Research paperThe IL6R gene polymorphisms are associated with sIL-6R, IgE and lung function in Chinese patients with asthma
Introduction
Asthma is a chronic inflammatory respiratory disease affecting more than 300 million people worldwide characterized by airway obstruction, hyperproduction of immunoglobulin E (IgE), mucus hypersecretion and hyperresponsiveness (Murphy and O'Byrne, 2010, Holgate, 2012). The pathological processes of asthma may be influenced by a combination of both genetic and environmental factors, but the detailed mechanism has not been fully explained.
Interleukin 6 (IL-6), like other inflammatory cytokines, is involved in allergic asthma (Doganci et al., 2005a, Neveu et al., 2010, Rincon and Irvin, 2012, Ferreira et al., 2011). IL-6 can directly act on target cells via specific membrane-bound IL-6 receptor (mIL-6R), which is known as classical IL-6 signaling. An alternative IL-6 signaling pathway is mediated by the soluble IL-6 receptor (sIL-6R), which is termed trans-signaling (Jones et al., 1999). sIL-6R can be produced either by proteolysis of the membrane receptor or by alternative mRNA splicing (Horiuchi et al., 1994, Lust et al., 1992, Mullberg et al., 1993, Rose-John and Heinrich, 1994). The persistently elevated IL-6 may down-regulate mIL-6R and make cells unresponsive to IL-6. Such a refractory state can be overcome by the elevation of sIL-6R (Taga et al., 1989). Thus, sIL-6R plays an important role in the responses mediated by IL-6. The activity of sIL-6R is implicated in a variety of inflammatory diseases, such as inflammatory bowel disease (Brulhart et al., 2010, Rose-John et al., 2009), rheumatoid arthritis (Febbraio et al., 2010) and asthma (Robinson et al., 2015, Ullah et al., 2015, Cho et al., 2015), and there are anti-IL-6R therapies, which target sIL-6R as well as the membrane-bound mIL-6R (Mima & Nishimoto, 2009).
An important genetic determinant of sIL-6R levels is the rs2228145 single-nucleotide polymorphism (SNP) (formerly rs8192284), which is located in exon 9 of the IL6R gene on chromosome 1 (Galicia et al., 2004). Rs2228145 is specifically localized to amino acid position 358, which is the main cleavage site of IL6R (Mullberg et al., 1994). The functional polymorphism of rs2228145 A–C results in the 358 Aspartic acid substituted by Alanine (Asp358Ala) (Hamid et al., 2004). Notably, rs2228145 C allele carriers (Ala358 allele) show an increase in sIL-6R levels (Galicia et al., 2004). Rs2228145 is also associated with a lower level of lung function (Hawkins et al., 2012) and an increased risk of asthma (Ferreira et al., 2011). Another SNP site, rs12083537 A/G, located in intron 1, 2.9 kb away from exon 1 of IL6R. The rs12083537 G SNP is also associated with higher sIL-6R levels, and may be associated with an increased risk of asthma (Revez et al., 2013). However, there has been no data published on an association of the two IL6R alleles to asthma risk or lung function in the Chinese population.
In the present case-control study of a Han Chinese population, we measured the associations of the two IL6R polymorphisms (rs2228145 and rs12083537) to asthma risk, sIL-6R, serum IgE levels and lung function. Furthermore, the correlations between sIL-6R and serum IgE, lung functions were determined.
Section snippets
Participants
In total, 394 patients and 395 controls from a Han population in China were included in this case–control study. Asthma subjects were patients seeking treatment for asthma symptoms at the Affiliated Hospital of Guangdong Medical College (Zhanjiang, China) between January 2013 and December 2014. None of the patients received treatment for asthma during the 4 weeks prior to their participation in this study. A clinical diagnosis of probable asthma was established according to the criteria of the
Characteristics of patients with asthma and controls
The mean year of age for the patients with asthma and healthy subjects was 45.37 and 45.23, respectively. There were no significant differences in both age and gender composition between patients with asthma and healthy subjects. In terms of characteristics associated with asthma, there were significant differences between patients and healthy subjects. Compared to healthy subjects, the patients with asthma exhibited increased serum IgE levels (542.00 ± 792.00 IU/ml vs. 48.00 ± 56.00, p < 0.0001),
sIL-6R increased in patients with asthma
IL-6 signaling is associated with asthma control and poor lung function and to the greatest frequency with asthma symptoms (Simpson et al., 2006, Hastie et al., 2010, Al-Ramli et al., 2009). IL-6 acts on target cells by binding to IL-6R that is in a complex with the gp130, resulting in the activation of the associated gene expression. In the present study, we demonstrated that the levels of sIL-6R increased in patients with asthma (129.3 ± 46.54 ng/ml vs. 95.63 ± 29.88 ng/ml), near to the levels
Conclusion
In the present study involving 394 Southern Han Chinese patients with asthma, we demonstrated that two independent IL6R variants, rs2228145 A/C and rs12083537 A/G were related to the influence of sIL6R on the lung function of patients with asthma. The rs2228145 C variant was also associated with higher sIL-6R and IgE levels. Increased sIL-6R levels were associated with higher serum IgE levels and lower lung function. However, in a case-control study involving 394 patients and 395 healthy
Author contributions
Yajun Wang and Huiting Hu: equal contributions to the study's conception and design, the collection and assembly of the data, the data analysis and interpretation, and the writing of the manuscript.
Yajun Wang: Ph.D. Affiliated Hospital of Guangdong Medical College; the revising of the manuscript.
Huiting Hu: Master Candidate, Guangdong Medical College; the revising of the manuscript.
Jun Wu: Ph.D. Affiliated Hospital of Guangdong Medical College; collection and assembly of the data, and the data
Acknowledgements
This project was supported by grants from the Natural Science Foundation of China (No. 81400023); Medical Science and Technology Research Fund of Guangdong (No. A2015338) and Natural Science Foundation of Guangdong Province (Grant No. 2015A030313523)
References (58)
- et al.
Recent advances in the pathophysiology of asthma
Chest
(2010) Identification of IL6R and chromosome 11q13.5 as risk loci for asthma
Lancet
(2011)Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor
Cytokine
(1992)Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130
Cell
(1989)Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists
Joint Bone Spine
(2010)T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma
J. Allergy Clin. Immunol.
(2009)- et al.
Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis
Blood
(1998) The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases
Biochim. Biophys. Acta
(2014)Cytokine-directed therapies for asthma
J. Allergy Clin. Immunol.
(2001)- et al.
Anti-interleukin-6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases
FEBS Lett.
(2011)