Yu-Fen Li

Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study

BACKGROUND Particulate pollution is associated with the occurrence of asthma and allergy. The model pollutant, diesel exhaust particles, can participate with allergens in starting and exacerbating allergic airway diseases in part by production of reactive oxygen species. Glutathione-S-transferases (GSTs) can metabolise reactive oxygen species and detoxify xenobiotics present in diesel exhaust particles. We tested the hypothesis that null genotypes for GSTM1 and GSTT1, and GSTP1 codon 105 variants (I105 and V105) are key regulators of the adjuvant effects of diesel exhaust particles on allergic responses. METHODS Patients sensitive to the ragweed allergen were challenged intranasally with allergen alone and with allergen plus diesel exhaust particles in a randomised order at separate visits. Nasal allergen-specific IgE, histamine, interleukin 4, and interferon gamma concentrations were measured before and 24 h after challenge. FINDINGS Individuals with GSTM1 null or the GSTP1 I105 wildtype genotypes showed enhanced nasal allergic responses in the presence of diesel exhaust particles. Compared with patients with a functional GSTM1 genotype, GSTM1 null patients had a significantly larger increase in IgE (median 102.5 U/mL [range 1.0-510.5] vs 45.5 U/mL [1.5-60.6], p=0.03) and histamine (14.0 nmol/L [-0.2-24.7] vs 7.4 nmol/L [1.2-12.3], p=0.02) after diesel exhaust particles plus allergen challenge. The I105 GSTP1 genotype was associated with an increase in IgE (120.3 U/mL [6.7-510.5] vs 27.7 U/mL [-1.5-60.6], p=0.03) and histamine (13.8 nmol/L [3.1-24.7] vs 5.2 nmol/L [-0.2-19.6], p=0.01) after challenge with diesel exhaust particles and allergens. The diesel exhaust particles enhancement was largest in patients with both the GSTM1 null and GSTP1 I/I genotypes. INTERPRETATION GSTM1 and GSTP1 modify the adjuvant effect of diesel exhaust particles on allergic inflammation.

Maternal and Grandmaternal Smoking Patterns Are Associated With Early Childhood Asthma

OBJECTIVE To investigate the associations of maternal and grandmaternal smoking before, during, and after pregnancy with childhood asthma. DESIGN, SETTING, AND PARTICIPANTS We conducted a case-control study nested within the Childrens Health Study in southern California. The case patients consisted of 338 children with asthma that had been diagnosed in the first 5 years of life, and 570 control subjects were countermatched on in utero exposure to maternal smoking within grade, sex, and community of residence. MEASUREMENTS Detailed maternal and household smoking histories and other asthma risk factor information was obtained by telephone interview. RESULTS The participation rates were 72.3% and 82.5%, respectively, for control subjects and case patients. In utero exposure to maternal smoking was associated with increased risk for asthma diagnosed in the first 5 years of life (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.0 to 2.3), and for persistent asthma (OR, 1.5; 95% CI, 1.0 to 2.3). The associations did not differ in children with early transient asthma compared to those with early persistent asthma. Relative to never-smokers, children whose mothers smoked throughout the pregnancy had an elevated risk of asthma in the first 5 years of life (OR, 1.6; 95% CI, 1.0 to 2.6). Children of mothers who quit smoking prior to the pregnancy showed no increased risk (OR, 0.9; 95% CI, 0.5 to 1.5). We were unable to assess the association of smoking cessation during pregnancy because very few mothers were reported to have done so (15%). Asthma risk did not increase in a monotonic pattern with smoking intensity during pregnancy. Postnatal secondhand smoke exposure was not independently associated with asthma. Grandmaternal smoking during the mothers fetal period was associated with increased asthma risk in her grandchildren (OR, 2.1; 95% CI, 1.4 to 3.2). CONCLUSIONS Maternal and grandmaternal smoking during pregnancy may increase the risk of childhood asthma.

Maternal Fish Consumption During Pregnancy and Risk of Early Childhood Asthma

Maternal fish consumption during pregnancy may affect childrens asthma risk by modulating early-life immune development. Type of fish intake may be important because of differences in fatty acid content. To test this hypothesis, we conducted a nested case-control study, selecting subjects from the Childrens Health Study, a population-based study of school-aged children in southern California. Cases had physician-diagnosed asthma and controls were asthma-free by age 5 years. Mothers or guardians provided information on fish consumption during pregnancy in telephone interviews. We computed odds ratio (OR) and 95% confidence interval (CI) by using conditional logistic regression models that accounted for the sampling. In children born to mothers with a history of asthma, the OR of asthma was 0.20 (95% CI = 0.06–0.65) when mothers ate oily fish at least monthly during pregnancy compared with no consumption (ptrend = 0.006). Maternal oily fish consumption during pregnancy did not benefit children of non-asthmatic mothers. In contrast, fish stick (a source of trans-fats) consumption during pregnancy increased asthma risk in children (OR = 2.04; 95% CI = 1.18–3.51). Our results suggest that maternal oily fish intake during pregnancy may protect offspring from asthma; however, eating fish sticks during pregnancy may increase asthma risk in children.

