Publications by authors named "Farzana Jasmine"

67 Publications

Interaction between Microsatellite Instability (MSI) and Tumor DNA Methylation in the Pathogenesis of Colorectal Carcinoma.

Cancers (Basel) 2021 Oct 1;13(19). Epub 2021 Oct 1.

Institute for Population and Precision Health, Department of Public Health Sciences, Biological Sciences Division, The University of Chicago, Chicago, IL 60637, USA.

In colorectal cancer (CRC), the role of microsatellite instability (MSI) is well known. In a genome-wide scale, for the first time, we explored whether differential methylation is associated with MSI. We analyzed 250 paired samples from 125 CRC patients (m = 72, f = 53) at different stages. Of them, 101 had left-sided CRC, 30 had MSI, 34 had somatic mutation in KRAS proto-oncogene (), and 6 had B-Raf proto-oncogene () exon 15p.V600E mutation. MSI was more frequent in right-sided tumors (54% vs. 17%, = 0.003). Among the microsatellite stable (MSS) CRC, a paired comparison revealed 1641 differentially methylated loci (DML) covering 686 genes at FDR 0.001 with delta beta ≥ 20%. Similar analysis in MSI revealed 6209 DML covering 2316 genes. ANOVA model including interaction (Tumor*MSI) revealed 23,322 loci, where the delta beta was different among MSI and MSS patients. Our study shows an association between MSI and tumor DNA methylation in the pathogenesis of CRC. Given the interaction seen in this study, it may be worth considering the MSI status while looking for methylation markers in CRC. The study also indicates an opportunity for potential use of certain immune checkpoint inhibitors ( and inhibitors) in CRC with MSI.
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http://dx.doi.org/10.3390/cancers13194956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508563PMC
October 2021

Urinary arsenic and relative telomere length in 5-7 year old children in Bangladesh.

Environ Int 2021 11 15;156:106765. Epub 2021 Jul 15.

Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, Chicago, IL 60612, United States.

Background: Telomere length has been associated with the occurrence and progression of common chronic and age-related diseases, and in younger populations, may represent a biomarker of disease susceptibility. Early childhood is a critical period for telomere biology as this period is characterized by a rapid decline in telomere length due to a large turnover of highly proliferative cells and may represent a period of unique sensitivity to environmental insults. Arsenic (As) exposure has been associated with both telomere lengthening and shortening in adults and children and some evidence suggests the effects may differ by level and timing of exposure.

Objectives: Given the lack of clarity across studies, we investigated the association between urinary As and leukocyte telomere length among 476 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort.

Methods: In a series of multivariable models, adjusted for key covariates, we examined associations between urinary As and relative telomere length (RTL) of whole blood DNA.

Results: We observed small but consistent, negative associations between urinary As and RTL, such that a doubling of urinary As was associated with a -0.017 (95% CI: -0.030, -0.005; p = 0.0056) decrease in RTL, in fully adjusted models. We also observed a somewhat stronger inverse relationship between urinary As concentration and RTL among children born to fathers ≥ 30 years of age at the time of birth, than those < 30 years; however, we did not observe a statistically significant interaction.

Discussion: Our study suggests that As influences RTL, with detectable associations in early to mid-childhood. Further studies are needed to confirm our findings and investigate the potential long-term impacts of telomere shortening in childhood on later life health outcomes. Additional studies exploring how dose and timing of exposure may relate to RTL are critical to understanding As's relationship to telomere length.
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http://dx.doi.org/10.1016/j.envint.2021.106765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380695PMC
November 2021

Epidemiology of soil transmitted helminths and risk analysis of hookworm infections in the community: Results from the DeWorm3 Trial in southern India.

PLoS Negl Trop Dis 2021 04 30;15(4):e0009338. Epub 2021 Apr 30.

The DeWorm3 Project, University of Washington, Seattle, Washington, United States of America.

Since 2015, India has coordinated the largest school-based deworming program globally, targeting soil-transmitted helminths (STH) in ~250 million children aged 1 to 19 years twice yearly. Despite substantial progress in reduction of morbidity associated with STH, reinfection rates in endemic communities remain high. We conducted a community based parasitological survey in Tamil Nadu as part of the DeWorm3 Project-a cluster-randomised trial evaluating the feasibility of interrupting STH transmission at three geographically distinct sites in Africa and Asia-allowing the estimation of STH prevalence and analysis of associated factors. In India, following a comprehensive census, enumerating 140,932 individuals in 36,536 households along with geospatial mapping of households, an age-stratified sample of individuals was recruited into a longitudinal monitoring cohort (December 2017-February 2018) to be followed for five years. At enrolment, a total of 6089 consenting individuals across 40 study clusters provided a single adequate stool sample for analysis using the Kato-Katz method, as well as answering a questionnaire covering individual and household level factors. The unweighted STH prevalence was 17.0% (95% confidence interval [95%CI]: 16.0-17.9%), increasing to 21.4% when weighted by age and cluster size. Hookworm was the predominant species, with a weighted infection prevalence of 21.0%, the majority of which (92.9%) were light intensity infections. Factors associated with hookworm infection were modelled using mixed-effects multilevel logistic regression for presence of infection and mixed-effects negative binomial regression for intensity. The prevalence of both Ascaris lumbricoides and Trichuris trichiura infections were rare (<1%) and risk factors were therefore not assessed. Increasing age (multivariable odds ratio [mOR] 21.4, 95%CI: 12.3-37.2, p<0.001 for adult age-groups versus pre-school children) and higher vegetation were associated with an increased odds of hookworm infection, whereas recent deworming (mOR 0.3, 95%CI: 0.2-0.5, p<0.001) and belonging to households with higher socioeconomic status (mOR 0.3, 95%CI: 0.2-0.5, p<0.001) and higher education level of the household head (mOR 0.4, 95%CI: 0.3-0.6, p<0.001) were associated with lower odds of hookworm infection in the multilevel model. The same factors were associated with intensity of infection, with the use of improved sanitation facilities also correlated to lower infection intensities (multivariable infection intensity ratio [mIIR] 0.6, 95%CI: 0.4-0.9, p<0.016). Our findings suggest that a community-based approach is required to address the high hookworm burden in adults in this setting. Socioeconomic, education and sanitation improvements alongside mass drug administration would likely accelerate the drive to elimination in these communities. Trial Registration: NCT03014167.
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http://dx.doi.org/10.1371/journal.pntd.0009338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184002PMC
April 2021

