Associations of the IL12B promoter polymorphism in longitudinal data from asthmatic patients 7 to 42 years of age

Background: The IL12B gene encodes the p40 chain of IL-12, a proinflammatory cytokine that antagonizes T(H)2 expression and hence may play a critical role in the pathogenesis of airway inflammation observed in asthma. A promoter polymorphism of the gene was recently shown to be associated with asthma severity in children but only in heterozygotes. Objective: The aim of the present study was to test the hypothesis that the IL12B promoter polymorphism is associated with asthma susceptibility, severity, and related phenotypes in a cohort with longitudinal phenotypic data, from childhood to adulthood. Methods: Four hundred one 7-year-old children (106 control children, 295 asthmatic children) and 83 10-year-old children with severe asthma were recruited from a 1957 birth cohort. Atopic status and respiratory functions were determined at ages 7, 10, 14, 21, 28, 35, and 42 years. At age 42 years, blood samples were taken from 244 individuals for genotyping and the determination of plasma IgE levels and PHA- and house dust mite-induced IFN-gamma responses. Genotyping was done by the PCR restriction fragment length polymorphism method, using Alu I, and confirmed in 10% of the samples by direct sequencing. Results: The IL12B genotypes were not associated with asthma susceptibility, severity, or atopy at ages 7 and 42 years. Total serum IgE levels at age 42 of men with at least one CTCTAA allele were higher than those homozygous for the GC allele (P = .042), whereas no difference was observed for women. At all ages, female subjects with at least 1 copy of the CTCTAA allele had lower mean percent predicted levels of FEV1 and FVC compared with those without this allele; these differences were significant at ages 10 and 14 years (P < .05) and in the asthmatic subgroup at age 7 years (P = .001). Conclusions: In this long-term study of asthmatic subjects with comprehensive data on asthma severity, we found no evidence to support the presence of a heterozygote effect of the IL12B promoter polymorphism on the level of asthma in early childhood or adulthood. The polymorphism was also not associated with asthma susceptibility, but the CTCTAA allele may have been associated with elevated serum IgE levels in male subjects and reduced pulmonary function in female subjects in early childhood.