Genetic variation in S-nitrosoglutathione reductase (GSNOR) and childhood asthma

BACKGROUND: S-nitrosothiols are potent endogenous bronchodilators depleted in asthmatic airway lining fluid. S-nitrosoglutathione reductase (GSNOR; also known as alcohol dehydrogenase 5 or formaldehyde dehydrogenase) catalyzes the metabolism of S-nitrosoglutathione (GSNO) and controls intracellular levels of S-nitrosothiols. GSNOR knockout mice have increased lung S-nitrosothiol levels and are therefore protected from airway hyperresponsiveness after methacholine or allergen challenge. OBJECTIVE: We sought to investigate whether genetic variation in GSNOR is associated with childhood asthma and atopy. METHODS: We genotyped 5 tagging and 2 additional single nucleotide polymorphisms (SNPs) in GSNOR in 532 nuclear families consisting of asthmatic children aged 4 to 17 years and both parents in Mexico City. Atopy was determined by means of skin prick testing. RESULTS: Carrying 1 or 2 copies of the minor allele of SNP rs1,154,404 was associated with decreased risk of asthma (relative risk [RR], 0.77; 95% CI, 0.61-0.97; P = .028 for 1 copy and RR, 0.66; 95% CI, 0.44-0.99; P = .046 for 2 copies). Homozygosity for the minor allele of SNP rs28,730,619 was associated with increased risk of asthma (RR, 1.60; 95% CI, 1.13-2.26; P = .0077). Haplotype analyses supported the single SNP findings. GSNOR SNPs were not associated with the degree of atopy. CONCLUSION: This is the first study of genetic polymorphisms in GSNOR and asthma. These data suggest that genetic variation in GSNOR might play a role in asthma susceptibility. CLINICAL IMPLICATIONS: The association of GSNOR polymorphisms with asthma suggests a potential therapeutic target.     

Inside the Premier/CMS Pay-for-Performance Project

In an H&HN exclusive roundtable discussion, representatives from the five top-performing hospitals describe what they've learned so far from the Premier/CMS Pay-for-Performance Project. For hospitals around the country, so-called value-based ent will soon be the primary way they get paid by both public and commercial insurers. The Premier/CMS participants offer valuable insights--and warnings--about the challenges ahead.     

Genetic polymorphisms in arginase I and II and childhood asthma and atopy

BACKGROUND: A recent microarray study implicated arginase I (ARG1) and arginase II (ARG2) in mouse allergic asthma models and human asthma. OBJECTIVES: To examine the association between genetic variation in ARG1 and ARG2 and childhood asthma and atopy risk. METHODS: We enrolled 433 case-parent triads, consisting of patients with asthma 4 to 17 years old and their biologic parents, from the allergy clinic of a public hospital in Mexico City between 1998 and 2003. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped 4 single nucleotide polymorphisms (SNPs) of ARG1 and 4 SNPs of ARG2 with minor allele frequencies higher than 10% by using the TaqMan assay (Roche Molecular Systems, Pleasanton, Calif). RESULTS: ARG1 SNPs and haplotypes were not associated with asthma, but all 4 ARG1 SNPs were associated with the number of positive skin tests (P = .007-.018). Carrying 2 copies of minor alleles for either of 2 highly associated ARG2 SNPs was associated with a statistically significant increased relative risk (RR) of asthma (1.5, 95% CI = 1.1-2.1 for arg2s1; RR = 1.6, 95% CI = 1.1-2.3 for arg2s2). The association was slightly stronger among children with a smoking parent (arg2s1 RR = 2.1, 95% CI = 1.2 - 3.9 with a smoking parent; RR = 1.2, 95% CI = 0.8-1.9 without; interaction P = .025). Haplotype analyses reduced the sample size but supported the single SNP results. One ARG2 SNP was related to the number of positive skin tests (P = .027). CONCLUSION: Variation in arginase genes may contribute to asthma and atopy in children.     

Assessment of personal exposure to ozone in asthmatic children residing in Mexico City

OBJECTIVE: A study was conducted to evaluate personal ozone exposure (O3p) among asthmatic children residing in Mexico City. MATERIAL AND METHODS: A total of 158 children were recruited from December 1998 to April 2000. On average, three O3p measurements were obtained per child using passive badges. Time-activity patterns were recorded in a diary. Daily ambient ozone measurements (O3a) were obtained from the fixed station, according to children's residence. Levels of O3a and ozone, weighted by time spent in different micro-environments (O3w), were used as independent variables in order to model O3p concentrations using a mixed-effects model. RESULTS: Mean O3p was 7.8 ppb. The main variables in the model were: time spent indoors, distance between residence and fixed station, follow-up group, and two interaction terms (overall R(2)=0.50, p<0.05). CONCLUSIONS: The O3w concentrations can be used as a proxy for O3p, taking into account time-activity patterns and the place of residence of asthmatic Mexican children.     

Identification of asthma risk factors in Mexico City in an International Study of Asthma and Allergy in Childhood survey.

