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
✍ Scribed by Zamani, Mahdi; Cassiman, Jean-Jacques
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 87 KB
- Volume
- 76
- Category
- Article
- ISSN
- 0148-7299
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✦ Synopsis
Several publications have shown that certain alleles at the HLA-DRB1, -DQA1, and -DQB1 loci are associated with insulindependent diabetes mellitus (IDDM). Many of these studies have claimed that HLA-DQ␣1 Arg52 and DQ1 Asp57 showed the strongest association with IDDM, but these results could not be confirmed in different populations. We have recently found that DR1 Lys71+ provided major susceptibility to IDDM and that DQ1 Asp57-had an additive effect to DR1 Lys71+ [Zamani et al., 1994a: Eur J Hum Genet 2:177-184]. This was confirmed with haplotype analysis in multiplex IDDM families [Zamani et al., 1996a: J Med Genet 33:899-905]. Therefore, we have reanalyzed the data from the literature on the association of the human leucocyte antigen (HLA) DRB1, DQB1, and DQA1 with IDDM in different ethnic groups to determine whether different amino acids in the antigen binding cleft of HLA class II molecules play a preponderant role in the development of IDDM. The results showed that the DR1 Lys71+ allele provided the highest relative risk for IDDM in the Belgian, Danish, Greek Taiwanese, and Chinese population while this was not the case in Norwegians, Sardinians, and Algerians. Indeed, in the Sardinian and Algerian population the DRB1*0401 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 DR1 Lys71 , DQ1 Asp57 , and DQ␣1 Arg52
by calculating a prevalence-corrected positive predictive value (PcPPV), a prevalence corrected negative predictive value (Pc-NPV), the sensitivity and specificity of these tests. The results indicated that the sensitivity of the test for DR1 Lys71+ was lower than for DQ␣1 Arg52+ and DQ1 Asp57-, while testing for DR1 Lys71+ was more specific than testing for DQ1 Asp57-and DQ␣1 Arg52+ and that the DR1 Lys71+ allele had a higher PcPPV than DQ␣1 Arg52+ and DQ1 Asp57-in all studied populations. These results also showed that testing for DR1 Lys71+/+ can be useful in IDDM risk assessment particularly in populations with a high prevalence (P) of IDDM such as the Danish (P IDDM = 0.65%). PcPPV for DR1 Lys71+/+ was 0.2313 in the Danish, indicating a 23.13% risk for an individual who is homozygous for the genotype DR1 Lys71+/+ to develop IDDM. Some mechanisms which might explain the role of these HLA class II alleles in susceptibility to IDDM are discussed. Am.