TO THE EDITOR—We read with interest the article entitled “The interleukin 6 −174 C/C genotype predicts greater rhinovirus illness” [1]. The authors reported that among healthy adults, the interleukin 6 (IL-6) −174 C/C genotype was associated with greater symptom magnitudes after experimental rhinovirus type 39 infection. In the article, the IL-6 −174 C/C genotype was referred to as the phenotype with “low IL-6 production,” on the basis of “the convention published by Gentile and colleagues” [2]. Their study showed no significant difference in IL-6 concentrations in nasal secretions between the group with IL-6 −174 C/C genotype (n = 9) and those with wild type G/G and heterozygous polymorphic G/C combined (n = 47).
IL-6 −174 polymorphic genotypes (G/C or C/C) have been reported to be functional; however, the literature on IL-6 production in cases with polymorphic genotypes has been controversial. Fishman et al [3] reported significantly lower levels of plasma IL-6 in healthy subjects with IL-6 −174 C/C genotype, compared with those with G/G or G/C genotypes. Similar findings have been reported in patients after coronary artery bypass surgery [4]. However, in other studies the results have been quite the opposite. Studies of adults with abdominal aneurysm [5] or coronary artery bypass surgery [6], as well as of children with thrombosis [7] and of healthy neonates [8], have reported higher levels of plasma IL-6 in participants with the IL-6 −174 C/C genotype, compared with carriers of the G allele. In 2 studies of healthy adults, no association was found between IL-6 −174 genotype and the level of plasma IL-6 [8, 9].
In vitro studies also show the controversy; IL-6 production by stimulated mononuclear cells of healthy adults with IL-6 −174 C/C genotype has either been low [10] or showed no difference in IL-6 production between different genotypes [8]. On the other hand, stimulation of cord blood neonatal monocytes resulted in higher IL-6 production in those with IL-6 −174 C/C genotype, compared with G/C or G/G genotype [8]. In our recent study, stimulation of adult monocytes with either lipopolysaccharide or respiratory syncytial virus resulted in significantly higher IL-6 production in the group of participants with polymorphic genotypes (G/C or C/C) than in wild-type (G/G) particpants [11]. Stimulation with rhinovirus, however, did not result in significant differences in IL-6 production between the genotype groups. The low prevalence of the IL-6 −174 C/C genotype did not allow us to independently compare IL-6 concentrations in heterozygous (G/C) and homozygous (C/C) polymorphic genotypes.
In the study by Doyle et al, no statistically significant relationship was revealed between the IL-6 genotypes and IL-6 concentrations in nasal secretions [1]. Interestingly, the wild-type G/G genotype was combined with the heterozygote genotype and then compared with the C/C genotype. We wonder whether the results could be different if IL-6 production were compared among 3 different genotypes (G/G, G/C, and C/C) separately or the combined polymorphic genotypes (G/C with C/C) were compared with the wild-type genotype (G/G). In our previous study of risk for otitis susceptibility in children, we combined G/C with C/C; the polymorphic group had significantly higher risk for otitis susceptibility than did the G/G group [12].
Doyle et al reported that the subjects with IL-6 −174 C/C genotype had more upper respiratory infection days and higher symptom scores, compared with carriers of the G allele [1]. Their presumption of C/C genotype as a low cytokine production phenotype does not correlate with our understanding of the expected role of IL-6 as a proinflammatory cytokine that has been shown to be associated with greater severity of inflammatory disease. In our study showing a positive correlation between IL-6 −174 G/C and C/C polymorphisms and susceptibility to otitis media [12], we presumed that the polymorphic genotypes were high IL-6 producing and that the high cytokine concentrations enhanced the inflammation in nasopharyngeal and Eustachian tube mucosa during a viral upper respiratory infection, thereby increasing the risk for otitis media development.
In summary, we agree with Doyle et al on the importance of the IL-6 −174 C/C genotype. The studies cited here, however, do not support the conclusion that the C/C genotype is “the low IL-6 production phenotype.”
Funding
This work was partly supported by National Institutes of Health grant R01DC005841.
References
- 1.Doyle WJ, Casselbrant ML, Li-Korotky HS, et al. The interleukin 6 –174 C/C genotype predicts greater rhinovirus illness. J Infect Dis. 2010;201:199–206. doi: 10.1086/649559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Gentile DA, Doyle WJ, Zeevi A, et al. Cytokine gene polymorphisms moderate illness severity in infants with respiratory syncytial virus infection. Hum Immunol. 2003;64:338–44. doi: 10.1016/s0198-8859(02)00827-3. [DOI] [PubMed] [Google Scholar]
- 3.Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102:1369–76. doi: 10.1172/JCI2629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Burzotta F, Iacoviello L, Di Castelnuovo A, et al. Relation of the –174 G/C polymorphism of interleukin-6 to interleukin-6 plasma levels and to length of hospitalization after surgical coronary revascularization. Am J Cardiol. 2001;88:1125–8. doi: 10.1016/s0002-9149(01)02046-x. [DOI] [PubMed] [Google Scholar]
- 5.Jones KG, Brull DJ, Brown LC, et al. Interleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms. Circulation. 2001;103:2260–5. doi: 10.1161/01.cir.103.18.2260. [DOI] [PubMed] [Google Scholar]
- 6.Brull DJ, Montgomery HE, Sanders J, et al. Interleukin-6 gene –174G>C and –572G>C promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol. 2001;21:1458–63. doi: 10.1161/hq0901.094280. [DOI] [PubMed] [Google Scholar]
- 7.Unal S, Gumruk F, Aytac S, Yalnzoglu D, Gurgey A. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) levels and IL-6, TNF-polymorphisms in children with thrombosis. J Pediatr Hematol Oncol. 2008;30:26–31. doi: 10.1097/MPH.0b013e31815b1a89. [DOI] [PubMed] [Google Scholar]
- 8.Kilpinen S, Hulkkonen J, Wang XY, Hurme M. The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults. Eur Cytokine Netw. 2001;12:62–8. [PubMed] [Google Scholar]
- 9.Hegedus CM, Skibola CF, Bracci P, Holly EA, Smith MT. Screening the human serum proteome for genotype-phenotype associations: an analysis of the IL6 –174G>C polymorphism. Proteomics. 2007;7:548–57. doi: 10.1002/pmic.200600366. [DOI] [PubMed] [Google Scholar]
- 10.Hoffmann SC, Stanley EM, Darrin Cox E, et al. Association of cytokine polymorphic inheritance and in vitro cytokine production in anti CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation. 2001;72:1444–50. doi: 10.1097/00007890-200110270-00019. [DOI] [PubMed] [Google Scholar]
- 11.Patel JA, Nair S, Ochoa EE, Huda R, Roberts NJ, Chonmaitree T. Interleukin-6−174 and tumor necrosis factor α−308 polymorphisms enhance cytokine production by human macrophages exposed to respiratory viruses. J Interferon Cytokine Res. 2010;30:917–21. doi: 10.1089/jir.2010.0033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Patel JA, Nair S, Revai K, et al. Association of proinflammatory cytokine gene polymorphisms with susceptibility to otitis media [published correction appears in Pediatrics 2007; 119:1270] Pediatrics. 2006;118:2273–9. doi: 10.1542/peds.2006-0764. [DOI] [PubMed] [Google Scholar]