title: Cord blood PRF1 methylation patterns and risk of lower respiratory tract infections in infants: findings from the Ulm Birth Cohort.
abstract: Lower respiratory tract infections (LRTIs) are a major cause of morbidity in children. DNA methylation provides a mechanism for transmitting environmental effects on the genome, but its potential role in LRTIs is not well studied. We investigated the methylation pattern of an enhancer region of the immune effector gene perforin-1 (PRF1), which encodes a cytolytic molecule of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK), in cord blood DNA of children recruited in a German birth cohort in association with LRTIs in the first year of life.Pyrosequencing was used to determine the methylation levels of target cytosine-phosphate-guanines (CpGs) in a 2-stage case-control design. Cases were identified as children who developed ≥2 episodes of physician-recorded LRTIs during the first year of life and controls as children who had none. Discovery (n = 87) and replication (n = 90) sets were arranged in trios of 1 case and 2 controls matched for sex and season of birth.Logistic regression analysis revealed higher levels of methylation at a CpG that corresponds to a signal transducer and activator of transcription 5 (STAT5) responsive enhancer in the discovery (odds ratio [OR] per 1% methylation difference 1.24, 95% confidence interval [CI] 1.03-1.50) and replication (OR per 1% methylation difference 1.25, 95% CI 1.04-1.50) sets. Adjustment for having siblings <5 years old in the discovery and replication sets produced ORs of 1.19 (95% CI 0.98-1.45) and 1.25 (95% CI 1.04-1.50), respectively. Adjustment for gestational age in the replication set had no influence on the results. Methylation levels at adjacent CpGs varied with maternal age, smoking, education, and having siblings <5 years old.Our data support an association between cord blood PRF1 enhancer methylation patterns and subsequent risk of LRTIs in infants. Methylation levels at specific CpGs of the PRF1 enhancer varied according to maternal and family environmental factors suggesting a role for DNA methylation in mediating environmental influences on gene function.
authors.affiliation: From the Center for Chronic Immunodeficiency (CCI) (ME, AN), University Medical Center Freiburg, Freiburg; Institute of Epidemiology and Medical Biometry (CL, DR), Ulm University, Ulm; and Division of Clinical Epidemiology and Aging Research (HB, DR), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Magdeldin
authors.initials: M
authors.lastname: Elgizouli
authors.forename: Chad
authors.initials: C
authors.lastname: Logan
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nieters
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Dietrich
authors.initials: D
authors.lastname: Rothenbacher
mesh_terms: D000328:Adult; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D005858:Germany; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D054353:Perforin / Q000235:genetics*; D011247:Pregnancy; D012141:Respiratory Tract Infections / Q000097:blood*
chemical_list: C510468:PRF1 protein, human; D054353:Perforin