An Explanation for the Neutral Effect of DR2 on IDDM Susceptibility in Central Italy

Susceptibility to IDDM is strongly associated with HLA. Some HLA allelic combinations (haplotypes) can be found in most patients, whereas other haplotypes are encountered only rarely. It has been proposed that this difference in susceptibility depends on the absence (in the DR3 and DR4 haplotypes) or the presence (in the DR2 haplotype) of Asp⁵⁷ in the DQ β-chain. Data on southern European populations challenge this hypothesis because the DR2 haplotype has not been associated negatively with IDDM, as reported in northern European populations. This study on a selected panel of DR2-positive Italian IDDM patients shows that 19 of 21 (90.5%) DR2 haplotypes possess a non-Asp⁵⁷ DQB allele. Moreover, the same non-Asp⁵⁷ subtype has a comparatively high frequency (9/28, or 32.1%, DR2 haplotypes) also in the DR2-positive healthy Italian population. The difference between patients and control subjects is significant (xP < 0.0001). This is the largest series of DR2-positive patients analyzed so far. Comparison with cumulated data in various white populations shows a distinct northern European-to-southern European gradient. Toward southern Europe, the relative frequency of the non-Asp⁵⁷ DR2 subtype increases. Concomitantly, the apparent protective effect of the DR2 haplotype disappears. Therefore, the observed differences in DR2-IDDM association in white populations can be explained adequately by the Asp⁵⁷ hypothesis, which this study's data strongly support.