Elsevier

Gene

Volume 585, Issue 1, 1 July 2016, Pages 51-57
Gene

Research paper
The IL6R gene polymorphisms are associated with sIL-6R, IgE and lung function in Chinese patients with asthma

https://doi.org/10.1016/j.gene.2016.03.026Get rights and content

Highlights

  • Serum sIL-6R increased in serum of patients with asthma, the elevated sIL6R correlated with higher IgE and lower FEV1

  • IL6R polymorphism rs2228145 C allele related to higher sIL6R, higher serum IgE levels and lower lung functions in patients with asthma

  • IL6R polymorphism rs12083537 G allele associated with lower lung functions in patients with asthma

Abstract

Background: sIL-6R is involved in a variety of inflammatory diseases. The present study analyzed the potential associations between two IL6R gene polymorphisms (rs2228145 and rs12083537) and asthma in a Han Chinese population. Methods: A cohort of 394 patients and 395 healthy controls were genotyped to detect the two polymorphisms using SNaPshot. In 66 asthma patients and 49 controls, peripheral eosinophil and serum immunoglobulin E (IgE) levels were determined using a routine blood test, and sIL-6R levels were measured by ELISA. Results: No statistically significant differences were detected between the patients and controls in the distribution of the two independent IL6R polymorphisms (p > 0.05). However, rs2228145 C and rs12083537 G were significantly associated with decreased lung function in patients with asthma; the rs2228145 A–C variant was also associated with increased sIL-6R and IgE levels. In addition, sIL-6R levels were positively associated with IgE and inversely associated with lung function in patients with asthma. Conclusions: Our results provide evidence that rs2228145 C and rs12083537 G are associated with poor lung function in patients with asthma. Furthermore, the rs2228145 A–C variant is associated with levels of sIL-6R and IgE.

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)

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