REEVALUATION OF THE IMPORTANCE OF POLYMORPHIC HLA CLASS-II ALLELES AND AMINO-ACIDS IN THE SUSCEPTIBILITY OF INDIVIDUALS OF DIFFERENT POPULATIONS TO TYPE-I DIABETES

Several publications have shown that certain alleles at the HLA-DRB1, -DQA1, and -DQB1 loci are associated with insulin-dependent diabetes m ellitus (IDDM), Many of these studies have claimed that HLA-DQ alpha 1 (Arg52) and DQ beta 1(Asp57) showed the strongest association with IDD M, but these results could not be confirmed in different populations. We have recently found that DR beta 1(Lys71+) provided major susceptib ility to IDDM and that DQ beta 1(Asp57-) had an additive effect to DR beta 1(Lys71+) [Zamani et al., 1994a: fur J Hum Genet 2:177-184]. This was confirmed with haplotype analysis in multiplex IDDM families [Zam ani et al., 1996a: J Med Genet 33:899-905]. Therefore, we have reanaly zed the data from the literature on the association of the human leuco cyte antigen (HLA) DRB1, DQB1, and DQA1 with IDDM in different ethnic groups to determine whether different amino acids in the antigen bindi ng cleft of HLA class II molecules play a preponderant role in the dev elopment of IDDM. The results showed that the DR beta 1(Lys71+) allele provided the highest relative risk for IDDM in the Belgian, Danish, G reek Taiwanese, and Chinese population while this was not the case in Norwegians, Sardinians, and Algerians. Indeed, in the Sardinian and Al gerian population the DRB10401 allele encoding Lys(71+) is very rare. Nevertheless, the few positive cases were always in the patient group . We also measured the clinical relevance of the testing for DR beta 1 (Lys71), DQ beta 1(Asp57),and DQ alpha 1(Arg52) by calculating a preva lence-corrected positive predictive value (PcPPV), a prevalence correc ted negative predictive value (PcNPV), the sensitivity and specificity of these tests. The results indicated that the sensitivity of the tes t for DR beta 1(Lys71+) was lower than for DQ alpha 1(Arg52+) and DQ b eta 1(Asp57-), while testing for DR beta 1(Lys71+) was more specific t han testing for DQ beta 1(Asp57-) and DQ alpha 1(Arg52+) and that the DR beta 1(Lys71+) allele had a higher PcPPV than DQ alpha 1(Arg52+) an d DQ beta 1(Asp57-) in all studied populations. These results also sho wed that testing for DR beta 1(Lys71+/+) can be useful in IDDM risk as sessment particularly in populations with a high prevalence (P) of IDD M such as the Danish (P-IDDM = 0.65%). PcPPV for DR beta 1(Lys71+/+) w as 0.2313 in the Danish, indicating a 23.13% risk for an individual wh o is homozygous for the genotype DR beta 1(Lys71+/+) to develop IDDM. Some mechanisms which might explain the role of these HLA class II all eles in susceptibility to IDDM are discussed. (C) 1998 Wiley-Liss, Inc .