The IL6R variation Asp358Ala is a potential modifier of lung function in subjects with asthma

Gregory A. Hawkins; Mac B. Robinson; Annette T. Hastie; Xingnan Li; Huashi Li; Wendy C. Moore; Timothy D. Howard; William W. Busse; Serpil C. Erzurum; Sally E. Wenzel; Stephen P. Peters; Deborah A. Meyers; Eugene R. Bleecker

doi:10.1016/j.jaci.2012.03.018

The IL6R variation Asp³⁵⁸Ala is a potential modifier of lung function in subjects with asthma

Gregory A. Hawkins, Mac B. Robinson, Annette T. Hastie, Xingnan Li, Huashi Li, Wendy C. Moore, Timothy D. Howard, William W. Busse, Serpil C. Erzurum, Sally E. Wenzel, Stephen P. Peters, Deborah A. Meyers, Eugene R. Bleecker

Research output: Contribution to journal › Article › peer-review

87 Scopus citations

Abstract

Background: The IL6R single nucleotide polymorphism (SNP) rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium (r² = 1) with the IL6R coding SNP rs2228145 (Asp³⁵⁸Ala). This IL6R coding change increases IL-6 receptor (IL-6R) shedding and promotes IL-6 transsignaling. Objectives: We sought to evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes. Methods: The IL6R SNP rs2228145 was evaluated in subjects of European ancestry with asthma from the Severe Asthma Research Program (SARP). Lung function associations were replicated in the Collaborative Study on the Genetics of Asthma (CSGA) cohort. Serum soluble IL-6R levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL-6R protein expression in bronchoalveolar lavage cells and endobronchial biopsies. Results: The minor C allele of IL6R SNP rs2228145 was associated with a lower percent predicted FEV₁ in the SARP cohort (P =.005), the CSGA cohort (P =.008), and in a combined cohort analysis (P =.003). Additional associations with percent predicted forced vital capacity (FVC), FEV₁/FVC ratio, and PC₂₀ were observed. The rs2228145 C allele (Ala³⁵⁸) was more frequent in severe asthma phenotypic clusters. Elevated serum soluble IL-6R levels were associated with lower percent predicted FEV₁ (P = .02) and lower percent predicted FVC (P =.008) (n = 146). IL-6R protein expression was observed in bronchoalveolar lavage macrophages, airway epithelium, vascular endothelium, and airway smooth muscle. Conclusions: The IL6R coding SNP rs2228145 (Asp ³⁵⁸Ala) is a potential modifier of lung function in subjects with asthma and might identify subjects at risk for more severe asthma. IL-6 transsignaling might have a pathogenic role in the lung.

Original language	English (US)
Pages (from-to)	510-515.e1
Journal	Journal of Allergy and Clinical Immunology
Volume	130
Issue number	2
DOIs	https://doi.org/10.1016/j.jaci.2012.03.018
State	Published - Aug 2012
Externally published	Yes

Keywords

IL-6
IL-6 transsignaling
Soluble IL-6 receptor
asthma
genetic variation
pulmonary lung function
severe asthma
single nucleotide polymorphism rs2228145

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1016/j.jaci.2012.03.018

Cite this

Hawkins, G. A., Robinson, M. B., Hastie, A. T., Li, X., Li, H., Moore, W. C., Howard, T. D., Busse, W. W., Erzurum, S. C., Wenzel, S. E., Peters, S. P., Meyers, D. A., & Bleecker, E. R. (2012). The IL6R variation Asp³⁵⁸Ala is a potential modifier of lung function in subjects with asthma. Journal of Allergy and Clinical Immunology, 130(2), 510-515.e1. https://doi.org/10.1016/j.jaci.2012.03.018

Hawkins, GA, Robinson, MB, Hastie, AT, Li, X, Li, H, Moore, WC, Howard, TD, Busse, WW, Erzurum, SC, Wenzel, SE, Peters, SP, Meyers, DA & Bleecker, ER 2012, 'The IL6R variation Asp³⁵⁸Ala is a potential modifier of lung function in subjects with asthma', Journal of Allergy and Clinical Immunology, vol. 130, no. 2, pp. 510-515.e1. https://doi.org/10.1016/j.jaci.2012.03.018