Rare, Protein-Altering Variants in and Arsenic Metabolism Efficiency: A Multi-Population Association Study.

Environ Health Perspect 2021 04 7;129(4):47007. Epub 2021 Apr 7.

Department of Public Health Sciences, University of Chicago (UChicago), Chicago, Illinois, USA.

Background: Common genetic variation in the arsenic methyltransferase () gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in could have even larger effects on AME, but their contribution to AME has not been investigated.

Objectives: We estimated the impact of rare, protein-coding variation in on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants.

Methods: We generated targeted DNA sequencing data for the coding regions of for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, ), Strong Heart Study (SHS, ), and New Hampshire Skin Cancer Study (NHSCS, ). We assessed the collective effects of rare (allele frequency ), protein-altering variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure).

Results: We identified 23 carriers of rare-protein-altering variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6-10% lower in carriers compared with noncarriers in HEALS [ (95% CI: , )], SHS [ (95% CI: , )], and NHSCS [ (95% CI: , )]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ (95% CI: , )].

Discussion: Rare, protein-altering variants in were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5-0.7%) carry these variants, they are associated with a 6-10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152.
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http://dx.doi.org/10.1289/EHP8152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041273PMC
April 2021

Exposure to metal mixtures in relation to blood pressure among children 5-7 years old: An observational study in Bangladesh.

Environ Epidemiol 2021 Apr 11;5(2):e135. Epub 2021 Feb 11.

Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois Chicago, Chicago, Illinois.

Hypertension in later life, a significant risk factor for cardiovascular disease, has been linked to elevated blood pressure in early life. Exposure to metals may influence childhood blood pressure; however, previous research is limited and has mainly focused on evaluating the toxicity of single metal exposures. This study evaluates the associations between exposure to metal mixtures and blood pressure among Bangladeshi children age 5-7 years.

Methods: We investigated the associations of 17 toenail metal concentrations with blood pressure using linear regression models. Principal component analysis (PCA), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were conducted as secondary analyses.

Results: Associations were observed for selenium with diastolic blood pressure (per doubling of exposure β = 2.91, 95% confidence interval [CI] = 1.08, 4.75), molybdenum with systolic (β = 0.33, 95% CI = 0.05, 0.61) and diastolic blood pressure (β = 0.39, 95% CI = 0.12, 0.66), tin with systolic blood pressure (β = -0.33, 95% CI = -0.60, -0.06), and mercury with systolic (β = -0.83, 95% CI = -1.49, -0.17) and diastolic blood pressure (β = -0.89, 95% CI = -1.53, -0.26). Chromium was associated with diastolic blood pressure among boys only (β = 1.10, 95% CI = 0.28, 1.92, for interaction = 0.02), and copper was associated with diastolic blood pressure among girls only (β = -1.97, 95% CI = -3.63, -0.32, for interaction = 0.01). These findings were largely robust to the secondary analyses that utilized mixture modeling approaches (PCA, WQS, and BKMR).

Conclusions: Future prospective studies are needed to investigate further the impact of early life exposure to metal mixtures on children's blood pressure trajectories and cardiovascular disease risk later in life.
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http://dx.doi.org/10.1097/EE9.0000000000000135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939402PMC
April 2021

Cohort profile: the ChicagO Multiethnic Prevention and Surveillance Study (COMPASS).

BMJ Open 2020 09 16;10(9):e038481. Epub 2020 Sep 16.

Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, USA.

Purpose: The ChicagO Multiethnic Prevention and Surveillance Study or 'COMPASS' is a population-based cohort study with a goal to examine the risk and determinants of cancer and chronic disease. COMPASS aims to address factors causing and/or exacerbating health disparities using a precision health approach by recruiting diverse participants in Chicago, with an emphasis on those historically underrepresented in biomedical research.

Participants: Nearly 8000 participants have been recruited from 72 of the 77 Chicago community areas. Enrolment entails the completion of a 1-hour long survey, consenting for past and future medical records from all sources, the collection of clinical and physical measurement data and the on-site collection of biological samples including blood, urine and saliva. Indoor air monitoring data and stool samples are being collected from a subset of participants. On collection, all biological samples are processed and aliquoted within 24 hours before long-term storage and subsequent analysis.

Findings To Date: The cohort reported an average age of 53.7 years, while 80.5% identified as African-American, 5.7% as Hispanic and 47.8% as men. Over 50% reported earning less than US$15 000 yearly, 35% were obese and 47.8% were current smokers. Moreover, 38% self-reported having had a diagnosis of hypertension, while 66.4% were measured as hypertensive at enrolment.