The International Study of Asthma and Allergy in Childhood (ISAAC) has assessed the prevalence of asthma, as well as the factors related to the disease in different countries. The aim of this study was to identify asthma risks factors in Mexico City. Data were obtained from questionnaires of children participating in a phase 3b ISAAC survey. Two thousand ninety-eight boys and 2008 girls were recruited in the 6- to 7-year-old group and 3243 boy and 3333 girls were recruited in the 13- to 14-year-old group. Logistic regression was used to determine the asthma risks factors. In the logistic regression for cumulative and current asthma prevalence, the variables allergic rhinitis and atopic dermatitis were the most important risk factors with the highest odds ratios (OR > 1.5; p < 0.05). The use of antibiotics and paracetamol in the first 12 months of life were related to cumulative asthma in both genders in the 6- to 7-year-old group. Contact of pregnant mother with farm animals was positively related with cumulative asthma in boys in the 6- to 7-year-old group. The main factors associated with the cumulative and current prevalence of asthma in both age groups were atopic dermatitis and allergic rhinitis. Future interventions for the prevention and early diagnosis and treatment could be focused in the natural history of the atopic march.     

Infant mortality and air pollution: modifying effect by social class

Studies link air pollution with increased mortality; however, information on infants is scarce and inconclusive. OBJECTIVE: We studied short-term PM10 exposure, relating to increased respiratory-related infant mortality, and estimated for poor living conditions. METHODS: A case-crossover approach modeled the relationship between infant mortality (1 month-1 year of age), and ambient PM10 levels on days before death in Ciudad Juarez, Mexico (1997-2001). Socioeconomic level (SES) of the deceased was defined by residence location. RESULTS: Overall air pollutants did not affect infant mortality (odds ratio [OR] = 1.02, 95% confidence interval [CI] = 0.94-1.11 for PM10, lag1) but low SES increased risk. Each 20 microg/m3 in PM10 (24-hour average, lag1, cumulative over 2 previous days) increased respiratory-related mortality (OR = 1.61, 95% CI = 0.97-2.66; OR = 2.56; 95% CI = 1.06-6.17, respectively). Ozone levels did not affect infant mortality for any SES. CONCLUSIONS: Worse living conditions among lower SES concurred with increased mortality.     

Antioxidant supplementation and nasal inflammatory responses among young asthmatics exposed to high levels of ozone

The inflammatory response to ozone in atopic asthma suggests that soluble mediators of inflammation are released in response to oxidant stress. Antioxidants may alleviate additional oxidative stress associated with photochemical oxidant pollution. This study investigates the impact of antioxidant supplementation on the nasal inflammatory response to ozone exposure in atopic asthmatic children. We conducted a randomized trial using a double-blinded design. Children with asthma (n = 117), residents of Mexico City, were given randomly a daily supplement of vitamins (50 mg/day of vitamin E and 250 mg/day of vitamin C) or placebo. Nasal lavages were performed three times during the 4-month follow-up and analysed for content of interleukin-6 (IL-6), IL-8, uric acid and glutathione (GSx). IL-6 levels in the nasal lavage were increased significantly in the placebo group after ozone exposure while no increase was observed in the supplement group. The difference in response to ozone exposure between the two groups was significant (P = 0.02). Results were similar for IL-8, but with no significant difference between the groups (P = 0.12). GSx decreased significantly in both groups. Uric acid decreased slightly in the placebo group. Our data suggest that vitamin C and E supplementation above the minimum dietary requirement in asthmatic children with a low intake of vitamin E might provide some protection against the nasal acute inflammatory response to ozone.     

Validity of peak flow record in asthmatic children residing in Mexico City

OBJECTIVE: To determine the concordance between maximum peak expiratory flow records (PEFr) reported by the parents of asthmatic children and the electronic values stored by the AirWatch device (PEFe). MATERIAL AND METHODS: Records of PEF measurements between October 1998 and 1999 were obtained from 42 asthmatic children 5 to 15 years of age recruited at the Hospital Infantil de Mexico Federico Gomez, in Mexico City. Parents recorded the maximum value in the health diary. Spearman correlation was calculated between PEFe and PEFr and a mixed-effects logistic model was used. RESULTS: The correlation between PEFe and PEFr was r=0.96 (p<0.05) among children with a diagnosis of moderate or severe asthma and r=0.40 (p<0.05) among children diagnosed with mild asthma. Follow-up time, asthma severity, gender and age of the child and their interactions were predictors of the differences between PEFe and PEFr. CONCLUSIONS: Parents of children with moderate or severe asthma from 6 to 8 years of age report PEF values with greater accuracy during follow-up than others.     

Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione S-transferase M1 polymorphisms and childhood asthma

Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) M1 are phase II enzymes important in response to oxidative stress, such as occurs during exposure to ozone. We examined the relationship between functionally significant polymorphisms in NQO1 (Pro187Ser) and GSTM1 (homozygous deletion) and asthma risk in children with high lifetime exposure to ozone. We enrolled children with asthma from the allergy referral clinic at a public pediatric hospital in Mexico City, together with their parents. We assayed for the Pro187Ser polymorphism in NQO1 using a polymerase chain reaction-restriction fragment length polymorphism assay and for the presence of GSTM1 by polymerase chain reaction among 218 case-parent triads. We did not find strong evidence of an association between NQO1 genotype alone and asthma risk. However, among subjects with homozygous deletion of GSTM1, carriers of a serine allele were at significantly reduced risk of asthma compared with Pro/Pro homozygotes (relative risk = 0.4; 95% confidence interval, 0.2-0.8). The p value for difference in relative risk for NQO1 by GSTM1 genotype = 0.013. These data are consistent with a protective effect of the NQO1 Ser allele in this population of GSTM1-null children with high ozone exposure.