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1.  Genome-wide association study of colorectal cancer identifies six new susceptibility loci 
Schumacher, Fredrick R. | Schmit, Stephanie L. | Jiao, Shuo | Edlund, Christopher K. | Wang, Hansong | Zhang, Ben | Hsu, Li | Huang, Shu-Chen | Fischer, Christopher P. | Harju, John F. | Idos, Gregory E. | Lejbkowicz, Flavio | Manion, Frank J. | McDonnell, Kevin | McNeil, Caroline E. | Melas, Marilena | Rennert, Hedy S. | Shi, Wei | Thomas, Duncan C. | Van Den Berg, David J. | Hutter, Carolyn M. | Aragaki, Aaron K. | Butterbach, Katja | Caan, Bette J. | Carlson, Christopher S. | Chanock, Stephen J. | Curtis, Keith R. | Fuchs, Charles S. | Gala, Manish | Giovannucci, Edward L. | Gogarten, Stephanie M. | Hayes, Richard B. | Henderson, Brian | Hunter, David J. | Jackson, Rebecca D. | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | LaCroix, Andrea | Laurie, Cathy C. | Laurie, Cecelia A. | Lemire, Mathieu | Levine, David | Ma, Jing | Makar, Karen W. | Qu, Conghui | Taverna, Darin | Ulrich, Cornelia M. | Wu, Kana | Kono, Suminori | West, Dee W. | Berndt, Sonja I. | Bezieau, Stéphane | Brenner, Hermann | Campbell, Peter T. | Chan, Andrew T. | Chang-Claude, Jenny | Coetzee, Gerhard A. | Conti, David V. | Duggan, David | Figueiredo, Jane C. | Fortini, Barbara K. | Gallinger, Steven J. | Gauderman, W. James | Giles, Graham | Green, Roger | Haile, Robert | Harrison, Tabitha A. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Jacobs, Eric | Iwasaki, Motoki | Jee, Sun Ha | Jenkins, Mark | Jia, Wei-Hua | Joshi, Amit | Li, Li | Lindor, Noralene M. | Matsuo, Keitaro | Moreno, Victor | Mukherjee, Bhramar | Newcomb, Polly A. | Potter, John D. | Raskin, Leon | Rennert, Gad | Rosse, Stephanie | Severi, Gianluca | Schoen, Robert E. | Seminara, Daniela | Shu, Xiao-Ou | Slattery, Martha L. | Tsugane, Shoichiro | White, Emily | Xiang, Yong-Bing | Zanke, Brent W. | Zheng, Wei | Le Marchand, Loic | Casey, Graham | Gruber, Stephen B. | Peters, Ulrike
Nature communications  2015;6:7138.
Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.
PMCID: PMC4967357  PMID: 26151821
3.  15q12 Variants, Sputum Gene Promoter Hypermethylation, and Lung Cancer Risk: A GWAS in Smokers 
Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis.
A genome-wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided.
Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3×10–8). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5×10–9). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin.
A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing.
PMCID: PMC4555640  PMID: 25713168
4.  Association of aspirin and non-steroidal anti-inflammatory drug use with risk of colorectal cancer according to genetic variants 
JAMA  2015;313(11):1133-1142.
Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. Prior studies examining a potential differential relationship of aspirin and NSAIDs with colorectal cancer risk according to genetic factors have been limited to analyses of candidate genes or pathways.
To comprehensively identify common genetic markers that characterize individuals who may obtain differential benefit from aspirin and/or NSAID chemoprevention, we tested gene by environment (G X E) interactions between regular use of aspirin and/or NSAIDs and single nucleotide polymorphisms (SNPs) across the genome in relation to risk of colorectal cancer.
