Association Between Donor HLA-DQ Heterodimers Group and Graft Loss in Kidney Transplant Recipients

Combinations of HLA-DQ α1 and β1 chains are restricted to specific groups: group 1 (G1), comprising DQA1*02/03/04/05/06 with DQB1*02/03/04, and group 2 (G2), comprising DQA1*01 with DQB1*05/06. A recently discovered role of HLA-DQ heterodimers in hematopoietic cell transplantation suggests poorer outcomes in patients carrying G2 heterodimers. However, the absence of a clear biological rationale has raised questions regarding the generalizability of this observation.

To further evaluate this finding, we investigated the impact of the HLA-DQ group genotype in 821 kidney recipients by multivariate survival modeling.

Compared with recipients of G1G1 donor grafts, those who received G2G2 donor grafts had a 1.9-fold (95% confidence interval [CI], 1.2-2.9; P < 0.01) increased risk of graft loss, independent of HLA-DQ and HLA-DR donor-recipient mismatches. Analysis of graft losses due to biopsy-proven rejection showed that this risk increased with an adjusted hazard ratio of 4.3 (95% CI, 1.1-16.4; P = 0.03). When further analyzed according to DQB1 alleles within the G1 genotype, these associations were restricted to HLA-DQB1*03 alleles, corresponding to DQ7, DQ8, and DQ9. Compared with recipients of donors possessing 2 HLA-DQB1*03 alleles, those with no DQB1*03 but 2 DQB1*05/06 alleles exhibited a 2.5-fold (95% CI, 1.3-4.5; P = 0.01) increased risk of graft failure, suggesting a biological gradient of effect. In sensitivity analyses, these results were independent of the usual predictors of graft loss.

The paradigm based on HLA-DQ heterodimers appears to be shared between hematopoietic and solid organ transplantation, strongly encouraging investigation into the underlying biological mechanisms.