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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.We sought to identify genetic determinants of early postnatal eNO levels and subsequent respiratory symptoms during the first year of life.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.We identified thus far unknown determinants of infant eNO levels: rs208515 (P= 3.3 × 10−8), which is located at 6q12, probably acting in “trans” and explaining 10.3% of eNO level variance, and rs1441519 (P= 1.6 × 10−6), which is located at 11p14, potentially affecting nitric oxide synthase 3(NOS3)expression, as shown by means ofin vitrofunctional 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).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.