Case-control study using the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) that enrolled cases of colorectal cancer ascertained between 1976 and 2011 and matched controls. Odds ratios (ORs) of colorectal cancer and 95% confidence intervals (95% CIs) were estimated using conventional logistic regression analysis and case-only interaction analysis, after adjusting for age, sex, center, the first three principal components to account for population structure, and known colorectal cancer risk factors. For all genome-wide analyses, a two-sided p-value<5.0×10-8, which yields a genome-wide significance level of 0.05, was considered statistically significant.
10 observational studies (5 case-control and 5 cohort studies) that were initiated between 1976 and 2003 across the U.S., Canada, Australia and Germany.
8,634 colorectal cancer cases and 8,553 controls of European descent.
Genome-wide SNP data generated from genome-wide association scans and imputation to HapMap II, as well as information on regular use of aspirin and/or NSAIDs and other colorectal cancer risk factors collected using in-person interviews and/or structured questionnaires.
Main Outcomes and Measures
Colorectal cancer
Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (OR=0.69; 95% CI=0.64-0.74; P=6.2×10-28) compared to non-regular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the microsomal glutathione S-transferase 1 (MGST1) gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P for interaction=4.6×10-9). Compared to non-regular use, regular use of aspirin and/or NSAIDs was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (OR=0.66; 95% CI=0.61-0.70; P=7.7×10-33), but a higher risk among those with much less common (4%) TA or AA genotypes (OR=1.89; 95% CI=1.27-2.81; P=0.002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the interleukin 16 (IL16) gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P for interaction=8.2×10-9). Compared to non-regular use, regular use of aspirin and/or NSAIDs was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (OR=0.66; 95% CI=0.62-0.71; P=1.9×10-30), but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (OR=0.97; 95% CI=0.78-1.20; P=0.76).
In this genome-wide investigation of G X E interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and the association of these medications with colorectal cancer risk differed according to genetic variation at two SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.
PMCID: PMC4382867  PMID: 25781442
5.  Genetic Ancestry Influences Asthma Susceptibility and Lung Function Among Latinos 
Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest.
To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children.
We analyzed 5,493 Latinos with and without asthma from three independent studies. For each participant we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry.
Native American ancestry was associated with lower odds of asthma (OR=0.72, 95% confidence interval [CI]: 0.66–0.78, p=8.0×10−15), while African ancestry was associated with higher odds of asthma (OR=1.40, 95%CI: 1.14–1.72, p=0.001). These associations were robust to adjustment for covariates related to early life exposures, air pollution and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of forced expiratory volume in the first second (−77±19 ml, p=5.8×10−5 and −83±19 ml, p=1.1×10−5, respectively) and forced vital capacity (−100±21 ml, p=2.7×10−6 and −107±22 ml, p=1.0×10−6, respectively).
Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.
PMCID: PMC4289103  PMID: 25301036
genetic admixture; childhood asthma; Hispanics; minority; pulmonary function
6.  Inducible Nitric Oxide Synthase Promoter Haplotypes and Residential Traffic-Related Air Pollution Jointly Influence Exhaled Nitric Oxide Level in Children 
PLoS ONE  2015;10(12):e0145363.
Exhaled nitric oxide (FeNO), a biomarker of airway inflammation, predicts asthma risk in children. We previously found that the promoter haplotypes in inducible nitric oxide synthase (NOS2) and exposure to residential traffic independently influence FeNO level. Because NOS2 is inducible by environmental exposures such as traffic-related exposure, we tested the hypothesis that common NOS2 promoter haplotypes modulate the relationship between residential traffic-related exposure and FeNO level in children.
In a cross-sectional population-based study, subjects (N = 2,457; 7–11 year-old) were Hispanic and non-Hispanic white children who participated in the Southern California Children’s Health Study and had FeNO measurements. For residential traffic, lengths of local roads within circular buffers (50m, 100m and 200m radii around homes) around the subjects’ homes were estimated using geographic information system (GIS) methods. We interrogated the two most common NOS2 promoter haplotypes that were found to affect FeNO level.
