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 journalArticlepeer-review

69 Scopus citations


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 languageEnglish (US)
Pages (from-to)510-515.e1
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Aug 2012
Externally publishedYes


  • 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


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