Future Plans: We plan to expand recruitment up to 100 000 participants from the Chicago metropolitan area in the next decade using a hybrid community and clinic-based recruitment framework that incorporates data collection through mobile medical units. Follow-up data collection from current cohort members will include serial samples, as well as longitudinal health, lifestyle and behavioural assessment. We will supplement self-reported data with electronic medical records, expand the collection of biometrics and biosamples to facilitate increasing digital epidemiological study designs and link to state and/or national level databases to ascertain outcomes. The results and findings will inform potential opportunities for precision disease prevention and mitigation in Chicago and other urban areas with a diverse population.

Registration: NA.
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http://dx.doi.org/10.1136/bmjopen-2020-038481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497521PMC
September 2020

Determinants of telomere length across human tissues.

Science 2020 09;369(6509)

Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.
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http://dx.doi.org/10.1126/science.aaz6876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108546PMC
September 2020

Development and application of an electronic treatment register: a system for enumerating populations and monitoring treatment during mass drug administration.

Glob Health Action 2020 12;13(1):1785146

DeWorm3, Division of Life Sciences, Natural History Museum , London, UK.

We developed an electronic treatment register for the DeWorm3 Project, a cluster-randomised, controlled trial in Benin, India, and Malawi testing the feasibility of interrupting transmission of soil-transmitted helminths through community-wide mass drug administration. The electronic treatment register was designed in xlsform, deployed via the SurveyCTO mobile data collection platform, and implemented on smartphones running the Android operating system. The versatile system enables collection of census and treatment status information, facilitates data aggregation and visualisation, and permits real-time feedback loops during implementation of mass drug administration. Here we describe the system's design and use within the DeWorm3 Project and key features, and by sharing the register here, we hope our readers will further explore its use within their research and disease-control activities.
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http://dx.doi.org/10.1080/16549716.2020.1785146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480461PMC
December 2020

Assessing the impact of arsenic metabolism efficiency on DNA methylation using Mendelian randomization.

Environ Epidemiol 2020 Apr 9;4(2):e083. Epub 2020 Apr 9.

Department of Public Health Sciences, The University of Chicago, Chicago, Illinois.

Background: Arsenic exposure affects >100 million people globally and increases risk for chronic diseases. One possible toxicity mechanism is epigenetic modification. Previous epigenome-wide association studies (EWAS) have identified associations between arsenic exposure and CpG-specific DNA methylation. To provide additional evidence that observed associations represent causal relationships, we examine the association between genetic determinants of arsenic metabolism efficiency (percent dimethylarsinic acid, DMA%, in urine) and DNA methylation among individuals from the Health Effects of Arsenic Longitudinal Study (n = 379) and Bangladesh Vitamin E and Selenium Trial (n = 393).

Methods: We used multivariate linear models to assess the association of methylation at 221 arsenic-associated CpGs with DMA% and measures of genetically predicted DMA% derived from three SNPs (rs9527, rs11191527, and rs61735836). We also conducted two-sample Mendelian randomization analyses to estimate the association between arsenic metabolism efficiency and CpG methylation.

Results: Among the associations between DMA% and methylation at each of 221 CpGs, 64% were directionally consistent with associations observed between arsenic exposure and the 221 CpGs from a prior EWAS. Similarly, among the associations between genetically predicted DMA% and each CpG, 62% were directionally consistent with the prior EWAS results. Two-sample Mendelian randomization analyses produced similar conclusions.

Conclusion: Our findings support the hypothesis that arsenic exposure effects DNA methylation at specific CpGs in whole blood. Our novel approach for assessing the impact of arsenic exposure on DNA methylation requires larger samples in order to draw more robust conclusions for specific CpG sites.
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http://dx.doi.org/10.1097/EE9.0000000000000083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147391PMC
April 2020

The Association Between Smoking and Gut Microbiome in Bangladesh.

Nicotine Tob Res 2020 07;22(8):1339-1346

Department of Population Health, New York University School of Medicine, New York, NY.

Introduction: Epidemiological studies that investigate alterations in the gut microbial composition associated with smoking are lacking. This study examined the composition of the gut microbiome in smokers compared with nonsmokers.

Aims And Methods: Stool samples were collected in a cross-sectional study of 249 participants selected from the Health Effects of Arsenic Longitudinal Study in Bangladesh. Microbial DNA was extracted from the fecal samples and sequenced by 16S rRNA gene sequencing. The associations of smoking status and intensity of smoking with the relative abundance or the absence and presence of individual bacterial taxon from phylum to genus levels were examined.

Results: The relative abundance of bacterial taxa along the Erysipelotrichi-to-Catenibacterium lineage was significantly higher in current smokers compared to never-smokers. The odds ratio comparing the mean relative abundance in current smokers with that in never-smokers was 1.91 (95% confidence interval = 1.36-2.69) for the genus Catenibacterium and 1.89 (95% confidence interval = 1.39-2.56) for the family Erysipelotrichaceae, the order Erysipelotrichale, and the class Erysipelotrichi (false discovery rate-adjusted p values = .0008-.01). A dose-response association was observed for each of these bacterial taxa. The presence of Alphaproteobacteria was significantly greater comparing current with never-smokers (odds ratio = 4.85, false discovery rate-adjusted p values = .04).

Conclusions: Our data in a Bangladeshi population are consistent with evidence of an association between smoking status and dosage with change in the gut bacterial composition.

Implications: This study for the first time examined the relationship between smoking and the gut microbiome composition. The data suggest that smoking status may play an important role in the composition of the gut microbiome, especially among individuals with higher levels of tobacco exposure.
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http://dx.doi.org/10.1093/ntr/ntz220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364824PMC
July 2020

The effect of age on DNA methylation in whole blood among Bangladeshi men and women.

BMC Genomics 2019 Sep 10;20(1):704. Epub 2019 Sep 10.

Department of Public Health Sciences, University of Chicago, 5841 S. Maryland Ave., W264, MC2000, Chicago, IL, 60637, USA.

