Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced

Abstract

We have investigated the association of the recently identified IL6R polymorphisms with the serum levels of soluble IL-6 receptor (sIL-6R). sIL-6R is generated by shedding of the membrane-bound receptor (IL-6Ralpha) or alternative mRNA splicing. In total, 115 healthy volunteers were genotyped, with 70 of them analyzed for sIL-6R levels. Using the PCR/RFLP methods, two important polymorphic sites were selected for genotyping: the 48892A/C (D358A) in exon 9 and the -183G/A in the promoter region. In exon 9, C allele carriers had higher sIL-6R level (P<0.0001) showing that this sequence variation, which corresponds to the proteolytic cleavage site of IL-6Ralpha, strongly influences the serum sIL-6R levels. In the promoter region, G allele carriers had lower sIL-6R levels (P<0.0082) compared with the A allele carriers. This could be attributed to the linkage disequilibrium (D'=0.54, chi2=51.3, P<0.0001) between the -183G/A and the 48892A/C gene polymorphisms.

Association of cognitive performance with interleukin-6 receptor Asp358Ala polymorphism in healthy adults

“…In particular, three of the verbal subtest scores and the total VIQ were lower in carriers of the Ala allele compared to non-carriers. Since the Ala allele is strongly associated with higher IL-6 and sIL-6R levels (Galicia et al 2004;Rafiq et al 2007;Reich et al 2007;Jiang et al 2010;Sasayama et al 2011b), our findings support the possibility that excessive IL-6 signaling may have a negative impact on cognitive ability.…”

“…A single nucleotide polymorphism (SNP) Asp358Ala (rs8192284) of the IL-6 receptor (IL-6R) gene, which substitutes an amino acid at the proteolytic cleavage site, is known to be strongly associated with the circulating levels of soluble IL-6R (sIL-6R) (Galicia et al 2004;Rafiq et al 2007;Reich et al 2007;Sasayama et al 2011b) and IL-6 (Rafiq et al 2007;Reich et al 2007;Jiang et al 2010;Sasayama et al 2011b). The Ala allele of this polymorphism is associated with increased levels of both IL-6 and sIL-6R, suggesting that possession of this allele may result in elevated levels of IL-6…”

Cancer-related fatigue: Links with inflammation in cancer patients and survivors

“…Fatigued breast cancer survivors also had a higher percentage of homozygous genotypes (G/ G) and (C/C) for the IL-6 -174 promoter polymorphism, and a higher percentage of homozygous (A/A) and heterozygous (G/A) genotypes for the IL-6R -183 polymorphism. Each of these genotypes has been associated with increased expression of their respective cytokine (e.g., Brull et al, 2001;Burzotta et al, 2001;Galicia et al, 2004;di Giovine et al, 1992). We did not find an association between fatigue-related genotypes and circulating cytokine concentrations, possibly due to the small sample size and the relatively low levels of these markers in this otherwise healthy sample; it is possible that differences might have emerged following in vivo immune stimulation, as seen in previous research (e.g., Bennermo et al, 2004).…”

Influence of the 48867A>C (Asp358Ala) IL6R polymorphism on response to a lifestyle modification intervention in individuals with metabolic syndrome

“…Among those, the SNP located at exon 9 [48892A>C; Asp358Ala; rs2228145 (rs8192284 merged into rs2228145)] has been associated with elevated serum levels of sIL6R (Galicia et al, 2004). Polymorphisms of the IL6R gene have been implicated in many studies on obesity, insulin resistance, metabolic syndrome, and risk for diabetes, showing a positive relationship of the A allele (Asp) with obesity and/or type 2 diabetes (Wolford et al, 2003;Hamid et al, 2005;Wang et al, 2005;Esteve et al, 2006).…”

“…IL6R has two subunits: the transmembrane 130-kD subunit (IL-6ST, IL6Rβ, or gp130), responsible for signal transduction with consequent activation of the inflammatory state, and the 80-kDa subunit (IL6Rα or gp80), to which IL-6 binds (Fernández-Real and Ricart, 2003;Wang et al, 2005). A soluble and biologically active form of IL6R (sIL6R) is present in the plas-ma, corresponding to the extracellular portion (gp80), produced by differential splicing or by proteolytic cleavage of IL6R (shedding) (Galicia et al, 2004;Esteve et al, 2006). When IL-6 binds to sIL6R, this complex can bind to gp130 present on the surface of cells that do not have IL-6R (and so would not respond to the inflammatory stimuli of IL-6), leading to the dimerization of gp130, consequent intracellular signaling (trans-signaling), resulting in a diffuse inflammatory state (Jones et al, 2001;Heinrich et al, 2003;Esteve et al, 2006;Qi et al, 2007;Rafiq et al, 2007;Santer et al, 2010).…”