6q12 and 11p14 variants are associated with postnatal exhaled nitric oxide levels and respiratory symptoms

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:140

Article

Fuchs, Oliver^1,2,3,4,5  Gorlanova, Olga¹  Latzin, Philipp^1,5  Schmidt, Anne¹  Schieck, Maximilian^6,7  Toncheva, Antoaneta A.⁶  Michel, Sven⁶  Gaertner, Vincent D.⁶  Kabesch, Michael^4,6,8,9  Frey, Urs¹ 

[1] Univ Basel, Univ Childrens Hosp UKBB, Basel, Switzerland

[2] Ludwig Maximilians Univ Munchen, Dr von Hauner Childrens Hosp, Munich, Germany

[3] CPC M, Munich, Germany

[4] German Ctr Lung Res DZL, Giessen, Germany

[5] Univ Bern, Inselspital, Dept Pediat, Div Resp Med, Bern, Switzerland

[6] Univ Childrens Hosp Regensburg KUNO, Dept Pediat Pneumol & Allergy, Regensburg, Germany

[7] Hannover Med Sch, Inst Human Genet, Hannover, Germany

[8] Hannover Med Sch, Dept Pediat Pneumol Allergol & Neonatol, Hannover, Germany

[9] Biomed Res Endstage & Obstruct Lung Dis Hannover, Hannover, Germany

关键词: Infants;    exhaled nitric oxide;    genetics;    airway inflammation;    genome-wide association study;    wheeze;    asthma;   

DOI  :  10.1016/j.jaci.2016.11.048

来源: Elsevier

【 摘 要 】

Background: Exhaled nitric oxide (eNO) is a biomarker of airway inflammation and seems to precede respiratory symptoms, such as asthma, in childhood. Identifying genetic determinants of postnatal eNO levels might aid in unraveling the role of eNO in epithelial function or airway inflammation and disease. Objective: We sought to identify genetic determinants of early postnatal eNO levels and subsequent respiratory symptoms during the first year of life. Methods: Within a population-based birth cohort, eNO levels were measured in healthy term infants aged 5 weeks during quiet tidal breathing in unsedated sleep. We assessed associations of single nucleotide polymorphisms with eNO levels in a genome-wide association study and subsequent symptoms of lower respiratory tract infections during the first year of life and asked whether this was modified by prenatal and early-life environmental factors. Results: We identified thus far unknown determinants of infant eNO levels: rs208515 (P = 3.3 x 10(-8)), which is located at 6q12, probably acting in trans'' and explaining 10.3% of eNO level variance, and rs1441519 (P = 1.6 x 10(-6)), which is located at 11p14, potentially affecting nitric oxide synthase 3 (NOS3) expression, as shown by means of in vitro functional analyses. Moreover, the 6q12 locus was inversely associated with subsequent respiratory symptoms (P < .05) and time to recovery after first respiratory symptoms during the first year of life (P < .05). Conclusion: The identification of novel genetic determinants of infant eNO levels might implicate that postnatal eNO metabolism in healthy infants before first viral infections and sensitization is related to mechanisms other than those associated with asthma, atopy, or increased risk thereof later in life.

【 授权许可】

Free