@article{00d5fd36b70f4ff7a010a8cc7e487e7d,

title = "The IL6R variation Asp358Ala is a potential modifier of lung function in subjects with asthma",

abstract = "Background: The IL6R single nucleotide polymorphism (SNP) rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium (r2 = 1) with the IL6R coding SNP rs2228145 (Asp358Ala). This IL6R coding change increases IL-6 receptor (IL-6R) shedding and promotes IL-6 transsignaling. Objectives: We sought to evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes. Methods: The IL6R SNP rs2228145 was evaluated in subjects of European ancestry with asthma from the Severe Asthma Research Program (SARP). Lung function associations were replicated in the Collaborative Study on the Genetics of Asthma (CSGA) cohort. Serum soluble IL-6R levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL-6R protein expression in bronchoalveolar lavage cells and endobronchial biopsies. Results: The minor C allele of IL6R SNP rs2228145 was associated with a lower percent predicted FEV1 in the SARP cohort (P =.005), the CSGA cohort (P =.008), and in a combined cohort analysis (P =.003). Additional associations with percent predicted forced vital capacity (FVC), FEV1/FVC ratio, and PC20 were observed. The rs2228145 C allele (Ala358) was more frequent in severe asthma phenotypic clusters. Elevated serum soluble IL-6R levels were associated with lower percent predicted FEV1 (P = .02) and lower percent predicted FVC (P =.008) (n = 146). IL-6R protein expression was observed in bronchoalveolar lavage macrophages, airway epithelium, vascular endothelium, and airway smooth muscle. Conclusions: The IL6R coding SNP rs2228145 (Asp 358Ala) is a potential modifier of lung function in subjects with asthma and might identify subjects at risk for more severe asthma. IL-6 transsignaling might have a pathogenic role in the lung.",

keywords = "IL-6, IL-6 transsignaling, Soluble IL-6 receptor, asthma, genetic variation, pulmonary lung function, severe asthma, single nucleotide polymorphism rs2228145",

author = "Hawkins, {Gregory A.} and Robinson, {Mac B.} and Hastie, {Annette T.} and Xingnan Li and Huashi Li and Moore, {Wendy C.} and Howard, {Timothy D.} and Busse, {William W.} and Erzurum, {Serpil C.} and Wenzel, {Sally E.} and Peters, {Stephen P.} and Meyers, {Deborah A.} and Bleecker, {Eugene R.}",