Background: It is well-known that methylation changes occur as humans age, however, understanding how age-related changes in DNA methylation vary by sex is lacking. In this study, we characterize the effect of age on DNA methylation in a sex-specific manner and determine if these effects vary by genomic context. We used the Illumina HumanMethylation 450 K array and DNA derived from whole blood for 400 adult participants (189 males and 211 females) from Bangladesh to identify age-associated CpG sites and regions and characterize the location of these age-associated sites with respect to CpG islands (vs. shore, shelf, or open sea) and gene regions (vs. intergenic). We conducted a genome-wide search for age-associated CpG sites (among 423,604 sites) using a reference-free approach to adjust for cell type composition (the R package RefFreeEWAS) and performed an independent replication analysis of age-associated CpGs.

Results: The number of age-associated CpGs (p < 5 x 10) were 986 among men and 3479 among women of which 2027(63.8%) and 572 (64.1%) replicated (using Bonferroni adjusted p < 1.2 × 10). For both sexes, age-associated CpG sites were more likely to be hyper-methylated with increasing age (compared to hypo-methylated) and were enriched in CpG islands and promoter regions compared with other locations and all CpGs on the array. Although we observed strong correlation between chronological age and previously-developed epigenetic age models (r ≈ 0.8), among our top (based on lowest p-value) age-associated CpG sites only 12 for males and 44 for females are included in these prediction models, and the median chronological age compared to predicted age was 44 vs. 51.7 in males and 45 vs. 52.1 in females.

Conclusions: Our results describe genome-wide features of age-related changes in DNA methylation. The observed associations between age and methylation were generally consistent for both sexes, although the associations tended to be stronger among women. Our population may have unique age-related methylation changes that are not captured in the established methylation-based age prediction model we used, which was developed to be non-tissue-specific.
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http://dx.doi.org/10.1186/s12864-019-6039-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734473PMC
September 2019

Lack of Association between Opioid-Receptor Genotypes and Smoking Cessation Outcomes in a Randomized, Controlled Naltrexone Trial.

Alcohol Alcohol 2019 Jan;54(5):559-565

Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, IL 60637, USA.

Aims: The present study examined how variation in mu- (OPRM1), kappa- (OPRK), and delta- (OPRD) opioid receptor genes may influence the efficacy of naltrexone in the context of a smoking cessation trial.

Methods: The study's primary objective was to examine the association of the Asn40Asp OPRM1 single nucleotide polymorphism (SNP) with naltrexone's effects on smoking quit rate, weight gain, and heavy drinking behavior during a double-blind, randomized clinical trial in 280 adult DSM-IV nicotine-dependent participants. The secondary goal of the study was to examine the relationship of 20 additional SNPs of OPRM1, OPRK, and OPRD with the aforementioned outcomes.

Results: Results indicated a null association between any opioid-receptor gene SNP and naltrexone's effects on smoking quit rate, weight gain, and heavy drinking behavior in this sample of nicotine dependent participants.

Conclusions: In sum, these results do not suggest that genetic variation in opioid-receptors is related to treatment responses to naltrexone in a smoking cessation trial.
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http://dx.doi.org/10.1093/alcalc/agz046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963143PMC
January 2019

The association between gut microbiome and anthropometric measurements in Bangladesh.

Gut Microbes 2020 29;11(1):63-76. Epub 2019 May 29.

Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, USA.

Our objective was to investigate the relationship between the gut microbiota and anthropometric measurements among 248 participants from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Our cohort represents a unique population that allows for the investigation of the gut microbiota and anthropometric measurements in lean individuals. We measured height, weight, arm, thigh, hip, and waist circumferences, and collected fecal samples. Microbial DNA was extracted from the stool samples and sequenced by 16S rRNA gene sequencing. We examined associations between relative abundance of individual bacterial taxa from phylum to genus levels and anthropometric measurements. We found that higher BMI, mid-upper arm circumference, waist circumference, and waist-to-hip ratio were associated with a lower alpha diversity of fecal bacteria. Relative abundance of the genus and the family were inversely related to all measurements after correction for multiple testing. Relative abundance of genus and family were also associated with several measurements. The positive associations of the genus with BMI, as well as waist and hip circumferences, were stronger in women than in men. Our data in this lean Bangladeshi population found a correlation between and leanness, as measured using multiple anthropometric measures.
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http://dx.doi.org/10.1080/19490976.2019.1614394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973329PMC
June 2020

Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults.

Environ Health Perspect 2019 05 28;127(5):57011. Epub 2019 May 28.

Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.

Background: Arsenic exposure affects [Formula: see text] people worldwide, including [Formula: see text] in Bangladesh. Arsenic exposure increases the risk of cancer and other chronic diseases, and one potential mechanism of arsenic toxicity is epigenetic dysregulation.

Objective: We assessed associations between arsenic exposure and genome-wide DNA methylation measured at baseline among 396 Bangladeshi adults participating in the Health Effects of Arsenic Longitudinal Study (HEALS) who were exposed by drinking naturally contaminated well water.

Methods: Methylation in whole blood DNA was measured at [Formula: see text] using the Illumina InfiniumMethylationEPIC (EPIC) array. To assess associations between arsenic exposure and CpG methylation, we used linear regression models adjusted for covariates and surrogate variables (SVs) (capturing unknown technical and biologic factors). We attempted replication and conducted a meta-analysis using an independent dataset of [Formula: see text] from 400 Bangladeshi individuals with arsenical skin lesions.

