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Biomedical subjects

W James Gauderman

Publications and source records attributed to W James Gauderman.

At least 19 recordsLinked to original sources
PubMed2025

Genetic risk factors modulate the association between physical activity and colorectal cancer.

BACKGROUND: Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-PA interaction analysis. METHODS: Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (&#x2265; 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. RESULTS: PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81-0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6&#xd7;10- 8). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75-0.85), but no significant PA-CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5&#xd7;10- 8). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72-0.82). CONCLUSIONS: In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.

GWAS↗
PubMed2006

Regular smoking and asthma incidence in adolescents.

RATIONALE: Although involuntary exposure to maternal smoking during the in utero period and to secondhand smoke are associated with occurrence of childhood asthma, few studies have investigated the role of active cigarette smoking on asthma onset during adolescence. OBJECTIVES: To determine whether regular smoking is associated with the new onset of asthma during adolescence. METHODS: We conducted a prospective cohort study among 2,609 children with no lifetime history of asthma or wheezing who were recruited from fourth- and seventh-grade classrooms and followed annually in schools in 12 southern California communities. Regular smoking was defined as smoking at least seven cigarettes per day on average over the week before and 300 cigarettes in the year before each annual interview. Incident asthma was defined using new cases of physician-diagnosed asthma. MEASUREMENTS AND MAIN RESULTS: Regular smoking was associated with increased risk of new-onset asthma. Children who reported smoking 300 or more cigarettes per year had a relative risk (RR) of 3.9 (95% confidence interval [95% CI], 1.7-8.5) for new-onset asthma compared with nonsmokers. The increased risk from regular smoking was greater in nonallergic than in allergic children. Regular smokers who were exposed to maternal smoking during gestation had the largest risk from active smoking (RR, 8.8; 95% CI, 3.2-24.0). CONCLUSIONS: Regular smoking increased risk for asthma among adolescents, especially for nonallergic adolescents and those exposed to maternal smoking during the in utero period.

Adolescent↗
PubMed2006

Health effects of the 2003 Southern California wildfires on children.

RATIONALE: In late October 2003, Southern California wildfires burned more than 3,000 km2. The wildfires produced heavy smoke that affected several communities participating in the University of Southern California Children's Health Study (CHS). OBJECTIVES: To study the acute effects of fire smoke on the health of CHS participants. METHODS: A questionnaire was used to assess smoke exposure and occurrence of symptoms among CHS high-school students (n = 873; age, 17-18 yr) and elementary-school children (n = 5,551; age, 6-7 yr), in a total of 16 communities. Estimates of particulate matter (PM10) concentrations during the 5 d with the highest fire activity were used to characterize community smoke level. MAIN RESULTS: All symptoms (nose, eyes, and throat irritations; cough; bronchitis; cold; wheezing; asthma attacks), medication usage, and physician visits were associated with individually reported exposure differences within communities. Risks increased monotonically with the number of reported smoky days. For most outcomes, reporting rates between communities were also associated with the fire-related PM10 levels. Associations tended to be strongest among those without asthma. Individuals with asthma were more likely to take preventive action, such as wearing masks or staying indoors during the fire. CONCLUSIONS: Exposure to wildfire smoke was associated with increased eye and respiratory symptoms, medication use, and physician visits.

Adolescent↗
PubMed2006

Associations of tumor necrosis factor G-308A with childhood asthma and wheezing.

RATIONALE: Tumor necrosis factor (TNF) mediates a spectrum of airway inflammatory responses, including those to air pollutants, and is an asthma candidate gene. One TNF promoter variant (G-308A) affects expression of TNF and has been associated with inflammatory diseases; however, studies of asthma have been inconsistent. Because ozone produces oxidative stress, increased airway TNF, and inflammation, the associations of the -308 TNF polymorphism with asthma may vary by ozone exposure and variants of oxidant defense genes glutathione-S-transferase (GST) M1 and GSTP1. OBJECTIVES: To investigate the association of TNF G-308A with asthma and wheezing and to determine whether these associations vary with ozone exposure and GSTM1 and GSTP1 genotype. METHODS: We studied associations of TNF-308 genotype with lifetime and current wheezing and asthma among 3,699 children in the Children's Health Study. We examined differences in associations with community ozone and by GSTM1 null and GSTP1 105 Ile/Val (A105G) genotype. RESULTS: Children with TNF-308 GG had decreased risk of asthma (odds ratio, 0.8; 95% confidence interval, 0.7-0.9) and lifetime wheezing (odds ratio, 0.8; 95% confidence interval, 0.7-0.9). The protective effects of GG genotype on wheezing outcomes were of greater magnitude in lower compared with higher ozone communities. These findings were replicated in the two cohorts of fourth-grade children recruited in 1993 and 1996. The reduction of the protective effect from the -308 GG genotype with higher ozone exposure was most marked in the GSTM1 null and GSTP1 Ile/Ile groups. CONCLUSIONS: The TNF-308 GG genotype may have a protective role in asthma pathogenesis, depending on airway oxidative stress levels.