The relationship between local road lengths within 100m and 200m circular buffers and FeNO level varied significantly by one of the NOS2 promoter haplotypes (P-values for interaction between road length and NOS2 promoter haplotype = 0.02 and 0.03, respectively). In children who had ≤250m of local road lengths within 100m buffer around their homes, those with two copies of the haplotype had significantly lower FeNO (adjusted geometric mean = 11.74ppb; 95% confidence intervals (CI): 9.99 to 13.80) than those with no copies (adjusted geometric mean = 15.28ppb; 95% CI: 14.04 to 16.63) with statistically significant trend of lower FeNO level with increasing number of haplotype copy (P-value for trend = 0.002). In contrast, among children who had >250m of local road lengths within 100m buffer, FeNO level did not significantly differ by the haplotype copy-number (P-value for trend = 0.34). Similar interactive effects of this haplotype and local road lengths within 200m buffer on FeNO were also observed.
Higher exposure from residential traffic nullifies the protective effect of one common NOS2 promoter haplotype on FeNO level. Regulation of traffic-related pollution may protect children’s respiratory health.
PMCID: PMC4695093  PMID: 26714306
7.  Finding Novel Genes by Testing G×E Interactions in a Genomewide Association Study 
Genetic epidemiology  2013;37(6):603-613.
In a genomewide association study (GWAS), investigators typically focus their primary analysis on the direct (marginal) associations of each SNP with the trait. Some SNPs that are truly associated with the trait may not be identified in this scan if they have a weak marginal effect and thus low power to be detected. However, these SNPs may be quite important in subgroups of the population defined by an environmental or personal factor, and may be detectable if such a factor is carefully considered in a gene-environment (G×E) interaction analysis. We address the question “Using a genome wide interaction scan (GWIS), can we find new genes that were not found in the primary GWAS scan?” We review commonly used approaches for conducting a GWIS in case-control studies, and propose a new 2-step screening and testing method (EDG×E) that is optimized to find genes with a weak marginal effect. We simulate several scenarios in which our 2-step method provides 70–80% power to detect a disease locus while a marginal scan provides less than 5% power. We also provide simulations demonstrating that the EDG×E method outperforms other GWIS approaches (including case only and previously proposed 2-step methods) for finding genes with a weak marginal effect. Application of this method to a G × Sex scan for childhood asthma reveals two potentially interesting SNPs that were not identified in the marginal-association scan. We distribute a new software program (G×Escan, available at that implements this new method as well as several other GWIS approaches.
PMCID: PMC4348012  PMID: 23873611
genomewide scan; environmental factor; power
8.  No evidence of gene-calcium interactions from genome-wide analysis of colorectal cancer risk 
Calcium intake may reduce risk of colorectal cancer (CRC), but the mechanisms remain unclear. Studies of interaction between calcium intake and single nucleotide polymorphisms (SNPs) in calcium-related pathways have yielded inconsistent results.
To identify gene-calcium interactions, we tested interactions between ~2.7 million SNPs across the genome with self-reported calcium intake (from dietary or supplemental sources) in 9,006 CRC cases and 9,503 controls of European ancestry. To test for multiplicative interactions, we used multivariable logistic regression and defined statistical significance using the conventional genome-wide α=5E-08.
After accounting for multiple comparisons, there were no statistically significant SNP-interactions with total, dietary, or supplemental calcium intake.
We found no evidence of SNP-interactions with calcium intake for CRC risk in a large population of 18,509 individuals.
These results suggest that in genome-wide analysis common genetic variants do not strongly modify the association between calcium intake and CRC in European populations.
PMCID: PMC4257872  PMID: 25192705
9.  Genome-wide interaction studies reveal sex-specific asthma risk alleles 
Human Molecular Genetics  2014;23(19):5251-5259.
Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10−6, of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.
PMCID: PMC4159149  PMID: 24824216
10.  Association of Improved Air Quality with Lung Development in Children 
The New England journal of medicine  2015;372(10):905-913.
