Abstract
Chronic inflammation plays an important role in the progression and outcome of chronic kidney disease (CKD). The circulating levels of the inflammatory biomarkers interleukin 6 (IL6) and pentraxin 3 (PTX3) are enhanced in CKD patients, and are associated with the progression of the disease and with higher risk for cardiovascular events, the major cause of death in CKD patients. Our aim was to study how specific polymorphisms of IL6 and PTX3 encoding genes affect the inflammatory response and outcome of end-stage renal disease (ESRD) patients on dialysis. Methodology included the analysis of two single nucleotide polymorphisms (SNP), namely the IL6 (rs1800795) polymorphism in the promoter region (-174G > C), and the PTX3 (rs2305619) polymorphism in the intron 1 (+ 281A > G), which were analyzed in ESRD patients on dialysis and in a group of heathy individuals. The allelic frequencies, genotype distribution and their association with circulating levels of the inflammatory markers C-reactive protein (CRP), IL6, growth differentiation factor 15 (GDF15) and PTX3, were determined in ESRD patients. Events of death were recorded along one year, to assess the association of the studied SNPs with all-cause mortality and the inflammatory biomarkers, in ESRD patients. Results showed that the allelic frequencies and genotype distribution for IL6 and PTX3 SNPs in the control group and ESRD patients were similar and in agreement with other European reports. For the IL6 polymorphism, we found a trend towards higher levels of high-sensitivity (hs) CRP, IL6 and PTX3 in the homozygous genotypes; the CC genotype also showed the highest levels of GDF15. The mortality rate after the 1-year follow-up was 10.4%. The CC genotype (IL6 SNP) was associated to a higher risk of mortality and deceased patients carrying this genotype also showed the highest levels of hsCRP. Regarding the studied PTX3 SNP, the AA genotype was linked to an enhanced inflammatory response, showing the highest values of hsCRP and IL6. Nevertheless, this genotype had no significant impact on the mortality rate. In conclusion, both studied SNPs seem to modulate the inflammatory response in ESRD and may, therefore, be determinant on disease progression and patients’ outcome. Our data also highlights the importance of research on genetic variants that, although less frequent, may have significant biological value.
Highlights
In end-stage renal disease (ESRD) and may, be determinant on disease progression and patients’ outcome
C-reactive protein (CRP), growth differentiation factor 15 (GDF15), pentraxin 3 (PTX3) and interleukin (IL6) are inflammatory mediators whose circulating levels are increased in Chronic kidney disease (CKD) patients, and enhanced in patients on hemodialysis (HD)[5,6,7]
Genotype prevalence and allelic frequencies in ESRD patients and controls were analyzed for both single nucleotide polymorphisms (SNP) of interleukin 6 (IL6) rs1800795 (-174G > C) and of PTX3 rs2305619 (+ 281A > G) (Table 3)
Summary
In ESRD and may, be determinant on disease progression and patients’ outcome. There are several genes correlated with biochemical and inflammatory markers in CKD, and their genetic variants were associated with kidney (dys)function and with the prevalence of CKD1,12,13. Different studies in ESRD patients on dialysis treatment reported the contribution of IL6 allelic variants in the promotor region to the variation/modulation of several biochemical and clinical parameters, such as serum erythropoietin, hemoglobin c oncentration[15], inflammatory b iomarkers[16], dysfunction in the vascular access for HD procedure[17], progression of kidney dysfunction[18], and in the risk for CVD, coronary artery disease[19,20], and a therosclerosis[21]. The influence of IL6 genetic variants in the inflammatory response, outcome and mortality risk in ESRD still requires more research
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