Air Pollution Aggravates Genetic Susceptibility to Asthma

LOS ANGELES, Aug. 21 -- Traffic-related air pollution increases asthma risk among children with genetic variants that affect the lungs' ability to clear toxins, researchers found.

Children with two such genetic risk factors were 2.63-times more likely to develop asthma than their peers who did not have the variants, according to a large study published online in the journal Thorax.

But for children who lived less than 82 yards from a major road, the excess asthma risk for genetically susceptible kids more than tripled to an odds ratio of 8.91 (95% CI 2.40 to 33.12), reported Frank D. Gilliland, Ph.D., of the University of Southern California here, and colleagues.

"Taken together, these data suggest that a considerable proportion of children (approximately 13%) in southern California with functional variants in polyaromatic hydrocarbon metabolizing genes are at a higher risk of asthma from local traffic-related pollution," they wrote.

The researchers correlated pollution exposure to genes for two enzymes -- glutathione S-transferase (GSTP) and microsomal epoxide hydrolase (EPHX1) -- involved in ridding the lungs of polyaromatic hydrocarbons produced by incomplete combustion of tobacco and fossil fuels.

To better characterize links with childhood asthma, the researchers analyzed data from 3,124 non-Hispanic and Hispanic white children in the larger Children's Health Study.

The participants had known asthma status and lived in 12 southern California communities. At the time of the original study (1993 to 1996), the children were in the fourth, seventh and 10th grades at school (average ages 10, 13 and 16, respectively).

The researchers genotyped and phenotyped each child from a buccal swab, calculated how far each lived from the nearest major road, and analyzed baseline questionnaires detailing lifetime tobacco smoke exposure.

Parents reported physician-diagnosed asthma for 476 children (15.5%). Among them, 60 had early transient asthma, diagnosed before age three but free of the condition by first grade; 175 had early persistent asthma continuing past first grade; and 241 had late onset asthma diagnosed after age three.

About 70% of the children carried genetic susceptibility factors looked at in the study. About 19% had the higher risk EPHX1 phenotypes and 60% had the higher risk GSTP1 Ile/Val (47%) or Val/Val (13%) genotypes.

About 20% lived within 75 meters (about 82 yards) of a major road.

EPHX1 and GSTP1 variants were not associated with atopy (all P>0.20), but the variants that increased activity of the enzymes -- and therefore would increase oxidative stress -- were significantly associated with asthma.

The genetic variant for high EPHX1 activity was associated with increased lifetime asthma risk compared with the lower activity variant (OR 1.51, 95% CI 1.14 to 1.98), a significant trend (P=0.007). The trend was similar for current asthma (P=0.004) and late onset asthma as well (P=0.001).

The more active GSTP1 105 Val/Val and Ile/Val genotypes were associated with elevated early persistent asthma risk as well, compared with the less active Ile/Ile variant (OR 1.95, 95% CI 1.19 to 3.18, and 1.37, 95% CI 0.95 to 1.96, respectively). The same pattern was seen for lifetime and current asthma risk but was not significant.

Children with the high activity variants for both GSTP1 and EPHX1 had a 4.01-times higher lifetime asthma risk than those with a lower EPHX1 activity phenotype (95% CI 1.97 to 8.16).

Proximity of the children's homes to major roads was a significant mediating factor (P=0.04).

The lifetime asthma odds ratios for genetically susceptible children living within 82 yards of a major road compared with risk for those living farther away were:

• 1.46 versus 0.94 for those with GSTP1 Val/Val but lower EPHX1 activity variants.
• 1.71 versus 1.03 for those with high EPHX1 activity but GSTP1 Ile/Ile variants.
• 8.91 versus 2.63 for those with both high EPHX1 activity and GSTP1 Val/Val variants.

The results were similar for current, early persistent, and late onset asthma as well as in an analysis for EPHX1 alone that included only children who were long-term residents in the same house, the researchers said.

Furthermore, adjusting for socioeconomic and demographic factors had "relatively little impact" on the associations. In utero smoke exposure, secondhand smoke exposure in childhood, the number of smokers in the home, race or ethnicity, gender, atopic status, and parental asthma did not modify the associations.