Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

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• 作者：Marjan Kerkhof ; H. Marike Boezen ; Raquel Granell ; Alet H. Wijga ; Bert Brunekreef ; Henri毛tte A. Smit ; Johan C. de Jongste ; Carel Thijs ; Monique Mommers ; John Penders ; John Henderson ; Gerard H. Koppelman ; Dirkje S. Postma
• 关键词：Chronic obstructive pulmonary disease ; transient early wheeze ; lung function growth ; in utero exposure
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：January, 2014
• 年：2014
• 卷：133
• 期：1
• 页码：68-76.e4
• 全文大小：364 K

文摘

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Background

It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects genetically predisposed to COPD show their first symptoms or reduced lung function in childhood.

Objective

We investigated whether replicated genes for COPD associate with transient early wheeze (TEW) and lung function levels in 6- to 8-year-old children and whether cigarette smoke exposure in utero and after birth (environmental tobacco smoke [ETS]) modifies these effects.

Methods

The association of COPD-related genotypes of 20 single nucleotide polymorphisms in 15 genes with TEW, FEV₁, forced vital capacity (FVC), and FEV₁/FVC ratio was studied in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort (n聽= 1996) and replicated in the Child, parents and health: lifestyle and genetic constitution (KOALA) and Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts.

Results

AGER showed replicated association with FEV₁/FVC ratio. TNS1 associated with more TEW in PIAMA and lower FEV₁ in ALSPAC. TNS1 interacted with ETS in PIAMA, showing lower FEV₁ in exposed children. HHIP rs1828591 interacted with cigarette smoke exposure in utero in PIAMA and with ETS in ALSPAC, with lower lung function in nonexposed children. SERPINE2, FAM13A, and MMP12 associated with higher FEV₁ and FVC, and SERPINE2, HHIP, and TGFB1 interacted with cigarette smoke exposure in utero in PIAMA only, showing adverse effects of exposure on FEV₁ being limited to children with genotypes conferring the lowest risk of COPD.

Conclusion

Our findings indicate relevant involvement of at least 3 COPD genes in lung development and lung growth by demonstrating associations pointing toward reduced airway caliber in early childhood. Furthermore, our results suggest that COPD genes are involved in the infant's lung response to smoke exposure in utero and in early life.