note = "Funding Information: In this study we have identified the IL6R coding SNP rs2228145 (Asp 358 Ala) as a potential genetic modifier of lung function in subjects with asthma and as a potential novel genetic marker of asthma severity. In separate and combined analyses of the SARP and CSGA European ancestry asthma cohorts, the minor C allele of rs2228145 (Ala 358 ) was consistently associated with lower percent predicted FEV 1 and lower FEV 1 /FVC ratio and the highest level of methacholine responsiveness. In addition, the the rs2228145 C allele frequency was found to be higher in SARP phenotypic asthma clusters consisting of subjects with more severe asthma. We have also shown, for the first time, that copious IL-6R protein is expressed in multiple cell types in the lung. These observations are important in light of the recent GWAS of approximately 58,000 subjects that identified IL6R as an asthma risk gene. 1 In this GWAS a single IL6R SNP (rs4129267) was identified as conferring asthma risk. Because of the small sizes of the SARP and CSGA cohorts used in this study, we were not able to replicate the asthma risk assessment performed in the large GWAS. In addition, direct comparison of the data from this study with the large GWAS was not possible because the GWAS did not evaluate lung function and presented no information on the proportion of subjects with severe asthma. Because our genotyping data were derived from the Illumina Human1M-Duo DNA BeadChip, additional IL6R SNP genotypes, including the risk SNP rs4129267, could be analyzed. We were thus able to show that rs4129267 was a tagging SNP ( r 2 = 1) for the coding SNP rs2228145 (Asp 358 Ala). We were also able to show that additional IL6R SNPs were associated with lung function, including the SNP rs4129267 from the original GWAS. However, the SNP rs2228145 was the only nonsynonymous coding change genotyped in our study and is the only known IL6R SNP that affects IL-6R protein function. On the basis of our observations and the strong LD between rs2228145 and rs4129267, we propose that the coding SNP rs2228145 is most probably the genetic variant conferring asthma risk in the large asthma GWAS. In a random subset of SARP subjects, the rs2228145 C allele (Ala 358 ) was strongly associated with increased serum sIL-6R levels, which is consistent with previous observations. 5 However, we did not observe a statistically significant difference in serum sIL-6R levels between subjects with asthma and unaffected control subjects, as has been reported in a smaller sampling of Japanese subjects (n = 38). 19 The discrepancy between our results and the Japanese study could be explained by ethnic differences; however, this discrepancy is most likely the result of the smaller sample size used in the Japanese study. An important advantage of this current study was the use of the SARP cohort. SARP consists of an asthma cohort enriched for severe asthma and, unlike other asthma cohorts, has subjects with a wide range of lung function and extensive phenotypic characterization that are complemented with comprehensive genetic studies. 11,12 The extensive phenotypes collected in the SARP cohort 11 have allowed the development of phenotypic asthma clusters 12 that better describe asthma heterogeneity and severity. Because the IL6R Ala 358 variant occurred at a higher frequency in the severe asthma clusters, subjects in these clusters might be important in evaluating the long-term effects of the IL6R coding SNP rs2228145 (Asp 358 Ala), perhaps providing one reason why subjects in asthma clusters 4 and 5 have lower lung function and more severe asthma. SARP is a cross-sectional study that is currently evolving into a longitudinal cohort, and thus we will be able to determine whether our IL6R observations can be used to predict changes in lung function over time. Unfortunately, we are not aware of other well-characterized asthma cohorts with longitudinal data and a wide range of lung function in which these data can be replicated. On the basis of our observations and reports linking IL-6 transsignaling to other inflammatory diseases, such as inflammatory bowel disease 9 and rheumatoid arthritis, 7 we propose that IL-6 transsignaling also has a pathogenic effect in the lung. The immunochemistry data from this study show that membrane-bound IL-6R is expressed in both BAL cells and lung epithelial cells, providing ample sources of IL-6R shedding in the lung that can be associated with increased bronchial inflammation. During inflammation, concurrent increases in IL-6 and IL-6R shedding would create an optimal environment for increased IL-6 transsignaling. 7 In subjects with mild episodic asthma, the pathologic effects of IL-6 transsignaling would be short lived because IL-6 levels return to normal when lung inflammation resolves. In subjects with more severe asthma and persistent bronchial inflammation, chronically increased IL-6 levels in the lung could sustain IL-6 transsignaling in the presence of high levels of sIL-6R. The pathogenic effects of short-term and long-term IL-6 transsignaling in the lung have not been investigated. The identification of the IL6R coding SNP rs2228145 (Asp 358 Ala) as a risk variant for lower lung function indicates that dysfunctional IL-6 transsignaling might be a potentially important therapeutic target in subjects with severe asthma. Currently, therapies targeting IL-6 transsignaling are under development for treating several inflammatory diseases, 8,10,20-24 and the results of this study might serve as the focus for the evaluation of this therapeutic class of drug in subjects with severe asthma. In the absence of a clinical genetic test for the IL6R mutation (Asp 358 Ala), it is possible that increased serum sIL-6R levels might be a surrogate biomarker to identify subjects at risk for more severe asthma and who might benefit from anti–IL-6R therapy. Clinical implications IL-6 transsignaling might have a pathogenic role in the airways relating to asthma severity. There are currently anti–IL-6R therapies that block IL-6 transsignaling and might have potential therapeutic value in subjects with asthma. The Severe Asthma Research Program (SARP) is a multicenter asthma research group funded by the National Heart, Lung, and Blood Institute and consisting of the following contributors (principal investigators are marked with an asterisk): Brigham & Women's Hospital —Elliot Israel,* Bruce D. Levy, Michael E. Wechsler, Shamsah Kazani, and Gautham Marigowda; Cleveland Clinic —Serpil C. Erzurum,* Raed A. Dweik, Suzy A. A. Comhair, Emmea Cleggett-Mattox, Deepa George, Marcelle Baaklini, and Daniel Laskowski; Emory University —Anne M. Fitzpatrick, Denise Whitlock, and Shanae Wakefield; Imperial College School of Medicine —Kian Fan Chung,* Mark Hew, Patricia Macedo, Sally Meah, and Florence Chow; University of Iowa —Eric Hoffman,* and Janice Cook-Granroth; University of Pittsburgh —Sally E. Wenzel,* Fernando Holguin, Silvana Balzar, and Jen Chamberlin; University of Texas–Medical Branch —William J. Calhoun,* and Bill T. Ameredes; University of Virginia —Benjamin Gaston,* W. Gerald Teague,* and Denise Thompson-Batt; University of Wisconsin —William W. Busse,* Nizar Jarjour, Ronald Sorkness, Sean Fain, and Gina Crisafi; Wake Forest University —Eugene R. Bleecker,* Deborah Meyers, Wendy Moore, Stephen Peters, Rodolfo M. Pascual, Annette Hastie, Gregory Hawkins, Jeffrey Krings, and Regina Smith; Washington University in St Louis —Mario Castro,* Leonard Bacharier, and Jaime Tarsi; Data Coordinating Center —Douglas Curran-Everett,* Ruthie Knowles, Maura Robinson, and Lori Silveira; National Heart, Lung, and Blood Institute —Patricia Noel and Robert Smith. We thank Dr Lilly Zheng, Brian Rector, Shelly Smith, Carla Marsh, Catherine Brewer, and Abdoulaye Diallo for their technical help and Dr Elizabeth Ampleford for help in data analysis. We also thank all of the participants in the SARP and CSGA. ",