Adolescent↗
PubMed2006

Differential twin concordance for multiple sclerosis by latitude of birthplace.

OBJECTIVE: To address the inconsistency in the reported concordance of multiple sclerosis (MS) among twins by zygosity, sex, and latitude. METHODS: Four hundred eighteen medically documented monozygotic (MZ) and 380 same-sex dizygotic (DZ) pairs were ascertained from 1980 to 1992 and followed. The study population was representative of twins with multiple sclerosis. Twins from Canada and adjacent US states (at or above 41-42 degrees N) were considered "northern," and ancestry was dichotomized from descent from high-risk populations. Diagnosis before median age 29.3 years was considered "early." RESULTS: The MZ/DZ concordance ratio was 2.9 (95% confidence interval [CI], 1.0-8.9) among men and 2.6 (95% CI, 1.5-4.5) among women. The average age at northern diagnosis was independent of ancestry and 2 years earlier for both MZ (p < 0.02) and DZ (p < 0.01) patients. Among DZ twins, concordance was independent of all characteristics. Among MZ twins, concordance was 1.9 times (95% CI, 1.2-3.2) greater among northern twins, 1.9 (95% CI, 1.1-3.6) times greater among twins with high-risk ancestry, and 2.1 (95% CI, 1.2-3.6) times greater if diagnosis was early. Ancestry and early diagnosis made independent significant contributions to the differential concordance by latitude. INTERPRETATION: Multiple sclerosis is similarly heritable by sex, and the apparent variation in MZ concordance by latitude is influenced by environmental and genetic factors.

Adult↗
PubMed2006

Dog ownership enhances symptomatic responses to air pollution in children with asthma.

BACKGROUND: Experimental data suggest that asthma exacerbation by ambient air pollutants is enhanced by exposure to endotoxin and allergens; however, there is little supporting epidemiologic evidence. METHODS: We evaluated whether the association of exposure to air pollution with annual prevalence of chronic cough, phlegm production, or bronchitis was modified by dog and cat ownership (indicators of allergen and endotoxin exposure). The study population consisted of 475 Southern California children with asthma from a longitudinal cohort of participants in the Children's Health Study. We estimated average annual ambient exposure to nitrogen dioxide, ozone, particulate matter < 10, 2.5, and 10-2.5 microm in aerodynamic diameter (PM10, PM2.5, and PM10-2.5, respectively), elemental and organic carbon, and acid vapor from monitoring stations in each of the 12 study communities. Multivariate models were used to examine the effect of yearly variation of each pollutant. Effects were scaled to the variability that is common for each pollutant in representative communities in Southern California. RESULTS: Among children owning a dog, there were strong associations between bronchitic symptoms and all pollutants examined. Odds ratios ranged from 1.30 per 4.2 microg/m3 for PM10-2.5 [95% confidence interval (CI), 0.91-1.87) to 1.91 per 1.2 microg/m3 for organic carbon (95% CI, 1.34-2.71). Effects were somewhat larger among children who owned both a cat and dog. There were no effects or small effects with wide CIs among children without a dog and among children who owned only a cat. CONCLUSION: Our results suggest that dog ownership, a source of residential exposure to endotoxin, may worsen the relationship between air pollution and respiratory symptoms in asthmatic children.

Adolescent↗
PubMed2005

Identifying susceptibility genes by using joint tests of association and linkage and accounting for epistasis.

