Cooperative Influence of the Interleukin-6 Promoter Polymorphisms –597, –572 and –174 on Long-Term Kidney Allograft Survival

Abstract

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/−174 haplotype) 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.

Single nucleotide polymorphisms in the interleukin-6 gene promoter, tumor necrosis factor-α gene promoter, and transforming growth factor-β1 gene signal sequence as predictors of time to onset of aseptic loosening after total hip arthroplasty: preliminary study

“…Considering that most of our patients suffered from developmental dysplasia of the hip (DDH), this may indicate an association between IL-6 promoter SNPs and DDH. Combination of genotypes G/G | G/G | G/G at -597, -572 and -174 appears to be predictive for a better kidney allograft survival: it is associated with lower hazard of allograft rejection than other combinations taken cumulatively 28 . In the current report, individual influences of the IL-6 (-597) and (-572) sites/genotypes did not appear to have 15 a relevant effect on the prosthesis survival.…”

“…Functional studies have demonstrated complex interactions among these sites in the regulation of IL-6 transcription 15 . A complete linkage disequilibrium between (-597G→A) and (-174G→C) sites 16,[25][26][27][28] , and no disequilibrium 16,25,26,28 or a complete negative disequilibrium 27 between (-597G→A) and (-572G→C) sites have been reported in European populations. 15,28 indicate -597/-572 haplotypes GG (around 50%) and AG (around 40%) as the most prevalent ones.…”

“…A complete linkage disequilibrium between (-597G→A) and (-174G→C) sites 16,[25][26][27][28] , and no disequilibrium 16,25,26,28 or a complete negative disequilibrium 27 between (-597G→A) and (-572G→C) sites have been reported in European populations. 15,28 indicate -597/-572 haplotypes GG (around 50%) and AG (around 40%) as the most prevalent ones. The most prevalent genotype combinations appear to be G/A -597G/G -572 (around 40%) and G/G -597G/G -572 (around 30%) 15,18 .…”

Variations of the interleukin-6 promoter are associated with features of the metabolic syndrome in Caucasian Danes

“…An ex-vivo functional study [25] demonstrated that the GGG haplotype of the IL6 promoter produces more IL-6 than other promoter haplotypes. Whether carriers of the GGG haplotype also secrete more IL-6 under physiological in-vivo conditions [26] is, however, unknown.…”

“…It has also been shown that these three SNPs (−174, −572, −597) of the IL6 promoter do not act independently in the regulation of IL6 transcription [25][26][27]. In a study of lipopolysaccharidestimulated IL-6 production by leucocytes it was demonstrated that leucocytes from the homozygous carrier of the GGG-haplotype (−597 GG, −572 GG and −174 GG) produced the highest amount of IL-6 [25].…”