Prevalence of multimorbidity among Bangladeshi adult population: a nationwide cross-sectional study.

OBJECTIVE: This study aimed to report prevalence and evaluate the association between multimorbidity and associated risk factors in the adult population of Bangladesh. DESIGN: A cross-sectional study was conducted using a multistage clustered random sampling strategy. SETTING: The study was conducted among the general population of 58 districts in Bangladesh. PARTICIPANTS: A total of 12 338 male and female individuals aged ≥35 were included for analysis in this study. Identified through a household listing conducted prior to the study, from 15 297 individuals meeting the inclusion criteria, 12 338 participants were included based on availability during data collection, consent and health condition. OUTCOME MEASURES: Multimorbidity in terms of hypertension, diabetes, cancer, cardiovascular diseases, stroke and chronic obstructive pulmonary disease. RESULTS: Approximately 8.4% (95% CI 7.0 to 9.7) of individuals suffer from multimorbidity, of which hypertension accounted for (30.1%) followed by diabetes (10.6%). The mean age of the population was 58.6 (SD ±9.2) years. The prevalence of multimorbidity was lower among men (7.7%) compared with women (8.9%). The likelihood of having multimorbidity among obese individuals were more than double than people with normal body mass index (BMI). Physical activity protected individuals from developing multimorbidity: however, the physical activity adjusted OR was 0.5 (95% CI 0.2 to 1.2). After adjusting for all covariates, higher age, higher educational status, economic status, and higher BMI were found to be significantly associated with the odds of developing multimorbidity, with an overall adjusted OR of 0.02 (95% CI 0.01 to 0.02). CONCLUSION: This study reported a high prevalence of multimorbidity in Bangladesh, although it explored the burden and identified risk factors considering only six chronic diseases. Further detailed exploration through longitudinal studies considering a wider range of diseases is needed to document the actual burden, develop effective preventive measures and clinical guidelines to improve the quality of life of the population.

Prevalence and Risk Factors of Cardiovascular Diseases among Bangladeshi Adults: Findings from a Cross-sectional Study.

Ever rising prevalence of Cardiovascular Diseases (CVD) is a major challenge for the health sector in Bangladesh. This study aimed to explore the prevalence of CVD and sociodemographic and lifestyle factors associated with it in Bangladesh. The data were collected through a cross-sectional survey following a two-stage cluster random sampling procedure. The present analysis was performed among 12,338 respondents aged ≥35 years, selected from rural areas and urban slums. Information was gathered using a structured questionnaire, whereas measurements were taken using standardized procedures. Logistic regression with exchangeable correlation structure among clusters was executed to explore the association. About 30% of participants had hypertension, 5% diabetes, 20% obesity; 77% were either smokers or consumed smokeless tobacco, and 28% were physically inactive. The prevalence of CVD was 4.5% (stroke: 1.8% and heart diseases: 3.2%). After adjusting for potential confounders, hypertension, diabetes, body mass index, extra salt intake, daily sleep, tiredness, age, gender, occupation, administrative division, and wealth quintile were found to be significantly associated with CVD. The study highlighted that the prevalence of CVD is high in Bangladesh, and its associated risk factors such as hypertension and diabetes are on the rise, especially in the older population, women, and high-income groups. Therefore, immediate public health intervention is warranted to address the issue.

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

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.

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

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.

Arsenic exposure and young adult's mortality risk: A 13-year follow-up study in Matlab, Bangladesh.

BACKGROUND: Widespread arsenic contamination in underground water is a well-documented public health concern that threatens millions of lives worldwide. We investigated the risk of young-adult mortality due to high chronic exposure to arsenic through years of drinking arsenic contaminated water. METHODS: A prospective cohort study of 58,406 individuals was enrolled who were 4-18 years at baseline. Since Matlab HDSS (Health and Demographic Surveillance System) has an active surveillance system, all individuals were included in the follow up. Each individual's arsenic exposure was calculated at (1) baseline As level as current exposure (2) time-weighted lifetime (average or lifetime average) and (3) cumulative arsenic exposure. Age, sex, educational attainment and SES were adjusted during the analysis. In this 13 years closed-cohort study (2003-2015), all young-adult deaths were captured through verbal autopsy (VA) using International Classification of Diseases (ICD-10) to define the causes. RESULTS: Although, girls had higher values of cumulative arsenic exposure via tube well water than boys (median: 1858.5 µg/year/L vs. 1798.8 µg/year/L) but higher mortality due to cancers and due to cerebro-vascular disease, cardio-vascular disease, and respiratory disease (7.0 vs. 5.7 per 100,000 person-years and 6.4 vs. 4.2 per 100,000 person-years respectively). Higher risk of deaths among young adults (Adjusted HR: 2.7, 1.3-5.8) due to all cancers among those who were exposed to As > 138.7 compared to As ≤ 1.1 µg/L. For cerebro-vascular disease, cardio-vascular disease, and respiratory disease deaths, average arsenic in well water (>223.1 µg/L vs. ≤90.9 µg/L) and cumulative arsenic in well water (>2711.0 µg/year/L vs. ≤1013.3 µg/year/L) had 4.8 (1.8-12.8) and 5.1 (1.7-15.1) times higher risks of mortality than to those lowest exposed. CONCLUSION: Higher concentration of, and chronic exposure to arsenic in drinking water, increases the mortality risk among the young adults, regardless of gender.

Relationship of sleep pattern and snoring with chronic disease: findings from a nationwide population-based survey.