year = "2012",

month = aug,

doi = "10.1016/j.jaci.2012.03.018",

language = "English (US)",

volume = "130",

pages = "510--515.e1",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "2",

}

TY - JOUR

T1 - The IL6R variation Asp358Ala is a potential modifier of lung function in subjects with asthma

AU - Hawkins, Gregory A.

AU - Robinson, Mac B.

AU - Hastie, Annette T.

AU - Li, Xingnan

AU - Li, Huashi

AU - Moore, Wendy C.

AU - Howard, Timothy D.

AU - Busse, William W.

AU - Erzurum, Serpil C.

AU - Wenzel, Sally E.

AU - Peters, Stephen P.

AU - Meyers, Deborah A.

AU - Bleecker, Eugene R.

N1 - Funding Information: In this study we have identified the IL6R coding SNP rs2228145 (Asp 358 Ala) as a potential genetic modifier of lung function in subjects with asthma and as a potential novel genetic marker of asthma severity. In separate and combined analyses of the SARP and CSGA European ancestry asthma cohorts, the minor C allele of rs2228145 (Ala 358 ) was consistently associated with lower percent predicted FEV 1 and lower FEV 1 /FVC ratio and the highest level of methacholine responsiveness. In addition, the the rs2228145 C allele frequency was found to be higher in SARP phenotypic asthma clusters consisting of subjects with more severe asthma. We have also shown, for the first time, that copious IL-6R protein is expressed in multiple cell types in the lung. These observations are important in light of the recent GWAS of approximately 58,000 subjects that identified IL6R as an asthma risk gene. 1 In this GWAS a single IL6R SNP (rs4129267) was identified as conferring asthma risk. Because of the small sizes of the SARP and CSGA cohorts used in this study, we were not able to replicate the asthma risk assessment performed in the large GWAS. In addition, direct comparison of the data from this study with the large GWAS was not possible because the GWAS did not evaluate lung function and presented no information on the proportion of subjects with severe asthma. Because our genotyping data were derived from the Illumina Human1M-Duo DNA BeadChip, additional IL6R SNP genotypes, including the risk SNP rs4129267, could be analyzed. We were thus able to show that rs4129267 was a tagging SNP ( r 2 = 1) for the coding SNP rs2228145 (Asp 358 Ala). We were also able to show that additional IL6R SNPs were associated with lung function, including the SNP rs4129267 from the original GWAS. However, the SNP rs2228145 was the only nonsynonymous coding change genotyped in our study and is the only known IL6R SNP that affects IL-6R protein function. On the basis of our observations and the strong LD between rs2228145 and rs4129267, we propose that the coding SNP rs2228145 is most probably the genetic variant conferring asthma risk in the large asthma GWAS. In a random subset of SARP subjects, the rs2228145 C allele (Ala 358 ) was strongly associated with increased serum sIL-6R levels, which is consistent with previous observations. 5 However, we did not observe a statistically significant difference in serum sIL-6R levels between subjects with asthma and unaffected control subjects, as has been reported in a smaller sampling of Japanese subjects (n = 38). 19 The discrepancy between our results and the Japanese study could be explained by ethnic differences; however, this discrepancy is most likely the result of the smaller sample size used in the Japanese study. An important advantage of this current study was the use of the SARP cohort. SARP consists of an asthma cohort enriched for severe asthma and, unlike other asthma cohorts, has subjects with a wide range of lung function and extensive phenotypic characterization that are complemented with comprehensive genetic studies. 