Linkage disequilibrium prevents precise definition of susceptibility determinants for idiopathic nephrotic syndrome.

Clark et al. (Clin. Sci. 1990; 78, 391-7) [ l ] have recently demonstrated positive associations between HLA-DR7, HLA-DQw2 and steroid-sensitive nephrotic syndrome (SSNS). Their conclusions, however, that the DR7 DRB chain and the DQw2 DQS chain may determine SSNS susceptibility over-interpret the presented data. Distinct effects of DR7 and DQw2 were inferred from the positive associations of the two markers with SSNS, while the disease was not significantly associated with the DR3-DQw2 haplotype. A synergistic effect between DR7 and DQw2 is suggested by examination of the frequencies of DR7 and DR3 haplotypes in SSNS subjects. DR7DQw9 and DR3-Dw2 haplotypes occurred together in the patients more frequently than expected by chance (6 observed versus 2.1 expected, x2=7.24, P < 0.01). A three-way interaction between the two haplotypes and SSNS might be tested by log-linear analysis of the raw data [2]. D R ~ D Q w ~ / D R ~ D Q w ~ heterozygotes were not observed more frequently than expected in SSNS patients (7 observed versus 5.5 expected, x2 = 0.43), consistent with both disease susceptibility factors occurring on the DR7-DQw2 haplotype. In spite of the strong associations described, linkage disequilibrium prevents clear identification of the susceptibility factors. The DQw2-associated factor could be any DQ-linked allele common to both the DR3-DQw2 and DR7-DQw2 haplotypes which does not occur on the DR7-DQw9 haplotype. Although DQw2 is a strong candidate, the susceptibility locus may lie in the DQ-DP region, much of which has not been mapped. The identity of the predisposing allele on the DR7-DQw9 haplotype is also uncertain. The relationships between the DRB1, DQAl and DQBl genes shown by Clark et al. [l] are misleading. Gene mapping has indicated that the DQAl gene lies between the DRBl and DQBl genes (Fig. 1) [3]. The data of Clark et al. [l] map SSNS susceptibility telomeric to the DQBl gene and centromeric to the HLA-B locus (as evidenced by the absence of strong linkage disequilibrium between DR7 and HLA-B alleles in SNS patients). Polymorphic loci in this region include the complement genes and DQA1. The A2 allele of the DQAl gene is in strong linkage disequilibrium with DR7 [4] and is an alternative susceptibility determinant to the DP Centromere + B1 A 1 Bl 83 A. @j@& ....... .........