DENND1B gene variants associate with elevated exhaled nitric oxide in healthy high-risk neonates

Increased neonatal fraction of exhaled nitric oxide (FeNO) is associated with lung symptoms early in life, while predictors of neonatal FeNO levels are unknown. The objective of this study was to investigate perinatal and genetic predictors of FeNO in healthy at-risk neonates.

FeNO was measured during sedation by single-breath and tidal-breathing techniques in 253 one-month-old neonates from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC2000 ) birth cohort. The risk factor analyses included genetic variants in DENND1B, Filaggrin, and ORMDL3; anthropometrics; demographics; socioeconomics; paternal atopy; maternal smoking, and mother's consumption of paracetamol and antibiotics during 3rd trimester; and neonatal bacterial airway colonization.

FeNO values measured by the single-breath versus tidal-breathing technique yielded slightly higher values (median, 21.0 ppb; range, 2.0-74.0 ppb vs. 16.0 ppb; 1.0-67.0 ppb; P<0.0001) with increasing differences conditional on increasing FeNO values (P<0.0001). The multivariable analysis including all risk factors showed that the DENND1B rs2786098 C allele was associated with increasing levels of FeNO (additive model; +2.30 ppb per C allele; 95% CI, 0.10-5.00 ppb; P=0.04) and that children of atopic fathers had elevated FeNO (+2.90 ppb; 95% CI, 0.38-5.43 ppb; P=0.02). We did not detect association between the remaining risk factors and neonatal FeNO levels.

Increased FeNO in healthy newborns seems strongly influenced by genetics including father's atopy and child's variants in the DENND1B locus at chromosome 1q31.3.