Simulated Genetic Analysis Workshop 14 data were analyzed by jointly testing linkage and association and by accounting for epistasis using a candidate gene approach. Our group was unblinded to the "answers." The 48 single-nucleotide polymorphisms (SNPs) within the six disease loci were analyzed in addition to five SNPs from each of two non-disease-related loci. Affected sib-parent data was extracted from the first 10 replicates for populations Aipotu, Kaarangar, and Danacaa, and analyzed separately for each replicate. We developed a likelihood for testing association and/or linkage using data from affected sib pairs and their parents. Identical-by-descent (IBD) allele sharing between sibs was explicitly modeled using a conditional logistic regression approach and incorporating a covariate that represents expected IBD allele sharing given the genotypes of the sibs and their parents. Interactions were accounted for by performing likelihood ratio tests in stages determined by the highest order interaction term in the model. In the first stage, main effects were tested independently, and in subsequent stages, multilocus effects were tested conditional on significant marginal effects. A reduction in the number of tests performed was achieved by prescreening gene combinations with a goodness-of-fit chi square statistic that depended on mating-type frequencies. SNP-specific joint effects of linkage and association were identified for loci D1, D2, D3, and D4 in multiple replicates. The strongest effect was for SNP B03T3056, which had a median p-value of 1.98 x 10(-34). No two- or three-locus effects were found in more than one replicate.

Databases, Genetic↗
PubMed2005

A testing framework for identifying susceptibility genes in the presence of epistasis.

An efficient testing strategy called the "focused interaction testing framework" (FITF) was developed to identify susceptibility genes involved in epistatic interactions for case-control studies of candidate genes. In the FITF approach, likelihood-ratio tests are performed in stages that increase in the order of interaction considered. Joint tests of main effects and interactions are performed conditional on significant lower-order effects. A reduction in the number of tests performed is achieved by prescreening gene combinations with a goodness-of-fit chi2 statistic that depends on association among candidate genes in the pooled case-control group. Multiple testing is accounted for by controlling false-discovery rates. Simulation analysis demonstrated that the FITF approach is more powerful than marginal tests of candidate genes. FITF also outperformed multifactor dimensionality reduction when interactions involved additive, dominant, or recessive genes. In an application to asthma case-control data from the Children's Health Study, FITF identified a significant multilocus effect between the nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase gene (NQO1), myeloperoxidase gene (MPO), and catalase gene (CAT) (unadjusted P = .00026), three genes that are involved in the oxidative stress pathway. In an independent data set consisting primarily of African American and Asian American children, these three genes also showed a significant association with asthma status (P = .0008).

Black or African American↗
PubMed2005

TNF-308 modifies the effect of second-hand smoke on respiratory illness-related school absences.

RATIONALE: Exposure to second-hand smoke (SHS) has been associated with increased risk of respiratory illness in children including respiratory illness-related school absences. The role of genetic susceptibility in risk for adverse effects from SHS has not been extensively investigated in children. OBJECTIVE: To determine whether the tumor necrosis factor (TNF) G-308A genotype influences the risk for respiratory illness-related school absences associated with SHS exposure. METHODS: Incident school absences were collected, using an active surveillance system, between January and June 1996, as part of the Air Pollution and Absence Study, a prospective cohort study nested in the Children's Health Study. Buccal cells and absence reports were collected on 1,351 students from 27 elementary schools in California. MEASUREMENTS AND MAIN RESULTS: Illness-related school absences were classified as nonrespiratory and respiratory illness-related, which were further categorized into upper or lower respiratory illness-related absences based on symptoms. The effect of SHS exposure on respiratory illness-related absences differed by TNF genotype (p interaction, 0.02). In children possessing at least one copy of the TNF-308 A variant, exposure to two or more household smokers was associated with a twofold risk of a school absence due to respiratory illness (relative risk, 2.13; 95% confidence interval, 1.34, 3.40) and a fourfold risk of lower respiratory illness-related school absence (relative risk, 4.15; 95% confidence interval, 2.57, 6.71) compared with unexposed children homozygous for the common TNF-308 G allele. CONCLUSIONS: These results indicate that a subgroup of genetically susceptible children are at substantially greater risk of respiratory illness if exposed to SHS.

Absenteeism↗
PubMed2005

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.

Adolescent↗
PubMed2005

Testing association and linkage using affected-sib-parent study designs.

