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?(r)C) and −597 (G?(r)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?(r)C)/−572 (G?(r)A)/−174 (G?(r)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.