TNF-308 Modifies the Effect of Second-hand Smoke on Respiratory Illness-Related School Absences
Authors: Hofmann Allison M. , Williams Larry W. 
Published: November 2007

Wenten, M, Berhane K, Rappaport EB, et al. Am J Respir Crit Care Med. 2005;172:1563–1568

PURPOSE OF THE STUDY. To investigate the role of tumor necrosis factor (TNF) G→308A, a variant in the promoter region of TNF, that has been associated with inflammatory diseases including asthma in the susceptibility of secondhand-smoke–exposed children to respiratory illness.

STUDY POPULATION. A prospective cohort of fourth-grade students (N = 1935) from 27 elementary schools in southern California from whom school-absence data were collected from January to June of 1996. Approximately 70% of the children (n = 1351) provided a buccal cell sample.

METHODS. Schools provided daily absence summary information for the study subjects, and each absence was recorded as illness or nonillness. Telephone interviews regarding each illness-related absence were conducted with parents. School absences were classified as lower respiratory illnesses if wet cough, wheeze, or asthma was present. Secondhand-smoke exposure was determined by parent/guardian written responses on self-administered questionnaires and categorized as none, 1 to 29, or ≥30 cigarettes smoked per day inside the home. Asthma status was determined by parental response to the question, “Has a doctor ever diagnosed this child as having asthma?” Buccal cell samples were collected, and the genomic DNA was analyzed for the G-to-A transition polymorphism at position 308 in TNF by polymerase chain reaction and allelic discrimination assays.

RESULTS. There was a 51% greater risk of lower respiratory illness–related school absences among children with secondhand-smoke exposure compared with those who were unexposed. Children with the TNF GG genotype exhibited similar absence rates regardless of whether they were exposed or unexposed to secondhand smoke. Unexposed children with at least 1 copy of the TNF G→308A allele had similar absence rates for lower respiratory illnesses compared with children with the TNF G→308GG genotype. However, absence rates in children with the variant A allele and secondhand-smoke exposure were markedly increased. Children with the variant A allele and secondhand-smoke exposure had a 75% increase in risk for illness-related absences compared with unexposed children with the GG genotype. In children with the variant A allele, illness-related absence risk increased as the number of smokers in the home increased. In addition, children with 1 variant A allele who were exposed to ≥30 cigarettes per day had a relative risk of 2.75 for respiratory illness–related school absence compared with unexposed children with the GG genotype. Restricting analysis to children without asthma did not substantially alter the findings.

CONCLUSIONS. Secondhand-smoke–exposed children who carried a TNF G→308A variant allele were at highest risk for respiratory illness–related school absences. A strong dose-response relationship in this group of patients was found for respiratory illness–related absence risk in relation to the number of household smokers and number of cigarettes smoked. The genetic susceptibility associated with the TNF G→308A allele is likely mediated by variation in inflammatory responses to secondhand smoke.

REVIEWER COMMENTS. Secondhand-smoke exposure is common among children and causes substantial morbidity. However, there is variation in susceptibility to the effects of secondhand smoke. This study demonstrated that differences in genotype of mediators of inflammation may explain variation in susceptibility to secondhand smoke. Additional studies are needed to elucidate differences in genotypes of other inflammatory mediators, which may produce a similar effect. This may provide one more weapon in our arsenal to convince parents to quit smoking or devise protective agents for the exposed.