Gene Signatures Show Why Boys are Predisposed to Asthma

Human airways have sex-based DNA methylation signatures at birth, providing evidence of why males are more prone to respiratory disorders than females, particularly during early life, according to a new study.

The results provide an early hint of which infants may be predisposed to develop respiratory disorders, such as asthma, later in life.

Boys and young men are more likely to develop neonatal respiratory distress syndrome, bronchopulmonary dysplasia, viral bronchiolitis, pneumonia, croup, and childhood asthma. Unlike boys, girls have two copies of the X chromosome, which is enriched with immune-related genes. Methylation prevents excessive gene activity in X-linked genes, noted researchers led by Cesar L. Nino, PhD, of Pontificia Universidad Javeriana in Bogota, Colombia.

The researchers published their results on April 3, 2018, in Scientific Reports.

“Characterizing early airway methylation signatures holds the promise of clarifying the nature of gender-based disparities in respiratory disorders and could usher in more personalized diagnostic and therapeutic approaches,” said senior author Gustavo Nino, MD, of the Children’s National Medical Center in Washington, DC.

The researchers investigated epigenetic differences in the airways of males and females during early life using genome-wide DNA methylation arrays. They compared male vs female genome-wide DNA methylation in nasal airway samples from 12 newborns and infants aged 1 to 6 months. Half of the infants were born preterm, and half were born full term.“It's clear as we round in the neonatal intensive care unit that baby boys remain hospitalized longer than girls and that respiratory ailments are quite common. Our work provides new insights about gender differences in airway disease risk that are pre-determined by genetics,” said Gustavo Nino.

A machine learning algorithm identified X-linked genes with significant differences in methylation patterns in boys as compared with girls. The researchers also retrieved pediatric nasal airway epithelial cultures from a study that looked at genomic DNA methylation patterns and gene expression in 36 children with persistent atopic asthma compared with 36 heathy children. Results of the machine learning algorithm were validated in this independent population of children.

X-linked genes with significant sex-based differential methylation in the nasal airway of infants represented only about 50% of the unique protein coding transcripts. X-linked genes without significant sex-based differential methylation included genes with evidence of escaping X-inactivation and female-biased airway expression. These genes, the authors stated, showed similar methylation patterns in males and females, suggesting unbalanced X-chromosome dosage.

Further, they suggested, other X-linked genes in the infant airway may have variable sex-based DNA methylation, and some may completely escape X-inactivation leading to enhanced expression in females.

“These results confirm that the X chromosome contains crucial information about gender-related genetic differences in different airway tissues. More detailed knowledge of the genetic basis for gender differences in the respiratory system may help to predict, prevent and treat respiratory disorders that can affect patients over their entire lifetimes,” said Gustavo Nino.

Elucidating the genetic basis of sex differences of the respiratory system may help guide personalized therapy to predict, prevent, and treat respiratory disorders in both sexes from childhood to adulthood, they stated.

References:

Nino CL, Perez GF, Isaza N, et al. Characterization of sex-based DNA methylation signatures in the airways during early life. Sci Rep. 2018;8.