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1.  Ambient air pollution, lung function and airway responsiveness in children with asthma 
Although ambient air pollution has been linked to reduced lung function in healthy children, longitudinal analyses of pollution effects in asthma are lacking.
To investigate pollution effects in a longitudinal asthma study and effect modification by controller medications.
We examined associations of lung function and methacholine responsiveness (PC20) with ozone, carbon monoxide (CO), nitrogen dioxide (NO2) and sulfur dioxide (SO2) levels in 1,003 asthmatic children participating in a 4-year clinical trial. We further investigated whether budesonide and nedocromil modified pollution effects. Daily pollutant concentrations were linked to zip/postal code of residence. Linear mixed models tested associations of within-subject pollutant concentrations with FEV1 and FVC %predicted, FEV1/FVC and PC20, adjusting for seasonality and confounders.
Same-day and 1-week average CO levels were negatively associated with post-bronchodilator %predicted FEV1 (change(95%CI) per IQR: −0.33(−0.49, −0.16), −0.41(−0.62, −0.21), respectively) and FVC (−0.19(−0.25, −0.07), −0.25(−0.43, −0.07)). Longer-term four-month averages of CO were negatively associated with prebronchodilator %predicted FEV1 and FVC (−0.36(−0.62, −0.10), −0.21(−0.42, −0.01)). Four-month averaged CO and ozone levels were negatively associated with FEV1/FVC (p<0.05). Increased four-month average NO2 levels were associated with reduced post-bronchodilator FEV1 and FVC %predicted. Long-term exposures to SO2 were associated with reduced PC20 (%change(95%CI) per IQR:-6(-11,-1.5)). Treatment augmented the negative short-term CO effect on PC20.
Air pollution adversely influences lung function and PC20 in asthmatic children. Treatment with controller medications may not protect but worsens the CO effects on PC20. This clinical trial design evaluates modification of pollution effects by treatment without confounding by indication.
PMCID: PMC4742428  PMID: 26187234
asthma; ambient air pollution; airway hyperresponsiveness; inhaled corticosteroids; lung function
2.  Folate network genetic variation, plasma homocysteine, and global genomic methylation content: a genetic association study 
BMC Medical Genetics  2011;12:150.
Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease.
330 SNPs in 52 genes were studied in relation to plasma homocysteine and global genomic DNA methylation. SNPs were selected based on functional effects and gene coverage, and assays were completed on the Illumina Goldengate platform. Age-, smoking-, and nutrient-adjusted genotype--phenotype associations were estimated in regression models.
Using a nominal P ≤ 0.005 threshold for statistical significance, 20 SNPs were associated with plasma homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes remained associated with plasma homocysteine. Gene by vitamin B-6 interactions were identified for both Alu and LINE-1 methylation, and epistatic interactions with the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Pleiotropy involving the MTHFD1L and SARDH genes for both plasma homocysteine and Alu methylation phenotypes was identified.
No single gene was associated with all three phenotypes, and the set of the most statistically significant SNPs predictive of homocysteine or Alu or LINE-1 methylation was unique to each phenotype. Genetic variation in folate-mediated one-carbon metabolism, other than the well-known effects of the MTHFR c.665C>T (known as c.677 C>T, rs1801133, p.Ala222Val), is predictive of cardiovascular disease biomarkers.
PMCID: PMC3266217  PMID: 22103680
3.  Modifying Effects of the HFE Polymorphisms on the Association between Lead Burden and Cognitive Decline 
Environmental Health Perspectives  2007;115(8):1210-1215.
As iron and lead promote oxidative damage, and hemochromatosis (HFE) gene polymorphisms increase body iron burden, HFE variant alleles may modify the lead burden and cognitive decline relationship.
Our goal was to assess the modifying effects of HFE variants on the lead burden and cognitive decline relation in older adults.
We measured tibia and patella lead using K-X-ray fluorescence (1991–1999) among participants of the Normative Aging Study, a longitudinal study of community-dwelling men from greater Boston. We assessed cognitive function with the Mini-Mental State Examination (MMSE) twice (1993–1998 and 1995–2000) and genotyped participants for HFE polymorphisms. We estimated the adjusted mean differences in lead-associated annual cognitive decline across HFE genotype groups (n = 358).
Higher tibia lead was associated with steeper cognitive decline among participants with at least one HFE variant allele compared with men with only wild-type alleles (p interaction = 0.03), such that a 15 μg/g increase in tibia lead was associated with a 0.2 point annual decrement in MMSE score among HFE variant allele carriers. This difference in scores among men with at least one variant allele was comparable to the difference in baseline MMSE scores that we observed among men who were 4 years apart in age. Moreover, the deleterious association between tibia lead and cognitive decline appeared progressively worse in participants with increasingly more copies of HFE variant alleles (p-trend = 0.008). Results for patella lead were similar.
Our findings suggest that HFE polymorphisms greatly enhance susceptibility to lead-related cognitive impairment in a pattern consistent with allelelic dose.
PMCID: PMC1940090  PMID: 17687449
cognitive decline; epidemiology; HFE; lead; longitudinal studies; neuropsychologic tests
4.  Glutathione-S-Transferase M1, Obesity, Statins, and Autonomic Effects of Particles 
Rationale: Air pollution by particulate matter (PM) has been associated with cardiovascular deaths, although the mechanism of action is unclear. One proposed pathway is through disturbances of the autonomic control of the heart.