Results: We identified 34 CpGs associated with [Formula: see text] creatinine-adjusted urinary arsenic [[Formula: see text]]. Sixteen of these CpGs annotated to the [Formula: see text] array, and 10 associations were replicated ([Formula: see text]). The top two CpGs annotated upstream of the ABR gene (cg01912040, cg10003262 ). All urinary arsenic-associated CpGs were also associated with arsenic concentration measured in drinking water ([Formula: see text]). Meta-analysis ([Formula: see text] samples) identified 221 urinary arsenic-associated CpGs ([Formula: see text]). The arsenic-associated CpGs from the meta-analysis were enriched in non-CpG islands and shores ([Formula: see text]) and depleted in promoter regions ([Formula: see text]). Among the arsenic-associated CpGs ([Formula: see text]), we observed significant enrichment of genes annotating to the reactive oxygen species pathway, inflammatory response, and tumor necrosis factor [Formula: see text] ([Formula: see text]) signaling via nuclear factor kappa-B ([Formula: see text]) hallmarks ([Formula: see text]).

Conclusions: The novel and replicable associations between arsenic exposure and DNA methylation at specific CpGs observed in this work suggest that epigenetic alterations should be further investigated as potential mediators in arsenic toxicity and as biomarkers of exposure and effect in exposed populations. https://doi.org/10.1289/EHP3849.
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http://dx.doi.org/10.1289/EHP3849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791539PMC
May 2019

A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

PLoS Genet 2019 03 20;15(3):e1007984. Epub 2019 Mar 20.

Department of Public Health Sciences, The University of Chicago, Chicago, IL, United States of America.

Inorganic arsenic (iAs) is a carcinogen, and exposure to iAs via food and water is a global public health problem. iAs-contaminated drinking water alone affects >100 million people worldwide, including ~50 million in Bangladesh. Once absorbed into the blood stream, most iAs is converted to mono-methylated (MMA) and then di-methylated (DMA) forms, facilitating excretion in urine. Arsenic metabolism efficiency varies among individuals, in part due to genetic variation near AS3MT (arsenite methyltransferase; 10q24.32). To identify additional arsenic metabolism loci, we measured protein-coding variants across the human exome for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS). Among the 19,992 coding variants analyzed exome-wide, the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD (formiminotransferase cyclodeaminase) was associated with increased urinary iAs% (P = 8x10-13), increased MMA% (P = 2x10-16) and decreased DMA% (P = 6x10-23). Among 2,401 individuals with arsenic-induced skin lesions (an indicator of arsenic toxicity and cancer risk) and 2,472 controls, carrying the low-efficiency A allele (frequency = 7%) was associated with increased skin lesion risk (odds ratio = 1.35; P = 1x10-5). rs61735836 is in weak linkage disequilibrium with all nearby variants. The high-efficiency/major allele (G/Valine) is human-specific and eliminates a start codon at the first 5´-proximal Kozak sequence in FTCD, suggesting selection against an alternative translation start site. FTCD is critical for catabolism of histidine, a process that generates one-carbon units that can enter the one-carbon/folate cycle, which provides methyl groups for arsenic metabolism. In our study population, FTCD and AS3MT SNPs together explain ~10% of the variation in DMA% and support a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e., skin lesions). In summary, this work identifies a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence supporting the established link between one-carbon/folate metabolism and arsenic toxicity.
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http://dx.doi.org/10.1371/journal.pgen.1007984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443193PMC
March 2019

IBD-associated Colon Cancers Differ in DNA Methylation and Gene Expression Profiles Compared With Sporadic Colon Cancers.

J Crohns Colitis 2019 Jul;13(7):884-893

University of Chicago, Department of Public Health Sciences.

Background And Aims: As ulcerative colitis [UC]-associated colorectal cancer [CRC] and sporadic CRC differ in presentation and molecular features, we sought to evaluate differences in the impact of DNA methylation on gene expression.

Methods: DNA methylation was assessed in 11 UC-CRCs and adjacent tissue and 11 sporadic CRCs and adjacent tissue, using Illumina arrays. RNA sequencing was performed on 10 UC-CRCs and adjacent tissue and eight sporadic CRCs and adjacent tissues. Differences in DNA methylation and transcript expression, as well as their correlation in the same tissues, were assessed. Immunohistochemistry was performed for three proteins, ANPEP, FAM92A1, and STK31, all of which exhibited an inverse correlation between DNA methylation and transcript expression in UC.

Results: Thirty three loci demonstrated differences in DNA methylation between UC-CRC and adjacent tissue. In contrast, there were 4204 differentially methylated loci between sporadic colon cancer and adjacent tissue. Eight hundred eighty six genes as well as 10 long non-coding RNAs [lncRNA] were differentially expressed between UC-CRC and adjacent tissues. Although there were no differentially methylated loci between UC and sporadic CRC, 997 genes and 38 lncRNAs were differentially expressed between UC-CRC and sporadic CRC. In UC, 18 genes demonstrated a negative correlation between DNA methylation and transcript expression. Evaluation of protein expression related to three genes, ANPEP, FAM92A1, and STK31, confirmed down-regulation of ANPEP and up-regulation of STK31 in UC-CRC.

Conclusions: Regulation of transcript expression by DNA methylation involves genes key to colon carcinogenesis and may account for differences in presentation and outcomes between inflammatory bowel disease and sporadic colon cancer.
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http://dx.doi.org/10.1093/ecco-jcc/jjz014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327274PMC
July 2019

The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans.

Hum Genet 2019 Jan 10;138(1):49-60. Epub 2018 Dec 10.

Department of Public Health Sciences, University of Chicago, Chicago, IL, 60615, USA.

Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., "direct" inheritance). Prior studies of LTL h have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5069 Bangladeshi adults with substantial relatedness. For each of the 6318 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (T). We then estimated the association between T and the squared pairwise difference in LTL ((ΔLTL)) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (ϕ). The association between T and (ΔLTL) was inverse among all relative pair types. In a meta-analysis including all relative pairs (ϕ > 0.05), the association between T and (ΔLTL) (P = 0.01) was stronger than the association between ϕ and (ΔLTL) (P = 0.43). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h despite telomere "reprogramming" during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h attributable to direct transmission of telomeres.
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http://dx.doi.org/10.1007/s00439-018-1964-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616344PMC
January 2019

The role of gut microbiome and its interaction with arsenic exposure in carotid intima-media thickness in a Bangladesh population.

Environ Int 2019 02 29;123:104-113. Epub 2018 Nov 29.

Department of Population Health, New York University School of Medicine, New York, NY, USA; Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA. Electronic address:

Background: Emerging data suggest that inorganic arsenic exposure and gut microbiome are associated with the risk of cardiovascular disease. The gut microbiome may modify disease risk associated with arsenic exposure. Our aim was to examine the inter-relationships between arsenic exposure, the gut microbiome, and carotid intima-media thickness (IMT)-a surrogate marker for atherosclerosis.

Methods: We recruited 250 participants from the Health Effects of Arsenic Longitudinal Study in Bangladesh, measured IMT and collected fecal samples in year 2015-2016. 16S rRNA gene sequencing was conducted on microbial DNA extracted from the fecal samples. Arsenic exposure was measured using data on arsenic concentration in drinking water wells over time to derive a time-weighted water arsenic index. Multivariable linear regression models were used to test the inter-relationships between arsenic exposure, relative abundance of selected bacterial taxa from phylum to genus levels, and IMT.

Results: We identified nominally significant associations between arsenic exposure, measured using either time-weighted water arsenic or urinary arsenic, and the relative abundances of several bacterial taxa from the phylum Tenericutes, Proteobacteria, and Firmicutes. However, none of the associations retained significance after correction for multiple testing. The relative abundances of the family Aeromonadaceae and genus Citrobacter were significantly associated with IMT after correction for multiple testing (P-value = 0.02 and 0.03, respectively). Every 1% increase in the relative abundance of Aeromonadaceae and Citrobacter was related to an 18.2-μm (95% CI: 7.8, 28.5) and 97.3-μm (95% CI: 42.3, 152.3) difference in IMT, respectively. These two taxa were also the only selected family and genus using the LASSO variable selection method. There was a significant interaction between Citrobacter and time-weighted water arsenic in IMT (P for interaction = 0.04).

Conclusions: Our findings suggest a role of Citrobacter in the development of atherosclerosis, especially among individuals with higher levels of arsenic exposure.
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http://dx.doi.org/10.1016/j.envint.2018.11.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371773PMC
February 2019

Germline Variation and Breast Cancer Incidence: A Gene-Based Association Study and Whole-Genome Prediction of Early-Onset Breast Cancer.

Cancer Epidemiol Biomarkers Prev 2018 09 13;27(9):1057-1064. Epub 2018 Jun 13.

Department of Public Health Sciences, University of Chicago, Chicago, Illinois.

Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established. To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset. Three gene regions were associated with breast cancer incidence: ( = 1.23 × 10; replication < 1.00 × 10), ( = 3.57 × 10; replication < 1.00 × 10), and ( = 5.49 × 10; replication < 1.00 × 10). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association ( < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614-0.659 compared with 0.601; 95% CI, 0.578-0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640-0.684). This research supports a role for variation within and in breast cancer incidence, and suggests as a novel risk locus. This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-1185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125194PMC
September 2018

A study of telomere length, arsenic exposure, and arsenic toxicity in a Bangladeshi cohort.

Environ Res 2018 07 20;164:346-355. Epub 2018 Mar 20.

Department of Public Health Sciences, University of Chicago, Chicago, IL 60615, United States; Department of Human Genetics, University of Chicago, Chicago, IL 60615, United States; Comprehensive Cancer Center, University of Chicago, Chicago, IL 60615, United States. Electronic address:

Background: Chronic arsenic exposure is associated with increased risk for arsenical skin lesions, cancer, and other adverse health outcomes. One potential mechanism of arsenic toxicity is telomere dysfunction. However, prior epidemiological studies of arsenic exposure, telomere length (TL), and skin lesion are small and cross-sectional. We investigated the associations between arsenic exposure and TL and between baseline TL and incident skin lesion risk among individuals participating in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2000-2009).

Methods: Quantitative PCR was used to measure the average TL of peripheral blood DNA collected at baseline. The association between baseline arsenic exposure (well water and urine) and TL was estimated in a randomly-selected subcohort (n = 1469). A nested case-control study (466 cases and 464 age- and sex-matched controls) was used to estimate the association between baseline TL and incident skin lesion risk (diagnosed < 8 years after baseline).

Results: No association was observed between arsenic exposure (water or urine) and TL. Among incident skin lesion cases and matched controls, we observed higher skin lesion risk among individuals with shorter TL (P = 1.5 × 10) with odds ratios of 2.60, 1.59, and 1.10 for the first (shortest), second, and third TL quartiles compared to the fourth (longest).

Conclusions: Arsenic exposure was not associated with TL among Bangladeshi adults, suggesting that leukocyte TL may not reflect a primary mode of action for arsenic's toxicity. However, short TL was associated with increased skin lesion risk, and may be a biomarker of arsenic susceptibility modifying arsenic's effect on skin lesion risk.
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http://dx.doi.org/10.1016/j.envres.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647858PMC
July 2018

A novel pooled-sample multiplex luminex assay for high-throughput measurement of relative telomere length.