Glutathione S-Transferase P1, Maternal Smoking, and Asthma in Children: A Haplotype-Based Analysis

Background Glutathione S-transferase P1 (GSTP1) plays a role in a spectrum of respiratory diseases; however, the effects of sequence variation across the entire locus in asthma pathogenesis have yet to be determined. Objectives This study was designed to investigate whether sequence variations in the GSTP1 coding and promoter regions are associated with asthma and wheezing outcomes and to determine whether variants affect susceptibility to maternal smoking. Methods Four haplotype tagging SNPs were selected that accounted for 83% of the common haplotypic variation in GSTP1. The associations of GSTP1 variants with asthma and wheezing were assessed among white children in the Children’s Health Study (CHS). Results The Ile105Val allele and a SNP in the upstream promoter region (SNP1: rs6591255, putative transcription factor 1 binding site) were associated with asthma and wheezing outcomes, an association observed in two cohorts of the CHS recruited in different years. Haplotypes that included both the promoter SNP (i.e., rs6591255) and the 105 Val variant were associated with an increased risk for asthma in non-Hispanic whites. Using SNP- and haplotype-based approaches, the effect of maternal smoking on wheezing was largest in children with the Ile105Val allele. Conclusions Variants in both the promoter and coding regions of the GSTP1 locus may contribute to the occurrence of childhood asthma and wheezing and may increase susceptibility to adverse effects of tobacco-smoke exposure.

In Utero Smoke Exposure, Glutathione S-Transferase P1 Haplotypes, and Respiratory Illness-Related Absence Among Schoolchildren

BACKGROUND. The GSTP1 Ile105Val variant and secondhand tobacco smoke exposure have been independently associated with acute respiratory illness; however, susceptibility to in utero and secondhand tobacco smoke has yet to be examined in relation to variation across the GSTP1 locus. OBJECTIVE. The purpose of this work was to determine whether variation across the GSTP1 locus is associated with respiratory illness–related school absences and to determine whether this relationship varies by in utero and secondhand tobacco smoke exposure. METHODS. Tobacco smoke exposure status, incident respiratory-related school absence records, and DNA samples was ascertained for 1132 Hispanic and non-Hispanic white elementary school children as part of the Childrens Health Study. RESULTS. Four GSTP1 single-nucleotide polymorphisms were selected that accounted for 93% of the variation across the locus. Individual single-nucleotide polymorphism analyses showed a protective effect for the minor alleles in single-nucleotide polymorphisms 1 (rs6591255), 3 (GSTP1 Ile105Val: rs1695), and 4 (rs749174) for respiratory illness. The haplotype, which includes a minor allele for single-nucleotide polymorphisms 1, 3, and 4 (h1011), was associated with a decreased risk of respiratory illness. The protective effect of GSTP1 variants was lost among individuals exposed to in utero and secondhand tobacco smoke. CONCLUSIONS. A common GSTP1 haplotype, which includes the functional Ile105Val polymorphism, was associated with respiratory-related school absences. The protection afforded by this haplotype was lost in children exposed to involuntary tobacco smoke. The paradigm of loss of genetic protection among those exposed to tobacco smoke has clinical and public health implications that warrant broader consideration in research and practice.

Intercellular adhesion molecule-1 and childhood asthma

We investigated the role of intercellular adhesion molecule-1 in childhood asthma by examining associations of functional variants at codons 29 (A→T), 241 (G→A), and 469 (A→G) in Children’s Health Study participants. Among African-Americans, 469G carriers had lower risk for asthma (ever asthma OR=0.4, 95% CI 0.2–0.9) but increased risk among 29T carriers (early onset active asthma OR=2.2, 95% CI 1.0–4.9). Protective associations with the 241A allele were observed among non-Hispanic and Hispanic whites (ever asthma OR=0.7, 95% CI 0.6–0.9; early onset active asthma OR=0.5, 95% CI 0.4–0.8), and these associations were not confounded by population stratification. To gauge the potential impact of confounding by population stratification, we performed analyses by ethnic group and in an independent family-based sample. Regional associations were stable across analyses. Haplotype associations of the four common haplotypes (29A/241G/469A, AGG, TGA, and AAG) with asthma showed that Hispanics with the AAG haplotype had lower asthma risk compared to carriers of two copies of AGA haplotype (OR=0.6, 95% CI 0.4–0.9). Among non-Hispanic whites, the AAG haplotype was associated with reduced risk for active asthma. For African-Americans, who had a low frequency of the AAG haplotype, carrying one copy of the AGG haplotype was associated with a lower risk of asthma (OR=0.3, 95% CI 0.1–0.8), as compared with two copies of the AGA haplotype. Consistent with information on variant function, the 241A and 469G variants may indicate haplotypes that are associated with reduced risk for asthma.