11,12 The extensive phenotypes collected in the SARP cohort 11 have allowed the development of phenotypic asthma clusters 12 that better describe asthma heterogeneity and severity. Because the IL6R Ala 358 variant occurred at a higher frequency in the severe asthma clusters, subjects in these clusters might be important in evaluating the long-term effects of the IL6R coding SNP rs2228145 (Asp 358 Ala), perhaps providing one reason why subjects in asthma clusters 4 and 5 have lower lung function and more severe asthma. SARP is a cross-sectional study that is currently evolving into a longitudinal cohort, and thus we will be able to determine whether our IL6R observations can be used to predict changes in lung function over time. Unfortunately, we are not aware of other well-characterized asthma cohorts with longitudinal data and a wide range of lung function in which these data can be replicated. On the basis of our observations and reports linking IL-6 transsignaling to other inflammatory diseases, such as inflammatory bowel disease 9 and rheumatoid arthritis, 7 we propose that IL-6 transsignaling also has a pathogenic effect in the lung. The immunochemistry data from this study show that membrane-bound IL-6R is expressed in both BAL cells and lung epithelial cells, providing ample sources of IL-6R shedding in the lung that can be associated with increased bronchial inflammation. During inflammation, concurrent increases in IL-6 and IL-6R shedding would create an optimal environment for increased IL-6 transsignaling. 7 In subjects with mild episodic asthma, the pathologic effects of IL-6 transsignaling would be short lived because IL-6 levels return to normal when lung inflammation resolves. In subjects with more severe asthma and persistent bronchial inflammation, chronically increased IL-6 levels in the lung could sustain IL-6 transsignaling in the presence of high levels of sIL-6R. The pathogenic effects of short-term and long-term IL-6 transsignaling in the lung have not been investigated. The identification of the IL6R coding SNP rs2228145 (Asp 358 Ala) as a risk variant for lower lung function indicates that dysfunctional IL-6 transsignaling might be a potentially important therapeutic target in subjects with severe asthma. Currently, therapies targeting IL-6 transsignaling are under development for treating several inflammatory diseases, 8,10,20-24 and the results of this study might serve as the focus for the evaluation of this therapeutic class of drug in subjects with severe asthma. In the absence of a clinical genetic test for the IL6R mutation (Asp 358 Ala), it is possible that increased serum sIL-6R levels might be a surrogate biomarker to identify subjects at risk for more severe asthma and who might benefit from anti–IL-6R therapy. Clinical implications IL-6 transsignaling might have a pathogenic role in the airways relating to asthma severity. There are currently anti–IL-6R therapies that block IL-6 transsignaling and might have potential therapeutic value in subjects with asthma. The Severe Asthma Research Program (SARP) is a multicenter asthma research group funded by the National Heart, Lung, and Blood Institute and consisting of the following contributors (principal investigators are marked with an asterisk): Brigham & Women's Hospital —Elliot Israel,* Bruce D. Levy, Michael E. Wechsler, Shamsah Kazani, and Gautham Marigowda; Cleveland Clinic —Serpil C. Erzurum,* Raed A. Dweik, Suzy A. A. Comhair, Emmea Cleggett-Mattox, Deepa George, Marcelle Baaklini, and Daniel Laskowski; Emory University —Anne M. Fitzpatrick, Denise Whitlock, and Shanae Wakefield; Imperial College School of Medicine —Kian Fan Chung,* Mark Hew, Patricia Macedo, Sally Meah, and Florence Chow; University of Iowa —Eric Hoffman,* and Janice Cook-Granroth; University of Pittsburgh —Sally E. Wenzel,* Fernando Holguin, Silvana Balzar, and Jen Chamberlin; University of Texas–Medical Branch —William J. Calhoun,* and Bill T. Ameredes; University of Virginia —Benjamin Gaston,* W. Gerald Teague,* and Denise Thompson-Batt; University of Wisconsin —William W. Busse,* Nizar Jarjour, Ronald Sorkness, Sean Fain, and Gina Crisafi; Wake Forest University —Eugene R. Bleecker,* Deborah Meyers, Wendy Moore, Stephen Peters, Rodolfo M. Pascual, Annette Hastie, Gregory Hawkins, Jeffrey Krings, and Regina Smith; Washington University in St Louis —Mario Castro,* Leonard Bacharier, and Jaime Tarsi; Data Coordinating Center —Douglas Curran-Everett,* Ruthie Knowles, Maura Robinson, and Lori Silveira; National Heart, Lung, and Blood Institute —Patricia Noel and Robert Smith. We thank Dr Lilly Zheng, Brian Rector, Shelly Smith, Carla Marsh, Catherine Brewer, and Abdoulaye Diallo for their technical help and Dr Elizabeth Ampleford for help in data analysis. We also thank all of the participants in the SARP and CSGA.