Air-pollution levels have been trending downward progressively over the past several decades in southern California, as a result of the implementation of air quality– control policies. We assessed whether long-term reductions in pollution were associated with improvements in respiratory health among children.
As part of the Children’s Health Study, we measured lung function annually in 2120 children from three separate cohorts corresponding to three separate calendar periods: 1994–1998, 1997–2001, and 2007–2011. Mean ages of the children within each cohort were 11 years at the beginning of the period and 15 years at the end. Linear-regression models were used to examine the relationship between declining pollution levels over time and lung-function development from 11 to 15 years of age, measured as the increases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) during that period (referred to as 4-year growth in FEV1 and FVC).
Over the 13 years spanned by the three cohorts, improvements in 4-year growth of both FEV1 and FVC were associated with declining levels of nitrogen dioxide (P<0.001 for FEV1 and FVC) and of particulate matter with an aerodynamic diameter of less than 2.5 μm (P = 0.008 for FEV1 and P<0.001 for FVC) and less than 10 μm (P<0.001 for FEV1 and FVC). These associations persisted after adjustment for several potential confounders. Significant improvements in lung-function development were observed in both boys and girls and in children with asthma and children without asthma. The proportions of children with clinically low FEV1 (defined as <80% of the predicted value) at 15 years of age declined significantly, from 7.9% to 6.3% to 3.6% across the three periods, as the air quality improved (P = 0.001).
We found that long-term improvements in air quality were associated with statistically and clinically significant positive effects on lung-function growth in children. (Funded by the Health Effects Institute and others.)
PMCID: PMC4430551  PMID: 25738666
11.  Respiratory Symptoms Following Wildfire Smoke Exposure 
Epidemiology (Cambridge, Mass.)  2009;20(3):451-459.
Associations between exposure to smoke during wild-fire events and respiratory symptoms are well documented, but the role of airway size remains unclear. We conducted this analysis to assess whether small airway size modifies these relationships.
We analyzed data from 465 nonasthmatic 16- to 19-year-old participants in the Children’s Health Study. Following an outbreak of wildfires in 2003, each student completed a questionnaire about smoke exposure, dry and wet cough, wheezing, and eye symptoms. We used log-binomial regression to evaluate associations between smoke exposure and fire-related health symptoms, and to assess modification of the associations by airway size. As a marker of airway size, we used the ratio of maximum midexpiratory flow to forced vital capacity.
Forty percent (186 of 465) of this population (including students from 11 of 12 surveyed communities) reported the odor of wildfire smoke at home. We observed increased respiratory and eye symptoms with increasing frequency of wildfire smoke exposure. Associations between smoke exposure and having any of 4 respiratory symptoms were stronger in the lowest quartile of the lung function ratio (eg, fire smoke 6+ days: prevalence ratio: 3.8; 95% confidence interval (CI = 2.0 –7.2), compared with the remaining quartiles (fire smoke 6+ days: prevalence ratio = 2.0; 1.2–3.2). Analysis of individual symptoms suggests that this interaction may be strongest for effects on wheezing.
Small airways may serve as a marker of susceptibility to effects of wildfire smoke. Future studies should investigate the role of airway size for more common exposures and should include persons with asthma.
PMCID: PMC4517186  PMID: 19276978
12.  Ethnic-Specific Associations of Rare and Low Frequency DNA Sequence Variants with Asthma 
Nature communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls, and 590 case-parent trios representing European Americans, African Americans/African Caribbeans, and Latinos. Our study reveals one low frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31×10−6; OR=1.25; MAF=1.21%) and two genes harboring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81×10−8 and 4.09×10−8, respectively) and MTHFR in the African ancestry sample (P=1.72×10−6). Our results suggest that associations with rare and low frequency variants are ethnic specific and not likely to explain a significant proportion of the “missing heritability” of asthma.
PMCID: PMC4309441  PMID: 25591454
13.  Fractional exhaled nitric oxide in childhood is associated with 17q11.2-q12 and 17q12-q21 variants 
The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes.