Am J Hum Biol 2018 07 12;30(4):e23118. Epub 2018 Mar 12.

Department of Public Health Sciences, Biological Sciences Division, University of Chicago, Chicago, Illinois.

Objectives: Relative telomere length (RTL) is a potential biomarker of aging and risk for chronic disease. Previously, we developed a probe-based RTL assay on Luminex platform, where probes for Telomere (T) and reference gene (R) for a given DNA sample were tested in a single well. Here, we describe a method of pooling multiple samples in one well to increase the throughput and cost-effectiveness.

Methods: We used four different microbeads for the same T-probe and four different microbeads for the same R-probe. Each pair of probe sets were hybridized to DNA in separate plates and then pooled in a single plate for all the subsequent steps. We used DNA samples from 60 independent individuals and repeated in multiple batches to test the precision.

Results: The precision was good to excellent with Intraclass correlation coefficient (ICC) of 0.908 (95% CI 0.856-0.942). More than 67% of the variation in the RTL could be explained by sample-to-sample variation; less than 0.1% variation was due to batch-to-batch variation and 0.3% variation was explained by bead-to-bead variation. We increased the throughput of RTL Luminex assay from 60 to 240 samples per run. The new assay was validated against the original Luminex assay without pooling (r = 0.79, P = 1.44 × 10 ). In an independent set of samples (n = 550), the new assay showed a negative correlation of RTL with age (r = -0.41), a result providing external validation for the method.

Conclusion: We describe a novel high throughput pooled-sample multiplex Luminex assay for RTL with good to excellent precision suitable for large-scale studies.
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http://dx.doi.org/10.1002/ajhb.23118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105449PMC
July 2018

Co-occurring expression and methylation QTLs allow detection of common causal variants and shared biological mechanisms.

Nat Commun 2018 02 23;9(1):804. Epub 2018 Feb 23.

Department of Public Health Sciences, The University of Chicago, Chicago, IL, 60637, USA.

Inherited genetic variation affects local gene expression and DNA methylation in humans. Most expression quantitative trait loci (cis-eQTLs) occur at the same genomic location as a methylation QTL (cis-meQTL), suggesting a common causal variant and shared mechanism. Using DNA and RNA from peripheral blood of Bangladeshi individuals, here we use co-localization methods to identify eQTL-meQTL pairs likely to share a causal variant. We use partial correlation and mediation analyses to identify >400 of these pairs showing evidence of a causal relationship between expression and methylation (i.e., shared mechanism) with many additional pairs we are underpowered to detect. These co-localized pairs are enriched for SNPs showing opposite associations with expression and methylation, although many SNPs affect multiple CpGs in opposite directions. This work demonstrates the pervasiveness of co-regulated expression and methylation in the human genome. Applying this approach to other types of molecular QTLs can enhance our understanding of regulatory mechanisms.
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http://dx.doi.org/10.1038/s41467-018-03209-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824840PMC
February 2018

Screening for gene-environment (G×E) interaction using omics data from exposed individuals: an application to gene-arsenic interaction.

Mamm Genome 2018 02 16;29(1-2):101-111. Epub 2018 Feb 16.

Department of Public Health Sciences, University of Chicago, Chicago, IL, 60637, USA.

Identifying gene-environment interactions is a central challenge in the quest to understand susceptibility to complex, multi-factorial diseases. Developing an understanding of how inter-individual variability in inherited genetic variation alters the effects of environmental exposures will enhance our knowledge of disease mechanisms and improve our ability to predict disease and target interventions to high-risk sub-populations. Limited progress has been made identifying gene-environment interactions in the epidemiological setting using existing statistical approaches for genome-wide searches for interaction. In this paper, we describe a novel two-step approach using omics data to conduct genome-wide searches for gene-environment interactions. Using existing genome-wide SNP data from a large Bangladeshi cohort study specifically designed to assess the effect of arsenic exposure on health, we evaluated gene-arsenic interactions by first conducting genome-wide searches for SNPs that modify the effect of arsenic on molecular phenotypes (gene expression and DNA methylation features). Using this set of SNPs showing evidence of interaction with arsenic in relation to molecular phenotypes, we then tested SNP-arsenic interactions in relation to skin lesions, a hallmark characteristic of arsenic toxicity. With the emergence of additional omics data in the epidemiologic setting, our approach may have the potential to boost power for genome-wide interaction research, enabling the identification of interactions that will enhance our understanding of disease etiology and our ability to develop interventions targeted at susceptible sub-populations.
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http://dx.doi.org/10.1007/s00335-018-9737-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908479PMC
February 2018

Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal.

J Med Genet 2018 01 18;55(1):64-71. Epub 2017 Nov 18.

Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.

Background: Leucocyte telomere length (TL) is a potential biomarker of ageing and risk for age-related disease. Leucocyte TL is heritable and shows substantial differences by race/ethnicity. Recent genome-wide association studies (GWAS) report ~10 loci harbouring SNPs associated with leucocyte TL, but these studies focus primarily on populations of European ancestry.

Objective: This study aims to enhance our understanding of genetic determinants of TL across populations.

Methods: We performed a GWAS of TL using data on 5075 Bangladeshi adults. We measured TL using one of two technologies (qPCR or a Luminex-based method) and used standardised variables as TL phenotypes.

Results: Our results replicate previously reported associations in the and regions (P=2.2×10 and P=6.4×10, respectively). We observed a novel association signal in the gene (intronic SNP rs2297439; P=2.82×10) that is independent of previously reported TL-associated SNPs in this region. The minor allele for rs2297439 is common in South Asian populations (≥0.25) but at lower frequencies in other populations (eg, 0.07 in Northern Europeans). Among the eight other previously reported association signals, all were directionally consistent with our study, but only rs8105767 () was nominally significant (P=0.003). SNP-based heritability estimates were as high as 44% when analysing close relatives but much lower when analysing distant relatives only.

