P1570INTERLEUKIN-6 (RS1800795) AND PENTRAXIN 3 (RS2305619) GENETIC POLYMORPHISMS AND THEIR RELATION WITH INFLAMMATION AND ALL-CAUSE MORTALITY IN ESRD PATIENTS ON DIALYSIS
Authors: Rocha Susana , Valente Maria João , Coimbra Susana , Catarino Cristina , Rocha-Pereira Petronila , Faria Maria do Sameiro , Oliveira José Gerardo , Madureira José , Fernandes João Carlos , Miranda Vasco M P , Belo Luís , Santos-Silva Alice , Bronze-da-Rocha Elsa 
Published: June 2020

Abstract

Background and Aims
Chronic inflammation plays an important role in progression and outcome of chronic kidney disease (CKD) patients. The interleukin-6 (IL-6) polymorphism, rs1800795, is a single nucleotide polymorphism (SNP) in the promoter region (-174G/C) that regulates gene transcription and affects the levels of this cytokine. Genetic variants in the promotor region have been associated with a poor outcome in several pathologies, namely in coronary artery disease. Pentraxin 3 (PTX3) is an inflammatory protein, produced locally by different cell types (e.g. mononuclear phagocytes, dendritic cells, fibroblasts and endothelial cells). PTX3 polymorphism, rs2305619, is a SNP (+281A&gt;G) in the intron 1 of PTX3 gene. PTX3 polymorphisms have been described as risk factor for development of coronary artery disease and for an impairment of kidney function. Our aim was to determine the allelic frequencies of IL6 and PTX3 in end-stage renal disease (ESRD) patients and controls, as well as their relationship with the inflammatory response.

Method
We studied 289 ESRD patients on hemodialysis (high-flux hemodialysis or hemodiafiltration) and 22 healthy individuals, matched for gender, body mass index, and, as far as possible, for age. Real-Time PCR TaqMan SNP genotyping assays were used to assess allelic frequencies of IL6 (rs1800795) and PTX3 (rs2305619). We evaluated the circulating levels of PTX3, growth differentiation factor (GDF)-15, high-sensitivity C-reactive protein (hsCRP), IL-6, tumor necrosis factor-alpha (TNF-α), soluble TNF receptor 2 (sTNFR2), hepcidin and transferrin, using commercially available kits. Deaths occurring along 1-year follow-up period were recorded and mortality rates were evaluated for homozygous and heterozygous alleles.

Results
Compared to controls, all inflammatory biomarkers were significantly higher in ESRD patients. Allelic frequencies in ESRD patients and controls were similar for both SNPs, IL-6 -174G/C and PTX3 +281A&gt;G, considering the homozygous and the heterozygous alleles. For the IL-6 -174G/C, the CC patients, compared to GG and heterozygous patients, showed significantly higher GDF-15 and CRP concentrations and significantly lower values of transferrin; moreover, we found that CC patients presented a trend towards higher mortality rate (21%, 10% and 7% for CC, GG and GC, respectively; P=0.072). For PTX3 +281A&gt;G polymorphism, the AA patients, compared to GG and heterozygous patients, presented higher hsCRP; no significant differences were found in mortality rate between different allele carrier groups (P=0.703).

Conclusion
Although no differences were found in the allelic frequencies between controls and ERSD patients, the CC patients for IL6 polymorphism (rs1800795) and AA patients for PTX3 polymorphism (rs2305619), showed an enhanced inflammatory response; the association of the IL6 polymorphism with a higher mortality needs further studies.