Objectives: We tested the hypothesis that such disturbances are mediated by PM increasing oxidative stress by examining the association between PM and the high-frequency (HF) component of heart rate variability as modified by the presence or absence of the allele for glutathione-S-transferase M1 (GSTM1) and the use of statins, obesity, high neutrophil counts, higher blood pressure, and older age.
Methods: We examined the association between particles less than 2.5 μM in aerodiameter (PM2.5) and HF in 497 participants in the Normative Aging Study, using linear regression controlling for covariates.
Main Results: A 10-μg/m3 increase in PM2.5 during the 48 h before HF measurement was associated with a 34% decrease in HF, 95% confidence interval (−9%, −52%), in subjects without the allele, but had no effect in subjects with GSTM1 present. Among GSTM1-null subjects, the use of statins eliminated the effect of PM2.5. Obesity and high neutrophil counts also worsened the PM effects with or without GSTM1.
Conclusion: The effects of PM2.5 on HF appear to be mediated by reactive oxygen species. This may be a key pathway for the adverse effects of combustion particles.
PMCID: PMC2718454  PMID: 16020798
genetic polymorphisms; heart rate variability; oxidative stress; particles
5.  Association between hemochromatosis genotype and lead exposure among elderly men: the normative aging study. 
Environmental Health Perspectives  2004;112(6):746-750.
Because body iron burden is inversely associated with lead absorption, genes associated with hemochromatosis may modify body lead burden. Our objective was to determine whether the C282Y and/or H63D hemochromatosis gene (HFE) is associated with body lead burden. Patella and tibia lead levels were measured by K X-ray fluorescence in subjects from the Normative Aging Study. DNA samples were genotyped for C282Y and H63D using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). A series of multivariate linear regression models were constructed with bone or blood lead as dependent variables; age, smoking, and education as independent variables; and C282Y or H63D as independent risk factors and/or effect modifiers. Of 730 subjects, 94 (13%) carried the C282Y variant and 183 (25%) carried the H63D variant. In the crude analysis, mean tibia, patella, and blood lead levels were consistently lower in carriers of either HFE variant compared with levels in subjects with wild-type genotypes. In multivariate analyses that adjusted for age, smoking, and education, having an HFE variant allele was an independent predictor of significantly lower patella lead levels (p < 0.05). These data suggest that HFE variants have altered kinetics of lead accumulation after exposure. Among elderly men, subjects with HFE variants had lower patella lead levels. These effects may be mediated by alterations in lead toxicokinetics via iron metabolic pathways regulated by the HFE gene product and body iron stores.
PMCID: PMC1241970  PMID: 15121519
6.  A delta-aminolevulinic acid dehydratase (ALAD) polymorphism may modify the relationship of low-level lead exposure to uricemia and renal function: the normative aging study. 
Environmental Health Perspectives  2003;111(3):335-341.
In this study we investigated whether a known delta-aminolevulinic acid dehydratase (ALAD) exon 4 polymorphism has a modifying effect on the association of blood or bone lead level with uricemia and indices of renal function among middle-aged and elderly men. We performed a cross-sectional study of subjects who participated between 1991 and 1995 in the Department of Veterans Affairs Normative Aging Study. Information on blood lead levels, bone lead levels (measured by K-shell X-ray fluorescence), serum uric acid, serum creatinine, estimated creatinine clearance, and ALAD polymorphism status was available in 709 subjects. Regression models were constructed to examine the relationships of serum uric acid, serum creatinine, and estimated creatinine clearance to blood or bone lead level, stratified by genotype. We also adjusted for age, body mass index, blood pressure, smoking, alcohol consumption, and ingestion of analgesic medications (n = 638). Of the 709 subjects, 7 (1%) and 107 (15%) were homozygous and heterozygous for the variant (ALAD-2) allele, respectively. The mean (range) serum uric acid and creatinine levels were 6.5 (2.9-10.6) and 1.2 (0.6-2.5) mg/dL. No significant differences were found in serum uric acid, serum creatinine, or estimated creatinine clearance by ALAD genotype. However, after adjusting for other potential confounders, we found a significant linear relationship between serum uric acid and patella bone lead (p = 0.040) among the ALAD 1-2/2-2 genotype individuals above a threshold patellar lead level of 15 micro g/g. In contrast, among the wild-type (ALAD 1-1) individuals, there was a suggestion of a significant linear relationship of serum uric acid with patella bone lead (p = 0.141), but only after a threshold of 101 micro g/g. There was evidence of a significant (p = 0.025) interaction of tibia lead with genotype (ALAD 1-1 vs. ALAD 1-2/2-2) regarding serum creatinine as an outcome, but in the same linear regression model tibia lead alone was not a significant predictor of serum creatinine. Conversely, for estimated creatinine clearance, patella lead, but not the interaction of patella lead with genotype, was a significantly independent predictor (p = 0.026). Our findings suggest that ALAD genotype may modify the effect of lead on the renal excretion of uric acid as well as overall renal function among middle-aged and elderly men who had community (nonoccupational) exposures to lead. Additional research is needed to ascertain whether this constitutes a true gene-environment interaction and, if so, its clinical impact.
PMCID: PMC1241391  PMID: 12611663

Results 1-6 (6)