We have developed a method for jointly testing linkage and association using data from affected sib pairs and their parents. We specify a conditional logistic regression model with two covariates, one that quantifies association (either direct association or indirect association via linkage disequilibrium), and a second that quantifies linkage. The latter covariate is computed based on expected identity-by-descend (ibd) sharing of marker alleles between siblings. In addition to a joint test of linkage and association, our general framework can be used to obtain a linkage test comparable to the mean test (Blackwelder and Elston [1985] Genet. Epidemiol. 2:85-97), and an association test comparable to the Family-Based Association Test (FBAT; Rabinowitz and Laird [2000] Hum. Hered. 50:211-223). We present simulation results demonstrating that our joint test can be more powerful than some standard tests of linkage or association. For example, with a relative risk of 2.7 per variant allele at a disease locus, the estimated power to detect a nearby marker with a modest level of LD was 58.1% by the mean test (linkage only), 69.8% by FBAT, and 82.5% by our joint test of linkage and association. Our model can also be used to obtain tests of linkage conditional on association and association conditional on linkage, which can be helpful in fine mapping.

Alleles↗
PubMed2005

Childhood asthma and exposure to traffic and nitrogen dioxide.

BACKGROUND: Evidence for a causal relationship between traffic-related air pollution and asthma has not been consistent across studies, and comparisons among studies have been difficult because of the use of different indicators of exposure. METHODS: We examined the association between traffic-related pollution and childhood asthma in 208 children from 10 southern California communities using multiple indicators of exposure. Study subjects were randomly selected from participants in the Children's Health Study. Outdoor nitrogen dioxide (NO2) was measured in summer and winter outside the home of each child. We also determined residential distance to the nearest freeway, traffic volumes on roadways within 150 meters, and model-based estimates of pollution from nearby roadways. RESULTS: Lifetime history of doctor-diagnosed asthma was associated with outdoor NO2; the odds ratio (OR) was 1.83 (95% confidence interval=1.04-3.22) per increase of 1 interquartile range (IQR=5.7 ppb) in exposure. We also observed increased asthma associated with closer residential distance to a freeway (1.89 per IQR; 1.19-3.02) and with model-based estimates of outdoor pollution from a freeway (2.22 per IQR; 1.36-3.63). These 2 indicators of freeway exposure and measured NO2 concentrations were also associated with wheezing and use of asthma medication. Asthma was not associated with traffic volumes on roadways within 150 meters of homes or with model-based estimates of pollution from nonfreeway roads. CONCLUSIONS: These results indicate that respiratory health in children is adversely affected by local exposures to outdoor NO2 or other freeway-related pollutants.

Air Pollutants↗
PubMed2004

The effect of air pollution on lung development from 10 to 18 years of age.

BACKGROUND: Whether exposure to air pollution adversely affects the growth of lung function during the period of rapid lung development that occurs between the ages of 10 and 18 years is unknown. METHODS: In this prospective study, we recruited 1759 children (average age, 10 years) from schools in 12 southern California communities and measured lung function annually for eight years. The rate of attrition was approximately 10 percent per year. The communities represented a wide range of ambient exposures to ozone, acid vapor, nitrogen dioxide, and particulate matter. Linear regression was used to examine the relationship of air pollution to the forced expiratory volume in one second (FEV(1)) and other spirometric measures. RESULTS: Over the eight-year period, deficits in the growth of FEV(1) were associated with exposure to nitrogen dioxide (P=0.005), acid vapor (P=0.004), particulate matter with an aerodynamic diameter of less than 2.5 microm (PM(2.5)) (P=0.04), and elemental carbon (P=0.007), even after adjustment for several potential confounders and effect modifiers. Associations were also observed for other spirometric measures. Exposure to pollutants was associated with clinically and statistically significant deficits in the FEV(1) attained at the age of 18 years. For example, the estimated proportion of 18-year-old subjects with a low FEV(1) (defined as a ratio of observed to expected FEV(1) of less than 80 percent) was 4.9 times as great at the highest level of exposure to PM(2.5) as at the lowest level of exposure (7.9 percent vs. 1.6 percent, P=0.002). CONCLUSIONS: The results of this study indicate that current levels of air pollution have chronic, adverse effects on lung development in children from the age of 10 to 18 years, leading to clinically significant deficits in attained FEV(1) as children reach adulthood.

Adolescent↗
PubMed2004

Predictors of improved mood over time in clinical trials for major depression.