To identify genetic variants associated with childhood FeNO, and their relation with asthma.
FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110).
We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.
PMCID: PMC4334587  PMID: 24315451
airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study
14.  Associations of Children’s Lung Function with Ambient Air Pollution: Joint Effects of Regional and Near-roadway Pollutants 
Thorax  2013;69(6):540-547.
Prior studies have reported adverse effects of either regional or near-roadway air pollution (NRAP) on lung function. However, there has been little study of the joint effects of these exposures.
To assess the joint effects of NRAP and regional pollutants on childhood lung function in the Children’s Health Study.
Lung function was measured on 1,811 children from eight Southern Californian communities. NRAP exposure was assessed based on (1) residential distance to the nearest freeway or major road and (2) estimated near-roadway contributions to residential nitrogen dioxide (NO2), nitric oxide (NO), and total nitrogen oxides (NOx). Exposure to regional ozone (O3), NO2, particulate matter with aerodynamic diameter less than 10 μm (PM10) and 2.5 μm (PM2.5) was measured continuously at community monitors.
A 17.9 ppb (two standard deviation) increase in near-roadway NOx was associated with deficits of 1.6% in FVC (p=0.005) and 1.1% in FEV1 (p=0.048). Effects were observed in all communities and were similar for NO2 and NO. Residential proximity to a freeway was associated with a reduction in FVC. Lung function deficits of 2–3% were associated with regional PM10 and PM2.5 (FVC and FEV1) and with O3 (FEV1), but not NO2, across the range of exposure between communities. Associations with regional pollution and NRAP were independent in models adjusted for each. Effects of NRAP were not modified by regional pollutant concentrations.
Results indicate that NRAP and regional air pollution have independent adverse effects on childhood lung function.
PMCID: PMC4191894  PMID: 24253832
traffic; lung function; air pollution; children; land-use regression
15.  Predictors of intra-community variation in air quality 
Air quality has emerged as a key determinant of important health outcomes in children and adults. This study aims to identify factors that influence local, within-community air quality, and to build a model for traffic-related air pollution (TRP).We utilized concentrations of NO2, NO, and total oxides of nitrogen (NOx), which were measured at 942 locations in 12 southern California communities. For each location, population density, elevation, land-use, and several indicators of traffic were calculated. A spatial random effects model was used to study the relationship of these predictors to each TRP.Variation in TRP was strongly correlated with traffic on nearby freeways and other major roads, and also with population density and elevation. After accounting for traffic, categories of land-use were not associated with the pollutants. Traffic had a larger relative impact in small urban (low regional pollution) communities than in large urban (high regional pollution) communities. For example, our best fitting model explained 70% of the variation in NOx in large urban areas and 76% in small urban areas. Compared with living at least 1,500m from a freeway, living within 250m of a freeway was associated with up to a 41% increase in TRP in a large urban area, and up to a 75% increase in small urban areas.Thus, traffic strongly affects local air quality in large and small urban areas, which has implications for exposure assessment and estimation of health risks.
PMCID: PMC4391642  PMID: 22252279
traffic-related air pollution; nitrogen oxides; exposure assessment; traffic; land-use; spatial random effects
16.  NOS1 Methylation and Carotid Artery Intima Media Thickness in Children 
Nitric oxide (NO) plays an important role in cardiovascular health by maintaining and regulating vascular tone and blood flow. Epigenetic regulation of nitric oxide synthase (NOS), the genes responsible for NO production, may affect cardiovascular disease including development of atherosclerosis in children.
