Maternal Smoking And Subsequent Dna Methylation Leading To Altered Lung Function

Abstract

Introduction: It has been suggested that maternal smoking during pregnancy may affect lung growth resulting in lower spirometric measurements in offspring. The aim is to test whether DNA methylation (DNA-M) can explain how the link between smoking and lung function is maintained over a long period of time. Methods: Information on smoking and birth weight was collected at birth. When the offspring were 18 years of age, spirometric tests were conducted to measure forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), maximum mid-expiratory flow (FEF25-75%), and exhaled nitric oxide; FEV1/FVC was calculated. DNA-M was measured at 18 years using the Illumina Infinium HumanMethylation450 beadchip. A total of 307,357 cytosine-phosphate-guanine sites (CpGs) that passed pre-processing were screened via a training and testing program to determine which CpG sites were affected by gestational smoking. Then CpGs with a smoking-related methylation were tested on whether they constitute mediating variables between smoking and lung function using path-analytical models. These models were adjusted for birth weight, sex, height, and maternal history of asthma. Results: Of 22 CpGs related to gestational smoking, two CpGs were identified in path-analyses to establish a link between maternal smoking during pregnancy and lung function measured at 18 age: ncg24780570 (fibrosin-like 1 - FBRSL1) and ncg25949550 (contactin associated protein-like 2 - CNTNAP2). The CpG in FBRSL1 linked maternal smoking during pregnancy with FEF25-75% at 18 years; the CpG in CNTNAP2 linked maternal smoking with FEV1, FEV1/FVC, and exhaled nitric oxide. No intermediate CpG was identified for FVC. Discussion: Long-term effects of maternal smoking during gestation on offspring lung function at age 18 may have been maintained by differential DNA-M. Reverse causation cannot be excluded, since spirometric tests and DNA-M measurements were conducted at the same age.