Are cytokine gene polymorphisms related to in vitro cytokine production profiles?

Abstract

Currently, there is much interest in the genetic basis for diseases or disease manifestations and, in particular, in whether they are related to cytokine gene polymorphisms. It has become accepted to denote such single‐nucleotide polymorphisms of cytokine genes by their presumed association with high or low in vitro cytokine production. In this article, we analyze the relationship between cytokine gene polymorphisms and in vitro tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and interleukin (IL)‐10 and IL‐13 production, both in liver transplant recipients and in healthy volunteers. The evaluated cytokine gene polymorphisms involved TNF‐A‐308; TNF‐d3; IFN‐G+874; IL‐10‐1082, ‐819, and ‐592; and IL‐13+2043, and ‐1055. For healthy volunteers, we observed a relationship between polymorphisms of TNF‐d3 and IL‐10‐1082 with in vitro production of TNFα and IL‐10, respectively, whereas no significant associations were found for the other tested cytokine gene polymorphisms. For liver transplant recipients, no significant relationship could be established between any of the cytokine gene polymorphisms and in vitro production of corresponding cytokines. Also, we reviewed the literature for the association between cytokine gene polymorphisms and in vitro cytokine production in various patient groups and healthy volunteers. We found that the cellular sources, from which the cytokines were released into the culture supernatant, were different between studies. They were either whole blood, isolated monocytes, or peripheral blood mononuclear cells (PBMC). Also, the in vitro incubation protocol varied to a great extent between studies. This applied for the used in vitro stimulant, the concentration of a particular stimulant, and the length of the incubation period. Moreover, the study populations were either healthy individuals or very diverse patient groups. Therefore, it was impossible to evaluate whether in vitro cytokine production profiles really can be deduced from a particular cytokine gene polymorphism. Given the inconclusive findings, we propose to set up a multicenter workshop in which the relationship between certain cytokine gene polymorphisms and in vitro cytokine production is analyzed, using an identical in vitro cell culture system and study population. Furthermore, we suggest that cytokine gene polymorphisms be described by their localization within the gene or gene‐promoter, rather than by their presumed in vitro cytokine production profile, to properly evaluate the relationship between cytokine gene polymorphisms and disease manifestations.

The influence of genetic variation on innate immune activation in an environment with high infectious pressure

“…However, in general, our results are in line with most previous studies suggesting an increased IL-10 production with rs1800896G and a decreased IL-10 production with rs1800871T and rs1800872A, [13][14][15][16][17][18][19][20][21][22] although there are also studies reporting on opposite results. [23][24][25] Taking into account the 2-year interval between measurements and the field conditions in which samples were collected and the stimulation assay was performed, we consider the repeated measurements to correlate well, especially for IL-10. This provides evidence that the strength of the IL-10 response of an individual is relatively stable over time in a pathogen-rich environment, suggesting an important role for genetics in the production of IL-10 even under high infectious pressure.…”

Cytokine gene polymorphisms in preeclampsia and eclampsia

“…Therefore, the relationship between genotype and phenotype cannot always be clearly demonstrated. 25 PE and E are considered as expressions of the same syndrome, with E being the most severe form of PE. Although other studies have investigated the relationship between PE and cytokine gene polymorphism, few have evaluated eclamptic patients.…”

“…Following the kit's manufacturer's suggestion and literature recommendations, [23][24][25] cytokine genotype and phenotype were grouped as follows: for the TNF-a gene, the alleles were distributed as A/A and A/G (high) and G/G (low); for the IL-6 gene, the groups were G/G and G/C (high) and C/C (low); for the IL-10 gene, the alleles for each polymorphism were grouped as GCC/GCC (high), GCC/ATA and GCC/ACC (intermediate) and ACC/ACC and ACC/ATA (low); for the IFN-g gene, the alleles were distributed as T/T (high), T/A (intermediate) and A/A (low); and for the TGF-b1 gene, the groups were T/T G/G and T/C G/G (high), T/C G/C and C/C G/G (intermediate) and C/C G/C, C/C C/C, T/T C/C and T/C C/C (low).…”

Lack of IFN-gamma 2/2 homozygous genotype independently of recipient age and intensity of conditioning regimen influences the risk of aGVHD manifestation after HLA-matched sibling haematopoietic stem cell transplantation

“…Using a number of different assays, several groups investigated the effect of STR and SNP ( þ 874) polymorphisms on IFN-gamma production (reviewed by Warle et al 4 and Vanderbroeck and Goris 5 ). It was generally found that individuals homozygous for STR allele 2 (or having T at polymorphic position þ 874), in contrast to those carrying allele 3 (or þ 874 A), had a greater IFN-gamma secretion by peripheral blood mononuclear cells (PBMC) upon different mitogen stimulations.…”