Methods and Results
We measured percentage DNA methylation using bisulfite conversion and Pyrosequencing assays on DNA from buccal cells provided by 377 participants of the Children’s Health Study on whom carotid artery intima-media thickness (CIMT) measurements were also collected. We examined a total of 16 CpG loci located within NOS1, NOS2A, NOS3, ARG1 and ARG, genes responsible for NO production. CIMT was measured using high-resolution B-mode carotid ultrasound. The association between percentage DNA methylation in ARG and NOS genes with CIMT was evaluated using linear regression adjusted for sex, Cethnicity, body mass index, age at CIMT, town of residence and experimental plate for pyrosequencing reactions. Differences in the association by ethnicity and ancestral group were also evaluated. For a 1% increase in average DNA methylation of NOS1, CIMT increased by 1.2 μm (p=0.02). This association was greater in Hispanic children of Native American descent (β = 2.3, p=0.004) than in Non-Hispanic Whites (β = 0.3, p=0.71) or Hispanic Whites (β = 1.0, p=0.35).
DNA methylation of NOS1 has a plausible role in atherogenesis through regulation of NO production, though ancestry may alter the magnitude of this association.
PMCID: PMC4008829  PMID: 24622112
epigenetics; intima-media thickness; cardiovascular disease; nitric oxide synthase
17.  Native American Ancestry Is Associated With Severe Diabetic Retinopathy in Latinos 
Diabetic retinopathy (DR) is a leading cause of blindness in working age adults. Studies have observed that Latinos have a higher prevalence of DR than whites. The purpose of this study is to test the association between genetic admixture and severe DR in Latinos with type 2 diabetes mellitus (T2DM).
We conducted a case–control study using 944 T2DM subjects from the Los Angeles Latino Eye Study. Cases (n = 135) were defined as proliferative or severe nonproliferative DR subjects. Controls (n = 809) were other diabetic subjects in the cohort. Genotyping was performed on the Illumina OmniExpress BeadChip. We estimated genetic ancestry in Latinos using STRUCTURE with the HapMap reference panels. Univariate and multivariate logistic regression analyses were used to test the relationship between the proportions of genetic ancestry and severe DR.
Native American ancestry (NAA) in Latino T2DM subjects is associated significantly with severe DR (P = 0.002). The association remained significant (P = 0.005) after adjusting for age, sex, duration of diabetes, hemoglobin A1c, body mass index, systolic blood pressure, education, and income. We also validated the NAA estimates in Latinos using ADMIXTURE with the 1000 Genomes Project reference panels and obtained consistent results.
Our results demonstrate for the first time to our knowledge that NAA is a significant risk factor for severe DR in Latinos.
Our results demonstrate for the first time to our knowledge that Native American ancestry is a significant risk factor for severe diabetic retinopathy in Latinos. Therefore, genetic ancestry should be included in the risk assessment of severe diabetic retinopathy in research studies of Latinos with type 2 diabetes mellitus.
PMCID: PMC4176415  PMID: 25146985
diabetic retinopathy; Latinos; genetic ancestry; Native American
18.  Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma 
Nature Communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
PMCID: PMC4309441  PMID: 25591454
19.  Invited Commentary: GE-Whiz! Ratcheting Gene-Environment Studies up to the Whole Genome and the Whole Exposome 
American Journal of Epidemiology  2011;175(3):203-207.
One goal in the post-genome-wide association study era is characterizing gene-environment interactions, including scanning for interactions with all available polymorphisms, not just those showing significant main effects. In recent years, several approaches to such “gene-environment-wide interaction studies” have been proposed. Two contributions in this issue of the American Journal of Epidemiology provide systematic comparisons of the performance of these various approaches, one based on simulation and one based on application to 2 real genome-wide association study scans for type 2 diabetes. The authors discuss some of the broader issues raised by these contributions, including the plausibility of the gene-environment independence assumption that some of these approaches rely upon, the need for replication, and various generalizations of these approaches.
PMCID: PMC3261438  PMID: 22199029
epidemiologic research design; genetic epidemiology; genome-wide association study; genotype-environment interaction; polymorphisms, single nucleotide
20.  Native American Ancestry Affects the Risk for Gene Methylation in the Lungs of Hispanic Smokers from New Mexico 
Rationale: Gene promoter methylation detected in sputum predicts lung cancer risk in smokers. Compared with non-Hispanic whites (NHW), Hispanics have a lower age-standardized incidence for lung cancer.