The objective of this exploratory analysis was to use a repeated measures modeling approach to identify potential predictors of improved mood over time in patients with major depression. Fifty-one subjects with major depressive disorder (MDD) were enrolled in a 1-week single blind placebo lead-in, followed by an 8-week, double-blind placebo-controlled treatment with either fluoxetine or venlafaxine. Hierarchical linear regression models were used to identify baseline and placebo lead-in predictors of change in repeated measures of the Hamilton Depression Rating Scale (HDRS) during treatment. Non-specific predictors of improved mood included decreased prefrontal activity during placebo lead-in as measured by quantitative electroencephalographic cordance, lower pretreatment depressed mood on the HDRS, shorter duration of current episode, increased verbalization of suicidal thoughts, no family history of mood disorders, less severe middle insomnia, higher guilt, lower somatic anxiety, and younger age. Moderators of improved mood included somatization, paranoid ideation, and self-reported depressed mood. We also found that change in prefrontal cordance after randomization mediated the effects of middle insomnia, suicidal thoughts, and family history of mood disorders. We recommend the use of repeated measures modeling, and the exploration of relationships among biological and psychological factors, for future analyses of clinical trial data.

Adult↗
PubMed2004

Polymorphism in the androgen receptor and mammographic density in women taking and not taking estrogen and progestin therapy.

There is some evidence that women with a higher number of CAG repeat lengths on the androgen receptor (AR) gene have increased breast cancer risk. We evaluated the association between AR-CAG repeat length and mammographic density, a strong breast cancer risk factor, in 404 African-American and Caucasian breast cancer patients. In postmenopausal estrogen progestin therapy users, carriers of the less active AR-CAG had statistically significantly higher mean percentage of density (41.4%) than carriers of the more active AR-CAG (25.7%; P = 0.04). Our results raise the question of whether the number of AR-CAG repeats predicts breast cancer risk in estrogen progestin therapy users.

Adult↗
PubMed2004

Does mammographic density reflect ethnic differences in breast cancer incidence rates?

Breast cancer incidence rates in the United States are substantially lower among Asian-American women than among White or African-American women. The authors determined whether mammographic density reflects these ethnic differences by evaluating mammograms from 442 White, African-American, and Asian-American women without breast cancer who served as controls in one of two population-based, breast cancer case-control studies conducted in Los Angeles, California, in 1994-1998. Absolute and percent mammographic densities were determined with a previously developed and validated computer-assisted method. Data were analyzed using multiple regression methods. Mean age-adjusted percent mammographic density was significantly higher in Asian Americans (35.9%) than in African Americans (27.8%, p < 0.05) but was no longer significant after further adjustment for body mass index. After adjustment for age, body mass index, selected menstrual/reproductive factors, and family history, absolute mammographic density was statistically significantly lower in Asian Americans than in African Americans (p < 0.05) but not than in Whites. The ethnic difference in absolute mammographic density was particularly evident among women older than age 50 years. Additional adjustment for breast size reduced these ethnic differences. This study suggests that absolute but not percent mammographic density reflects the lower breast cancer incidence rates of Asian Americans in relation to those of African Americans and Whites.

Adult↗
PubMed2004

SNPs, haplotypes, and model selection in a candidate gene region: the SIMPle analysis for multilocus data.

Modern molecular techniques make discovery of numerous single nucleotide polymorphims (SNPs) in candidate gene regions feasible. Conventional analysis relies on either independent tests with each variant or the use of haplotypes in association analysis. The first technique ignores the dependencies between SNPs. The second, though it may increase power, often introduces uncertainty by estimating haplotypes from population data. Additionally, as the number of loci expands for a haplotype, ambiguity in interpretation increases for determining the underlying genetic components driving a detected association. Here, we present a genotype-level analysis to jointly model the SNPs via a SNP interaction model with phase information (SIMPle) to capture the underlying haplotype structure. This analysis estimates both the risk associated with each variant and the importance of phase between pairwise combinations of SNPs. Thus, rather than selecting between genotype- or haplotype-level approaches, the SIMPle method frames the analysis of multilocus data in a model selection paradigm, the aim to determine which SNPs, phase terms, and linear combinations best describe the relation between genetic variation and a trait of interest. To avoid unstable estimation due to sparse data and to incorporate both the dependencies among terms and the uncertainty in model selection, we propose a Bayes model averaging procedure. This highlights key SNPs and phase terms and yields a set of best representative models. Using simulations, we demonstrate the utility of the SIMPle model to identify crucial SNPs and underlying haplotype structures across a variety of causal models and genetic architectures.

Bayes Theorem↗