PY - 2012/8

Y1 - 2012/8

N2 - Background: The IL6R single nucleotide polymorphism (SNP) rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium (r2 = 1) with the IL6R coding SNP rs2228145 (Asp358Ala). This IL6R coding change increases IL-6 receptor (IL-6R) shedding and promotes IL-6 transsignaling. Objectives: We sought to evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes. Methods: The IL6R SNP rs2228145 was evaluated in subjects of European ancestry with asthma from the Severe Asthma Research Program (SARP). Lung function associations were replicated in the Collaborative Study on the Genetics of Asthma (CSGA) cohort. Serum soluble IL-6R levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL-6R protein expression in bronchoalveolar lavage cells and endobronchial biopsies. Results: The minor C allele of IL6R SNP rs2228145 was associated with a lower percent predicted FEV1 in the SARP cohort (P =.005), the CSGA cohort (P =.008), and in a combined cohort analysis (P =.003). Additional associations with percent predicted forced vital capacity (FVC), FEV1/FVC ratio, and PC20 were observed. The rs2228145 C allele (Ala358) was more frequent in severe asthma phenotypic clusters. Elevated serum soluble IL-6R levels were associated with lower percent predicted FEV1 (P = .02) and lower percent predicted FVC (P =.008) (n = 146). IL-6R protein expression was observed in bronchoalveolar lavage macrophages, airway epithelium, vascular endothelium, and airway smooth muscle. Conclusions: The IL6R coding SNP rs2228145 (Asp 358Ala) is a potential modifier of lung function in subjects with asthma and might identify subjects at risk for more severe asthma. IL-6 transsignaling might have a pathogenic role in the lung.

AB - Background: The IL6R single nucleotide polymorphism (SNP) rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium (r2 = 1) with the IL6R coding SNP rs2228145 (Asp358Ala). This IL6R coding change increases IL-6 receptor (IL-6R) shedding and promotes IL-6 transsignaling. Objectives: We sought to evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes. Methods: The IL6R SNP rs2228145 was evaluated in subjects of European ancestry with asthma from the Severe Asthma Research Program (SARP). Lung function associations were replicated in the Collaborative Study on the Genetics of Asthma (CSGA) cohort. Serum soluble IL-6R levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL-6R protein expression in bronchoalveolar lavage cells and endobronchial biopsies. Results: The minor C allele of IL6R SNP rs2228145 was associated with a lower percent predicted FEV1 in the SARP cohort (P =.005), the CSGA cohort (P =.008), and in a combined cohort analysis (P =.003). Additional associations with percent predicted forced vital capacity (FVC), FEV1/FVC ratio, and PC20 were observed. The rs2228145 C allele (Ala358) was more frequent in severe asthma phenotypic clusters. Elevated serum soluble IL-6R levels were associated with lower percent predicted FEV1 (P = .02) and lower percent predicted FVC (P =.008) (n = 146). IL-6R protein expression was observed in bronchoalveolar lavage macrophages, airway epithelium, vascular endothelium, and airway smooth muscle. Conclusions: The IL6R coding SNP rs2228145 (Asp 358Ala) is a potential modifier of lung function in subjects with asthma and might identify subjects at risk for more severe asthma. IL-6 transsignaling might have a pathogenic role in the lung.

KW - IL-6

KW - IL-6 transsignaling

KW - Soluble IL-6 receptor

KW - asthma

KW - genetic variation

KW - pulmonary lung function

KW - severe asthma

KW - single nucleotide polymorphism rs2228145

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U2 - 10.1016/j.jaci.2012.03.018

DO - 10.1016/j.jaci.2012.03.018

M3 - Article

AN - SCOPUS:84864485029

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SP - 510-515.e1

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JF - Journal of Allergy and Clinical Immunology

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ER -