Cooperative influence of the interleukin-6 promoter polymorphisms -597, -572 and -174 on long-term kidney allograft survival.

Recently, we demonstrated an association of the IL-6 promoter polymorphism at position -174 (G-->C) with kidney allograft survival whereby carriers of the -174GG genotype were identified as having superior graft survival. As two additional polymorphisms were discovered in the neighborhood at positions -572 (G-->C) and -597 (G-->A), respectively, and as functional studies revealed a cooperative impact of all three on the IL-6 gene transcription, we investigated whether there is a combined effect on kidney transplant outcome. We determined IL-6 promoter haplotypes -597 (G-->C)/-572 (G-->A)/-174 (G-->C)(-597/-572/-174haplotype) using a PCR system with sequence-specific primers in 158 patients after primary cadaveric kidney transplantation. We here show that the -597 and -174 polymorphism are in tight-linkage disequilibrium and that homozygous carriers of the GGG-597/-572/-174 haplotype (GGG/GGG genotype) have superior 3-year graft survival rates compared with the 8.0-fold increased risk of premature graft loss in all other patients. Interestingly, patients carrying the GGG/GCG genotype had the lowest allograft survival rate. Thus determination of the combined -597/-572/-174 genotype allows for further differentiation of -174GG patients into subgroups and consequently for a more accurate identification of patients at risk. Our results indicate that the three polymorphisms act in a cooperative fashion and we provide evidence for an exceptional clinical impact of the IL-6-597/-572/-174 genotype on the success of kidney transplantation.