Objectives: This study compared the methylation prevalence in sputum of NHWs with Hispanics using the Lovelace Smokers cohort (n = 1998) and evaluated the effect of Native American ancestry (NAA) and diet on biomarkers for lung cancer risk.
Methods: Genetic ancestry was estimated using 48 ancestry markers. Diet was assessed by the Harvard University Dietary Assessment questionnaire. Methylation of 12 genes was measured in sputum using methylation-specific polymerase chain reaction. The association between NAA and risk for methylation was assessed using generalized estimating equations. The ethnic difference in the association between pack-years and risk for lung cancer was assessed in the New Mexico lung cancer study.
Measurements and Main Results: Overall Hispanics had a significantly increased risk for methylation across the 12 genes analyzed (odds ratio, 1.18; P = 0.007). However, the risk was reduced by 32% (P = 0.032) in Hispanics with high versus low NAA. In the New Mexico lung cancer study, Hispanic non–small cell lung cancer cases have significantly lower pack-years than NHW counterparts (P = 0.007). Furthermore, compared with NHW smokers, Hispanic smokers had a more rapidly increasing risk for lung cancer as a function of pack-years (P = 0.058).
Conclusions: NAA may be an important risk modifier for methylation in Hispanic smokers. Smoking intensity may have a greater impact on risk for lung cancer in Hispanics compared with NHWs.
PMCID: PMC3863742  PMID: 24032348
ethnicity; sputum; diet; risk; lung cancer
21.  Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis 
BMC Medical Genomics  2014;7:48.
Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.
GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72).
Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.
PMCID: PMC4127082  PMID: 25085501
Genome-wide association study; Allergic rhinitis; Coexpression network; Expression single-nucleotide polymorphism; Coexpression module; Pathway; Mitochondria; Hay fever; Allergy
22.  Efficient Genome-Wide Association Testing of Gene-Environment Interaction in Case-Parent Trios 
American Journal of Epidemiology  2010;172(1):116-122.
Complex trait variation is likely to be explained by the combined effects of genes, environmental factors, and gene × environment (G × E) interaction. The authors introduce a novel 2-step method for detecting a G × E interaction in a genome-wide association study (GWAS) of case-parent trios. The method utilizes 2 sources of G × E information in a trio sample to construct a screening step and a testing step. Across a wide range of models, this 2-step procedure provides substantially greater power to detect G × E interaction than a standard test of G × E interaction applied genome-wide. For example, for a disease susceptibility locus with minor allele frequency of 15%, a binary exposure variable with 50% prevalence, and a GWAS scan of 1 million markers in 1,000 case-parent trios, the 2-step method provides 87% power to detect a G × E interaction relative risk of 2.3, as compared with only 25% power using a standard G × E test. The method is easily implemented using standard software. This 2-step scan for G × E interaction is independent of any prior scan that may have been conducted for genetic main effects, and thus has the potential to uncover new genes in a GWAS that have not been previously identified.
PMCID: PMC2915477  PMID: 20543031
environmental exposure; epidemiologic methods; genetic association studies; genetics; genome-wide association study; models, genetic
23.  Microsomal epoxide hydrolase, glutathione S‐transferase P1, traffic and childhood asthma 
Thorax  2007;62(12):1050-1057.
Microsomal epoxide hydrolase (EPHX1) metabolises xenobiotics including polyaromatic hydrocarbons (PAHs). Functional variants at this locus have been associated with respiratory diseases. The effects of EPHX1 variants may depend upon exposures from tobacco smoke and traffic emissions that contain PAHs as well as variants in other enzymes in the PAH metabolic pathway such as glutathione S‐transferase (GST) genes. A study was undertaken to investigate associations of variants in EPHX1, GSTM1, GSTP1 and GSTT1 with asthma and the relationships between asthma, EPHX1 metabolic phenotypes and exposure to sources of PAHs.
Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate the associations of genetic variants and exposures with asthma phenotypes using data from 3124 children from the Children's Health Study.
High EPHX1 activity was associated with an increased risk for lifetime asthma (OR 1.51, 95% CI 1.14 to 1.98) which varied by GSTP1 Ile105Val genotype and by residential proximity to major roads (p for interaction = 0.006 and 0.03, respectively). Among children with GSTP1 105Val/Val genotype, those who had high EPHX1 phenotype had a fourfold (95% CI 1.97 to 8.16) increased risk of lifetime asthma than children with low/intermediate EPHX1 phenotype. Among children living within 75 metres of a major road, those with high EPHX1 activity had a 3.2‐fold (95% CI 1.75 to 6.00) higher lifetime asthma risk than those with low/intermediate activity. The results were similar for current, early persistent and late onset asthma. Children with high EPHX1 phenotype, GSTP1 Val/Val genotype who lived <75 metres from a major road were at the highest asthma risk.
EPHX1 and GSTP1 variants contribute to the occurrence of childhood asthma and increase asthma susceptibility to exposures from major roads.
PMCID: PMC2094290  PMID: 17711870
24.  Relationship between air pollution, lung function and asthma in adolescents 
Thorax  2007;62(11):957-963.
The interrelationships between air pollution, lung function and the incidence of childhood asthma have yet to be established. A study was undertaken to determine whether lung function is associated with new onset asthma and whether this relationship varies by exposure to ambient air pollutants.
A cohort of children aged 9–10 years without asthma or wheeze at study entry were identified from the Children's Health Study and followed for 8 years. The participants resided in 12 communities with a wide range of ambient air pollutants that were measured continuously. Spirometric testing was performed and a medical diagnosis of asthma was ascertained annually. Proportional hazard regression models were fitted to investigate the relationship between lung function at study entry and the subsequent development of asthma and to determine whether air pollutants modify these associations.
The level of airway flow was associated with new onset asthma. Over the 10th–90th percentile range of forced expiratory flow over the mid‐range of expiration (FEF25–75, 57.1%), the hazard ratio (HR) of new onset asthma was 0.50 (95% CI 0.35 to 0.71). This protective effect of better lung function was reduced in children exposed to higher levels of particulate matter with an aerodynamic diameter <2.5 μm (PM2.5). Over the 10th–90th percentile range of FEF25–75, the HR of new onset asthma was 0.34 (95% CI 0.21 to 0.56) in communities with low PM2.5 (<13.7 μg/m3) and 0.76 (95% CI 0.45 to 1.26) in communities with high PM2.5 (⩾13.7 μg/m3). A similar pattern was observed for forced expiratory volume in 1 s. Little variation in HR was observed for ozone.
Exposure to high levels of PM2.5 attenuates the protective effect of better lung function against new onset asthma.
PMCID: PMC2117135  PMID: 17517830
25.  Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer 
PLoS Genetics  2014;10(4):e1004228.
Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
Author Summary
High intake of red and processed meat and low intake of fruits, vegetables and fiber are associated with a higher risk of colorectal cancer. We investigate if the effect of these dietary factors on colorectal cancer risk is modified by common genetic variants across the genome (total of about 2.7 million genetic variants), also known as gene-diet interactions. We included over 9,000 colorectal cancer cases and 9,000 controls that were not diagnosed with colorectal cancer. Our results provide strong evidence for a gene-diet interaction and colorectal cancer risk between a genetic variant (rs4143094) on chromosome 10p14 near the gene GATA3 and processed meat consumption (p = 8.7E-09). This genetic locus may have interesting biological significance given its location in the genome. Our results suggest that genetic variants may interact with diet and in combination affect colorectal cancer risk, which may have important implications for personalized cancer care and provide novel insights into prevention strategies.
PMCID: PMC3990510  PMID: 24743840

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