Linkage and association of the HLA gene complex with IDDM in 81 Danish families: strong linkage between DR beta 1Lys71+ and IDDM.
Many studies have shown an association of IDDM with polymorphisms in the HLA region on chromosome 6p21. Previously our case-control study in the Belgian population showed significant association between IDDM and certain HLA class II alleles, in particular Lys71+, 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 studies in the Belgian population and show that DRB1Lya71+/+ homozygotes have a relative risk (RR) of 103.5. Linkage between IDDM and DRB1 alleles that encode Lys71+ was shown by affected zib pair analysis which showed strong linkage (p < 1 x 10(-6). By family based association studies, the DRB1Lys71+ was identified as the allale which increased susceptibility to develop IDDM most in the HLA region (haplotype relative risk = 8.38). Haplotype analysis confirmed the increased risk contributed by DRB1Lys71+ alleles and in addition showed that DRB1Lys71- provides protection against IDDM even in the presence of DQB1Aep47-. These results indicate that DRB1Lys71+ 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 probability than shown previously for the Belgians.
Zamani
M
M
Centre for Human Genetics, University of Leuven, Belgium.
Pociot
F
F
Spaepen
M
M
Raeymaekers
P
P
Nerup
J
J
Cassiman
J J
JJ
D000483:Alleles; D003718:Denmark; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics*; D005828:Genetics, Population; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics; D016555:Matched-Pair Analysis; D009679:Nuclear Family; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D006680:HLA Antigens; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha