IL-6 -174 C/C Genotype Is Not Conclusively a Low IL-6 Production Phenotype

Abstract

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.”