Association between IL-18/18R gene polymorphisms and coronary artery disease: influence of IL-18/18R genetic variants on cytokine expression

Vadim Mitrokhin,1 Alexey Nikitin,2 Olga Brovkina,2 Dmitry Khodyrev,2 Alexander Zotov,2 Nikita Vachrushev,1 Dmitry Dragunov,3 Andrey Shim,1 Mitko Mladenov,1,4 Andre Kamkin1 1Department of Fundamental and Applied Physiology, Russian National Research Medical University, Moscow, Russia; 2Federal Scientific Clinical Center for Specialized Types of Medical Assistance and Medical Technologies for the Federal Medical and Biological Agency, Moscow, Russia; 3Scientific Research Institute of Healthcare Organization and Medical Management, Moscow, Russia; 4Faculty of Natural Sciences and Mathematics, Institute of Biology, “Ss. Cyril and Methodius” University, Skopje, Macedonia Purpose: The present study investigated the influence of IL-18/18R genetic variants on cytokine expression in patients with stable coronary artery disease (CAD). Materials and methods: The polymorphisms rs1946518, rs187238, rs326, rs1169288, and rs183130 were determined in patients with and without CAD. Circulating cytokine levels were measured immunologically. Results: The rs1946518-GG genotype shows higher IL-18 concentration in the group with CAD, but still not significant. The TG genotype from rs1946518 in carriers with CAD showed a significant decrease in relation to the pro-inflammatory cytokines IL-6, IL-8, and IL-18. The decreases of IL-6 and IL-8 were also specific for rs187238 CAD carriers with the GC genotype. The CAD carriers with the AA genotype from rs326 in the IL-18R gene showed significant increase in IL-8 and IL-18 in comparison with those without CAD. Regarding rs1169288 from the IL-18R gene, IL-8 showed a T allele-dependent increase. In the last rs183130 polymorphism of the IL-18R gene, the pro-inflammatory onset showed a C allele-dependent disease-associated decrease in IL-8 CC and IL-6 CT carriers. In contrast, the CAD CT carriers in relation to IL-8 showed significant increase. Conclusions: Most of the IL-18/18R single-nucleotide polymorphisms were mainly associated with pro-inflammatory cytokines. It is surmised that these associations between some pro-inflammatory cytokines (mainly IL-8) and some IL-18R genotypes in the subjects with CAD from this study are most likely based on inflammatory-induced upregulation of IL-18R expression. Keywords: Russian patients, inflammation, gene polymorphisms, IL-18/IL-18R genetic variants, inflammation, cytokine

Association between interleukin-6/6R gene polymorphisms and coronary artery disease in Russian population: influence of interleukin-6/6R gene polymorphisms on inflammatory markers

Vadim Mitrokhin,1 Alexey Nikitin,2 Olga Brovkina,2 Dmitry Khodyrev,2 Alexander Zotov,2 Nikita Vachrushev,1 Dmitry Dragunov,3 Andrey Shim,1 Mitko Mladenov,1,4 Andre Kamkin1 1Department of Fundamental and Applied Physiology, Russian National Research Medical University, 2Federal Scientific Clinical Center for Specialized Types of Medical Assistance and Medical Technologies for the Federal Medical and Biological Agency, 3Scientific Research Institute of Healthcare Organization and Medical Management, Moscow, Russia; 4Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, Skopje, Macedonia Abstract: This study determined the genotype effects of interleukin (IL)-6/IL-6R single nucleotide polymorphisms (SNPs) on circulating levels of different cytokines in healthy and coronary artery disease (CAD) patients with different allele frequencies. In the control patients, rs1800795 showed significant differences in IL-18 concentrations between CC and CG and CC and GG genotypes (P=0.003 and 0.004, respectively). Furthermore, circulatory IL-1β was significantly different between GC and GG genotypes from the same SNP (P=0.038). In the diseased patients, significance was determined only for IL-2 (P=0.021) between the C and G homozygote allele carriers of rs1800795. The diseased GC and GG genotype carriers were statistically different for IL-2 (P=0.049) from the rs1800796 and for IL-4 (P=0.049) from the rs2228044. IL-4 was also statistically significant between the GC and CC genotypes from the rs2228043 of the IL-6R gene (P=0.025). The last combination of genotypes in the same gene for the same SNP was statistically significant for IL-10 (P=0.036). According to the logistic regression, only gender (odds ratio [OR] =2.43) and triglycerides (OR =1.98) could be taken as determinants of CAD, while examined SNPs genotypes were not identified as risk factors for CAD. In general, the IL-6 polymorphism genotypes were mainly associated with inflammatory cytokines, while the IL-6R polymorphism genotypes were associated with anti-inflammatory cytokines. Keywords: IL-6/IL-6R gene polymorphisms, coronary artery disease, cytokines, inflammatio

Biological nano-functionalization of titanium-based biomaterial surfaces: a flexible toolbox

Surface functionalization with bioactive molecules (BAMs) on a nanometre scale is a main field in current biomaterial research. The immobilization of a vast number of substances and molecules, ranging from inorganic calcium phosphate phases up to peptides and proteins, has been investigated throughout recent decades. However, in vitro and in vivo results are heterogeneous. This may be at least partially attributed to the limits of the applied immobilization methods. Therefore, this paper highlights, in the first part, advantages and limits of the currently applied methods for the biological nano-functionalization of titanium-based biomaterial surfaces. The second part describes a new immobilization system recently developed in our groups. It uses the nanomechanical fixation of at least partially single-stranded nucleic acids (NAs) into an anodic titanium oxide layer as an immobilization principle and their hybridization ability for the functionalization of the surface with BAMs conjugated to the respective complementary NA strands