1(Lys71+) alleles and in addition showed that DRB1(Lys71-) provides protection against IDDM even in the presence of DQB1(Asp57). These results indicate that DRB1(Lys71+) screening is a powerful test compared to full HLA typing to determine the risk for a random person to develop IDDM in the Danish population, with an even higher probabi lity than shown previously for the Belgians.