Conclusions: In this first GWAS of TL in a South Asian population, we replicate some, but not all, of the loci reported in prior GWAS of individuals of European ancestry, and we identify a novel second association signal at the locus.
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http://dx.doi.org/10.1136/jmedgenet-2017-104922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749304PMC
January 2018

Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators.

Occup Environ Med 2018 02 3;75(2):79-89. Epub 2017 Aug 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Objectives: Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. We evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators.

Methods: Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. We used multivariate logistic regression to estimate ORs and 95% CIs for subclinical hypothyroidism (TSH >4.5 mIU/L) compared with normal TSH (0.4-4.5 mIU/L) and for anti-TPO positivity. We also examined pesticide associations with TSH, T4 and T3 in multivariate linear regression models.

Results: Higher exposure to the insecticide aldrin (third and fourth quartiles of intensity-weighted days vs no exposure) was positively associated with subclinical hypothyroidism (OR=4.15, 95% CI 1.56 to 11.01, OR=4.76, 95% CI 1.53 to 14.82, p <0.01), higher TSH (p=0.01) and lower T4 (p=0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: OR=2.78, 95% CI 1.30 to 5.95, p=0.02), higher TSH (p=0.04) and anti-TPO positivity (p=0.01). The fumigant methyl bromide was inversely associated with TSH (p=0.02) and positively associated with T4 (p=0.01).

Conclusions: Our results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators.
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http://dx.doi.org/10.1136/oemed-2017-104431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771820PMC
February 2018

Association between genome-wide copy number variation and arsenic-induced skin lesions: a prospective study.

Environ Health 2017 07 18;16(1):75. Epub 2017 Jul 18.

Department of Public Health Sciences, University of Chicago, 900 E 57th Street, KCBD Bldg Room 6110, Chicago, IL, 60637, USA.

Background: Exposure to arsenic in drinking water is a global health problem and arsenic-induced skin lesions are hallmark of chronic arsenic toxicity. We and others have reported germline genetic variations as risk factors for such skin lesions. The role of copy number variation (CNV) in the germline DNA in this regard is unknown.

Methods: From a large prospectively followed-up cohort, exposed to arsenic, we randomly selected 2171 subjects without arsenic-induced skin lesions at enrollment and genotyped their whole blood DNA samples on Illumina Cyto12v2.1 SNP chips to generate DNA copy number. Participants were followed up every 2 years for a total of 8 years, especially for the development of skin lesions. In Cox regression models, each CNV segment was used as a predictor, accounting for other potential covariates, for incidence of skin lesions.

Result: The presence of genomic deletion(s) in a number of genes (OR5J2, GOLGA6L7P, APBA2, GALNTL5, VN1R31P, PHKG1P2, SGCZ, ZNF658) and lincRNA genes (RP11-76I14.1, CTC-535 M15.2, RP11-73B2.2) were associated with higher risk [HR between 1.67 (CI 1.3-2.1) and 2.15 (CI 1.5-2.9) for different CNVs] for development of skin lesions independent of gender, age, and arsenic exposure. Some deletions had stronger effect in a specific gender (ZNF658 in males, SGCZ in females) and some had stronger effect in higher arsenic exposure (lincRNA CTD-3179P9.1) suggesting a possible gene-environment interaction.

Conclusion: This first genome-wide CNV study in a prospectively followed-up large cohort, exposed to arsenic, suggests that DNA deletion in several genes and lincRNA genes may predispose an individual to a higher risk of development of arsenic-induced skin lesions.
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http://dx.doi.org/10.1186/s12940-017-0283-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516382PMC
July 2017

The association between telomere length and mortality in Bangladesh.

Aging (Albany NY) 2017 06;9(6):1537-1551

Department of Public Health Sciences, University of Chicago, Chicago, IL 60637, USA.

Telomeres are tandem repeat sequences at the end of chromosomes that bind proteins to protect chromosome ends. Telomeres shorten with age, and shorter leukocyte telomere length (TL) has been associated with overall mortality in numerous studies. However, this association has not been tested in populations outside of Europe and the U.S. We assessed the association between TL and subsequent mortality using data on 744 mortality cases and 761 age-/sex-matched controls sampled from >27,000 participants from three longitudinal Bangladeshi cohorts: Health Effects of Arsenic Longitudinal Study (HEALS), HEALS Expansion (HEALS-E), and Bangladesh Vitamin E and Selenium Trial (BEST). We used conditional logistic regression to estimate odds ratios (ORs) for the association between a standardized TL variable and overall mortality, as well as mortality from chronic diseases, respiratory diseases, circulatory diseases, and cancer. In HEALS and BEST, we observed an association between shorter TL and increased overall mortality (P=0.03 and P=0.03), mortality from chronic disease (P=0.01 and P=0.03) and mortality from circulatory disease (P=0.03 and P=0.04). Results from pooled analyses of all cohorts were consistent with HEALS and BEST. This is the first study demonstrating an association between short TL and increased mortality in a population of non-European ancestry.
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http://dx.doi.org/10.18632/aging.101246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509454PMC
June 2017

Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction.

Breast Cancer Res Treat 2017 Aug 13;164(3):707-717. Epub 2017 May 13.

University of Chicago, Chicago, IL, USA.

Purpose: Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor.

Methods: We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods.

Results: No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association.

Conclusion: Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.
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http://dx.doi.org/10.1007/s10549-017-4287-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510603PMC
August 2017
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