Showing papers by "Margaret R. Karagas published in 2011"
TL;DR: A positive association between rice consumption and urinary arsenic excretion, a biomarker of recent arsenic exposure, in 229 pregnant women is documented, indicating that rice consumption should be considered when designing arsenic reduction strategies in the United States.
Abstract: Emerging data indicate that rice consumption may lead to potentially harmful arsenic exposure. However, few human data are available, and virtually none exist for vulnerable periods such as pregnancy. Here we document a positive association between rice consumption and urinary arsenic excretion, a biomarker of recent arsenic exposure, in 229 pregnant women. At a 6-mo prenatal visit, we collected a urine sample and 3-d dietary record for water, fish/seafood, and rice. We also tested women's home tap water for arsenic, which we combined with tap water consumption to estimate arsenic exposure through water. Women who reported rice intake (n = 73) consumed a median of 28.3 g/d, which is ∼0.5 cup of cooked rice each day. In general linear models adjusted for age and urinary dilution, both rice consumption (g, dry mass/d) and arsenic exposure through water (μg/d) were significantly associated with natural log-transformed total urinary arsenic (βrice = 0.009, βwater = 0.028, both P 2 cups/d. Rice arsenic content and speciation also vary, with some strains predominated by dimethylarsinic acid, particularly those grown in the United States. Our findings along with others indicate that rice consumption should be considered when designing arsenic reduction strategies in the United States.
319 citations
TL;DR: Elevated cancer mortality in the Oinofita area of Greece supports the hypothesis of hexavalent chromium carcinogenicity via the oral ingestion pathway of exposure, and is needed to establish preventive guidelines and public health recommendations.
Abstract: Hexavalent chromium is a known carcinogen when inhaled, but its carcinogenic potential when orally ingested remains controversial. Water contaminated with hexavalent chromium is a worldwide problem, making this a question of significant public health importance. We conducted an ecological mortality study within the Oinofita region of Greece, where water has been contaminated with hexavalent chromium. We calculated gender, age, and period standardized mortality ratios (SMRs) for all deaths, cancer deaths, and specific cancer types of Oinofita residents over an 11-year period (1999 - 2009), using the greater prefecture of Voiotia as the standard population. A total of 474 deaths were observed. The SMR for all cause mortality was 98 (95% CI 89-107) and for all cancer mortality 114 (95% CI 94-136). The SMR for primary liver cancer was 1104 (95% CI 405-2403, p-value < 0.001). Furthermore, statistically significantly higher SMRs were identified for lung cancer (SMR = 145, 95% CI 100-203, p-value = 0.047) and cancer of the kidney and other genitourinary organs among women (SMR = 368, 95% CI 119-858, p-value = 0.025). Elevated SMRs for several other cancers were also noted (lip, oral cavity and pharynx 344, stomach 121, female breast 134, prostate 128, and leukaemias 168), but these did not reach statistical significance. Elevated cancer mortality in the Oinofita area of Greece supports the hypothesis of hexavalent chromium carcinogenicity via the oral ingestion pathway of exposure. Further studies are needed to determine whether this association is causal, and to establish preventive guidelines and public health recommendations.
185 citations
TL;DR: The network approach characterized a global picture of gene-gene interactions in a population-based genetic data and suggested that this particular statistical epistasis network captured important features of the genetic architecture of bladder cancer that have not been described previously.
Abstract: Epistasis is recognized ubiquitous in the genetic architecture of complex traits such as disease susceptibility. Experimental studies in model organisms have revealed extensive evidence of biological interactions among genes. Meanwhile, statistical and computational studies in human populations have suggested non-additive effects of genetic variation on complex traits. Although these studies form a baseline for understanding the genetic architecture of complex traits, to date they have only considered interactions among a small number of genetic variants. Our goal here is to use network science to determine the extent to which non-additive interactions exist beyond small subsets of genetic variants. We infer statistical epistasis networks to characterize the global space of pairwise interactions among approximately 1500 Single Nucleotide Polymorphisms (SNPs) spanning nearly 500 cancer susceptibility genes in a large population-based study of bladder cancer. The statistical epistasis network was built by linking pairs of SNPs if their pairwise interactions were stronger than a systematically derived threshold. Its topology clearly differentiated this real-data network from networks obtained from permutations of the same data under the null hypothesis that no association exists between genotype and phenotype. The network had a significantly higher number of hub SNPs and, interestingly, these hub SNPs were not necessarily with high main effects. The network had a largest connected component of 39 SNPs that was absent in any other permuted-data networks. In addition, the vertex degrees of this network were distinctively found following an approximate power-law distribution and its topology appeared scale-free. In contrast to many existing techniques focusing on high main-effect SNPs or models of several interacting SNPs, our network approach characterized a global picture of gene-gene interactions in a population-based genetic data. The network was built using pairwise interactions, and its distinctive network topology and large connected components indicated joint effects in a large set of SNPs. Our observations suggested that this particular statistical epistasis network captured important features of the genetic architecture of bladder cancer that have not been described previously.
120 citations
TL;DR: Evidence is provided that the NAT2 slow acetylation genotype interacts with tobacco smoking as a function of exposure intensity, and the effect of GSTM1-null genotype was not greater among smokers, regardless of intensity.
Abstract: Associations between bladder cancer risk and NAT2 and GSTM1 polymorphisms have emerged as some of the most consistent findings in the genetic epidemiology of common metabolic polymorphisms and cancer, but their interaction with tobacco use, intensity and duration remain unclear. In a New England population-based case‐control study of urothelial carcinoma, we collected mouthwash samples from 1088 of 1171 cases (92.9%) and 1282 of 1418 controls (91.2%) for genotype analysis of GSTM1, GSTT1 and NAT2 polymorphisms. Odds ratios and 95% confidence intervals of bladder cancer among New England Bladder Cancer Study subjects with one or two inactive GSTM1 alleles (i.e. the ‘null’ genotype) were 1.26 (0.85‐1.88) and 1.54 (1.05‐2.25), respectively (P-trend 5 0.008), compared with those with two active copies. GSTT1 inactive alleles were not associated with risk. NAT2 slow acetylation status was not associated with risk among never (1.04; 0.71‐1.51), former (0.95; 0.75‐1.20) or current smokers (1.33; 0.91‐ 1.95); however, a relationship emerged when smoking intensity was evaluated. Among slow acetylators who ever smoked at least 40 cigarettes/day, risk was elevated among ever (1.82; 1.14‐2.91, P-interaction 5 0.07) and current heavy smokers (3.16; 1.22‐8.19, P-interaction 5 0.03) compared with rapid acetylators in each category; but was not observed at lower intensities. In contrast, the effect of GSTM1-null genotype was not greater among smokers, regardless of intensity. Meta-analysis of the NAT2 associations with bladder cancer showed a highly significant relationship. Findings from this large USApopulation-basedstudy provided evidence that the NAT2 slow acetylation genotype interacts with tobacco smoking as a function of exposure intensity.
111 citations
TL;DR: Some reproductive and menstrual factors appear to be related to the incidence of bladder cancer among women; but whether effects are due to female hormones is uncertain.
60 citations
TL;DR: It is demonstrated that CpGs are differentially methylated dependent upon the genomic features of the sequence in which they are embedded, and that C pG methylation is associated with age and hair dye use in a CpG context-dependent manner in healthy individuals.
Abstract: In order to properly comprehend the epigenetic dysregulation that occurs during the course of disease, there is a need to characterize the epigenetic variability in healthy individuals that arises in response to aging and exposures, and to understand such variation within the biological context of the DNA sequence. We analyzed the methylation of 26,486 autosomal CpG loci in blood from 205 healthy subjects, using three complementary approaches to assess the association between methylation, age or exposures, and local sequence features, such as CpG island status, repeat sequences, location within a polycomb target gene or proximity to a transcription factor binding site. We clustered CpGs (1) using unsupervised recursively partitioned mixture modeling (RPMM) and (2) bioinformatically-informed methods, and (3) also employed a marginal model-based (non-clustering) approach. We observed associations between age and methylation and hair dye use and methylation, where the direction and magnitude was contingent o...
58 citations
TL;DR: Although there is no relation between hair dye use and bladder cancer risk in women overall, evidence of associations and gene‐environment interaction with permanent hair dyed use is detected; however, this was limited to educated women.
Abstract: Aromatic amine components in hair dyes and polymorphisms in genes that encode enzymes responsible for hair dye metabolism may be related to bladder cancer risk. We evaluated the association between hair dye use and bladder cancer risk and effect modification by N-acetyltransferase-1 (NAT1), NAT2, glutathione S-transferase Mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) genotypes in a population-based case–control study of 1193 incident cases and 1418 controls from Maine, Vermont and New Hampshire enrolled between 2001 and 2004. Individuals were interviewed in person using a computer-assisted personal interview to assess hair dye use and information on potential confounders and effect modifiers. No overall association between age at first use, year of first use, type of product, color, duration or number of applications of hair dyes and bladder cancer among women or men was apparent, but increased risks were observed in certain subgroups. Women who used permanent dyes and had a college degree, a marker of socioeconomic status, had an increased risk of bladder cancer [odds ratio (OR) = 3.3, 95% confidence interval (CI): 1.2–8.9]. Among these women, we found an increased risk of bladder cancer among exclusive users of permanent hair dyes who had NAT2 slow acetylation phenotype (OR = 7.3, 95% CI: 1.6–32.6) compared to never users of dye with NAT2 rapid/intermediate acetylation phenotype. Although we found no relation between hair dye use and bladder cancer risk in women overall, we detected evidence of associations and gene-environment interaction with permanent hair dye use; however, this was limited to educated women. These results need confirmation with larger numbers, requiring pooling data from multiple studies.
57 citations
TL;DR: In this article, entropy‐based test statistics are developed to identify two‐way and higher order gene‐gene and gene‐environment interactions and applied to a bladder cancer data set to investigate the complex interactions between DNA repair gene single nucleotide polymorphisms, smoking status, and bladder cancer susceptibility.
Abstract: For complex diseases, the relationship between genotypes, environment factors and phenotype is usually complex and nonlinear. Our understanding of the genetic architecture of diseases has considerably increased over the last years. However, both conceptually and methodologically, detecting gene-gene and gene-environment interactions remains a challenge, despite the existence of a number of efficient methods. One method that offers great promises but has not yet been widely applied to genomic data is the entropy-based approach of information theory. In this paper we first develop entropy-based test statistics to identify 2-way and higher order gene-gene and gene-environment interactions. We then apply these methods to a bladder cancer data set and thereby test their power and identify strengths and weaknesses. For two-way interactions, we propose an information-gain approach based on mutual information. For three-ways and higher order interactions, an interaction-information-gain approach is used. In both case we develop one-dimensional test statistics to analyze sparse data. Compared to the naive chi-square test, the test statistics we develop have similar or higher power and is robust. Applying it to the bladder cancer data set allowed to investigate the complex interactions between DNA repair gene SNPs, smoking status, and bladder cancer susceptibility. Although not yet widely applied, entropy-based approaches appear as a useful tool for detecting gene-gene and gene-environment interactions. The test statistics we develop add to a growing body methodologies that will gradually shed light on the complex architecture of common diseases.
51 citations
TL;DR: Exposures to secondhand smoke in adulthood, childhood, occupationally, and in total are each significantly associated with changes in DNA methylation of several CpG loci in bladder tumors, adding biological plausibility to SHS as a risk factor for bladder cancer.
Abstract: Background
The association between secondhand smoke (SHS) exposure and bladder cancer is inconclusive. Epigenetic alterations in bladder tumors have been linked to primary cigarette smoking and could add to the biological plausibility of an association between SHS exposure and bladder cancer.
41 citations
TL;DR: Estimates of arsenic concentrations in the water supplies of 2,611 participants in a population-based case–control study in northern New England found their estimated levels to be comparable with available measured concentrations.
Abstract: Background: Ingestion of inorganic arsenic in drinking water is recognized as a cause of bladder cancer when levels are relatively high (≥ 150 µg/L). The epidemiologic evidence is less clear at the low-to-moderate concentrations typically observed in the United States. Accurate retrospective exposure assessment over a long time period is a major challenge in conducting epidemiologic studies of environmental factors and diseases with long latency, such as cancer.
Objective: We estimated arsenic concentrations in the water supplies of 2,611 participants in a population-based case–control study in northern New England.
Methods: Estimates covered the lifetimes of most study participants and were based on a combination of arsenic measurements at the homes of the participants and statistical modeling of arsenic concentrations in the water supply of both past and current homes. We assigned a residential water supply arsenic concentration for 165,138 (95%) of the total 173,361 lifetime exposure years (EYs) and a workplace water supply arsenic level for 85,195 EYs (86% of reported occupational years).
Results: Three methods accounted for 93% of the residential estimates of arsenic concentration: direct measurement of water samples (27%; median, 0.3 µg/L; range, 0.1–11.5), statistical models of water utility measurement data (49%; median, 0.4 µg/L; range, 0.3–3.3), and statistical models of arsenic concentrations in wells using aquifers in New England (17%; median, 1.6 µg/L; range, 0.6–22.4).
Conclusions: We used a different validation procedure for each of the three methods, and found our estimated levels to be comparable with available measured concentrations. This methodology allowed us to calculate potential drinking water exposure over long periods.
33 citations
TL;DR: A framework in which to integrate these novel approaches, both empirical and theoretical, in the form of a genome‐wide regulatory network (GWRN) is proposed, by processing experimental data into networks, emerging data types based on chromatin immunoprecipitation are made computationally tractable.
Abstract: The conceptual foundation of the genome-wide association study (GWAS) has advanced unchecked since its conception. A revision might seem premature as the potential of GWAS has not been fully realized. Multiple technical and practical limitations need to be overcome before GWAS can be fairly criticized. But with the completion of hundreds of studies and a deeper understanding of the genetic architecture of disease, warnings are being raised. The results compiled to date indicate that risk-associated variants lie predominantly in noncoding regions of the genome. Additionally, alternative methodologies are uncovering large and heterogeneous sets of rare variants underlying disease. The fear is that, even in its fulfillment, the current GWAS paradigm might be incapable of dissecting all kinds of phenotypes. In the following text, we review several initiatives that aim to overcome these limitations. The overarching theme of these studies is the inclusion of biological knowledge to both the analysis and interpretation of genotyping data. GWAS is uninformed of biology by design and although there is some virtue in its simplicity, it is also its most conspicuous deficiency. We propose a framework in which to integrate these novel approaches, both empirical and theoretical, in the form of a genome-wide regulatory network (GWRN). By processing experimental data into networks, emerging data types based on chromatin immunoprecipitation are made computationally tractable. This will give GWAS re-analysis efforts the most current and relevant substrates, and root them firmly on our knowledge of human disease.
TL;DR: The present findings suggest that ALA may have a protective role against developing bladder cancer; however, further investigation and replication in other epidemiological studies are required.
Abstract: The role of dietary fat in bladder cancer aetiology is currently unclear due to few studies, equivocal findings and a lack of information on important dietary fatty acids. The aim of the present study was to investigate the association between the intake of major dietary fats and fatty acids and the risk of bladder cancer. A case‐control study was conducted in New Hampshire, USA. Dietary data were collected from 322 cases and 239 controls, and OR and 95 % CI were calculated using unconditional logistic regression. Adjustment was made for potential confounders: sex, age, smoking status, pack-years smoked, cholesterol and energy intake. Statistically significant reduced odds of bladder cancer were observed for high intakes (highest quartile v. lowest quartile) of a-linolenic acid (ALA) (OR 0·26, 95 % CI 0·10, 0·65; P for trend¼0·01) and vegetable fat (OR 0·39, 95 % CI 0·18, 0·86; P for trend¼0·03). Borderline statistically significant reduced odds were detected for polyunsaturated fat (OR 0·43, 95 % CI 0·19, 0·98; P for trend¼0·07) and linoleic acid (OR 0·43, 95 % CI 0·19, 0·96; P for trend¼0·06). These fats and fatty acids were highly correlated and following adjustment for each other, the only potential inverse association to remain was for ALA. The present findings suggest that ALA may have a protective role against developing bladder cancer; however, further investigation and replication in other epidemiological studies are required. Future research should focus on the type, source and quantities of different dietary fatty acids consumed.
QIMR Berghofer Medical Research Institute1, Dartmouth College2, York University3, University of Western Australia4, University of Southern California5, University of California, San Francisco6, University of Turin7, University of Sydney8, Franciscan Health9, King's College London10, The Hertz Corporation11, University of Glasgow12, University of New Mexico13
TL;DR: The working hypothesis was that head and neck melanomas have stronger associations with solar keratoses and weaker associations with sunburn than trunk melanomas, and reported sunburn is strongly associated with melanoma on all major body sites.
Abstract: A model has been proposed whereby melanomas arise through two distinct pathways dependent on the relative influence of host susceptibility and sun exposure. Such pathways may explain site-specific patterns of melanoma occurrence. To explore this model, we investigated the relationship between melanoma risk and general markers of acute (recalled sunburns) and chronic (prevalent solar keratoses) sun exposure, stratified by anatomic site and host phenotype. Our working hypothesis was that head and neck melanomas have stronger associations with solar keratoses and weaker associations with sunburn than trunk melanomas. We conducted a collaborative analysis using original data from women subjects of 11 case-control studies of melanoma (2,575 cases, 3,241 controls). We adjusted for potential confounding effects of sunlamp use and sunbathing. The magnitude of sunburn associations did not differ significantly by melanoma site, nevus count or histologic subtype of melanoma. Across all sites, relative risk of melanoma increased with an increasing number of reported lifetime "painful" sunburns, lifetime "severe" sunburns and "severe" sunburns in youth (p(trend) < 0.001), with pooled odds ratios (pORs) for the highest category of sunburns versus no sunburns of 3.22 [95% confidence interval (CI) 2.04-5.09] for lifetime "painful" sunburns, 2.10 (95%CI 1.30-3.38) for lifetime "severe" sunburns and 2.43 (95%CI 1.61-3.65) for "severe" sunburns in youth. Solar keratoses strongly increased the risk of head and neck melanoma (pOR 4.91, 95%CI 2.10-11.46), but data were insufficient to assess risk for other sites. Reported sunburn is strongly associated with melanoma on all major body sites.
TL;DR: The data indicate that a common viral illness may drive specific DNA methylation patterns in susceptible B-precursor cells, contributing to the leukemogenic potential of such cells.
Abstract: Acute lymphoblastic leukemia (ALL) likely has a multistep etiology, with initial genetic aberrations occurring early in life. An abnormal immune response to common infections has emerged as a plausible candidate for triggering the proliferation of pre-leukemic clones and the fixation of secondary genetic mutations and epigenetic alterations. We investigated whether evidence of infection with a specific common myelotropic childhood virus, parvovirus B19 (PVB19), relates to patterns of gene promoter DNA methylation in ALL patients. We serologically tested bone marrow samples at diagnosis of B-cell ALL for PVB19 infection and DNA methylation using a high-throughput bead array and found that 4.2% and 36.7% of samples were seroreactive to PVB19 IgM and IgG, respectively. Leukemia samples were grouped by DNA methylation pattern. Controlling for age and immunophenotype, unsupervised modeling confirmed that the DNA methylation pattern was associated with history of PVB19 (assessed by IgG, p = 0.02), but not recent infection (assessed by IgM). Replication assays on single genes were consistent with the association. The data indicate that a common viral illness may drive specific DNA methylation patterns in susceptible B-precursor cells, contributing to the leukemogenic potential of such cells. Infections may impact childhood leukemia by altering DNA methylation patterns and specific key genes in susceptible cells; these changes may be retained even after the clearance of infection.
TL;DR: The results indicate that controlling allergy and IgE levels may be a new avenue of skin cancer prevention in susceptible populations, and implicate immune mechanisms in skin carcinogenesis.
Abstract: Background: Individuals diagnosed with non-melanoma skin cancer have a high risk of developing a second skin cancer diagnosis. We assessed whether a marker of immune function related to atopic allergy, IgE, was associated with diagnosis of subsequent squamous cell carcinoma (SCC) of the skin in patients with a previous skin cancer enrolled in a skin cancer prevention trial. Methods: One hundred twelve cases with a repeat skin cancer diagnosis were compared to 227 controls, matched on age, sex, and study center. Total, respiratory, and food-specific IgE were measured in the baseline or year one (prior to diagnosis) sera samples for each subject. Results: IgE levels were higher in cases with a second SCC than controls (comparing the highest quartile to the lowest, ORtotal IgE=1.44; 95% CI:0.73-2.85; ORrespiratory IgE =2.43; 95% CI:1.16-5.06; ORfood IgE =2.53; 95%CI:1.19-5.35). The association between respiratory IgE and subsequent skin cancer was strongest among individuals with a tendency to sunburn (ORrespiratory IgE =3.82; 95%CI: 1.05-13.88) compared with those with a tendency to tan (ORrespiratory IgE = 0.95; 95%CI:0.20-4.76). Among 25 subjects with repeat IgE measurements taken over several years, IgE levels were remarkably stable (interclass coefficient = 0.90 for total IgE). Conclusions: These results indicate that allergy or allergy-associated IgE may be indicative of an immune phenotype that enhances risk of SCC, possibly via immune-associate inflammatory mediators. Impact: Our results indicate that controlling allergy and IgE levels may be a new avenue of skin cancer prevention in susceptible populations, and implicate immune mechanisms in skin carcinogenesis.
13 Sep 2011
TL;DR: This data indicates that in addition to drinking water contamination, rice consumption may lead to substantial inorganic arsenic exposure (As) and here, urinary arsenic exposure is reported.
Abstract: Background and Aims: Emerging data indicate that in addition to drinking water contamination, rice consumption may lead to substantial inorganic arsenic exposure (As). Here, we report urinary arsen...
TL;DR: Patients whose tumors harbored mutant IDH had significantly improved survival and this association remained significant when controlling for patient age and tumor histology (likelihood ratio P); and in younger patients (P = .0009).
Abstract: Although much is known about molecular and chromosomal characteristics that distinguish glioma histologic subtypes, DNA methylation patterns of gliomas and their association with mutation of isocitrate dehydrogenase (IDH) genes has only recently begun to be investigated. We measured DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at UCSF, as well as non-tumor brain tissues (n = 7), with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Next, differential DNA methylation between tumor and non-tumor was assessed. RPMM was again used to model methylation data for tumors with IDH mutation data (n = 95). Associations between IDH mutation and survival were also examined. Among all gliomas (n = 131), RPMM resulted in eleven methylation classes, and there was a statistically significant association between methylation class and glioma histologic subtype (P −16 ). Comparing non-tumor brain tissues to gliomas to investigate differential methylation, glioblastomas showed a low ratio of hyper- to hypomethylated loci (ratio = 1.3) compared with the ratio for astrocytomas, oligoastrocytomas, and oligodendrogliomas (ratios = 3.7, 7.6, and 9.7, respectively). Ependymomas had increased hypomethylation (ratio = 0.3). These ratios were significantly different across glioma subtypes (Permutation P −9 ); in lower-grade tumors (P = .01); in tumors with TP53 mutation (P = .06); and in younger patients (P = .0009). In addition, patients whose tumors harbored mutant IDH had significantly improved survival (HR = 0.27, 95% CI = 0.10 to 0.72). In tumors with available IDH mutation data, RPMM resulted in nine methylation classes, methylation class was significantly associated with IDH mutation (P = 3.0 × 10 −16 ), and this association remained significant when controlling for patient age and tumor histology (likelihood ratio P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 878. doi:10.1158/1538-7445.AM2011-878