OBJECTIVES: To investigate the association of total sleep time and presence or absence of snoring with chronic disease among the Bangladeshi adult population. DESIGN: Cross-sectional survey. SETTING: Urban and rural Bangladesh. PARTICIPANTS: A total of 12,338 men and women aged ≥35 years. MEASUREMENTS: Total sleep time was considered as the total hours of sleep in 24 hours. Furthermore, sleep time was categorized into <7, 7-9, and >9 hours according to National Sleep Foundation (2015) guidelines. Self-reported snoring history was captured and corroborated with their respective sleep partner/spouse in more than 80% cases. Registered physician-diagnosed current and/or previous cases of hypertension, diabetes, coronary heart disease, cancer, stroke, chronic obstructive pulmonary disease, and any other chronic conditions were counted. RESULTS: Overall prevalence of at least 1 chronic disease in our study population was around 18%: men (15.4%) and women (20.0%). Hypertension has the highest prevalence (overall: 12.7%, men: 12.2%, women: 15%) followed by diabetes (4.9%), coronary heart diseases (3.2%), stroke (1.8%), chronic obstructive pulmonary disease (0.9%), and cancer (any type: 0.1%). Sleep pattern and snoring are significantly associated with all individual chronic disease except cancer. Sociodemographic, behavioral, and lifestyle variables were adjusted, and inadequate total sleep time (<7 hours) and snoring (yes/no) showed significant association with chronic disease status (risk ratio = 1.11, 95% confidence interval 1.00-1.22 and risk ratio = 1.20, 95% confidence interval 1.11-1.29, respectively). CONCLUSION: Inadequate sleep and snoring are independently associated with chronic disease in Bangladeshi adult population and perhaps elsewhere.

Demographic, Socio-economic and Lifestyle Determinants of Under- and Over-nutrition among Bangladeshi Adult Population: Results from a Large Cross-Sectional Study.

Bangladesh is currently going through a nutritional transition with rapid increase in overnutrition while undernutrition is still remaining prevalent. Nevertheless, population-based data on demographic, socio-economic and lifestyle factors associated with underweight and overweight among adult population is scarce. Employing a nationwide cross-sectional survey, we collected anthropometric, demographic, socio-economic, lifestyle and dietary information from 12,180 adults aged ≥35 years. Body Mass Index (BMI) was calculated using standard formula and categorized into underweight (<18.50), normal weight (18.50-22.99), and overweight (≥23.00). Multivariable multinomial logistic regression was performed to identify factors associated with underweight and overweight. Overall, prevalence of underweight and overweight was 18.1% (95% CI: 17.5-18.8) and 33.7% (95% CI: 32.9-34.6), respectively. All the demographic, socio-economic, dietary and lifestyle factors showed significant association with nutritional status in bivariate analysis. In adjusted analysis, factors showing significant positive association with underweight included female gender (ARRR-1.38, 95% CI: 1.11-1.71), older age [compared to 35-39 years age group, ARRR (95% CI) for ≥ 70 years is 2.32 (1.89-2.86), for 60-69 years is 1.62 (1.36-1.93), for 50-59 years 1.34 (1.13-1.58) and for 40-49 years 1.05 (0.87-1.15)] and smoking habit (ARRR-1.32, 95% CI: 1.14-1.52) while factors showing significant inverse association with underweight included higher household wealth [compared to lowest wealth quintile, ARRR (95% CI) for highest quintile is 0.68 (0.55-0.84), for second highest quintile 0.77 (0.65-0.91), for middle quintile 0.81 (0.69-0.94) and for second lowest quintile 0.89 (0.77-1.03)], urban residence (ARRR-0.66, 95% CI: 0.66-0.90), and more frequent meat/fish and fruits consumption (ARRR-0.76, 95% CI: 0.65-0.90). On the other hand, factors significantly associated with increased risk of overweight included female gender (ARRR-1.35, 95% CI: 1.12-1.63), higher household wealth [compared to lowest wealth quintile, ARRR (95% CI) for highest quintile is 2.27 (1.93-2.68), for second highest quintile 1.67 (1.44-1.94), for middle quintile 1.26 (1.10-1.46) and for second lowest quintile 1.07 (0.93-1.24), excess food availability [compared to food shortage, ARRR (95% CI) for excess food in the household is 1.29 (1.12-1.47) and for no shortage/no excess is 1.23 (1.09-1.38) and more frequent fruits consumption [compared to no fruits, ARRR (95% CI) for 5-7 days per week consumption is 1.61 (1.41-1.83) and for 3-4 days per week is 1.28 (1.16-1.41) and factors significantly associated with decreased risk of overweight included older age [compared to 35-39 years age group, ARRR (95% CI) for ≥ 70 years is 0.77 (0.64-0.93), for 60-69 years is 0.82 (0.71-0.94), for 50-59 years 0.91 (0.80-1.04) and for 40-49 years 1.01 (0.89-1.15)] and smoking (ARRR-0.76, 95% CI: 0.68-0.86). Both underweight and overweight are prevalent in Bangladeshi adult population. Several demographic, socio-economic, dietary and lifestyle factors are associated with underweight and overweight in Bangladesh. Population level impact of these factors should be examined to design suitable public health and nutrition interventions to address this dual challenge.

The association between telomere length and mortality in Bangladesh.

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.

Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals.

BACKGROUND: Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water. METHODS: We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1799 individuals. Association between arsenic exposure and a qPCR-based telomere length measure was assessed among 167 individuals. RESULTS: Urinary arsenic was positively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P<0.00035, Bonferroni-corrected threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction =0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02). DISCUSSION: Our findings suggest that arsenic's carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes.

Mediation analysis demonstrates that trans-eQTLs are often explained by cis-mediation: a genome-wide analysis among 1,800 South Asians.

A large fraction of human genes are regulated by genetic variation near the transcribed sequence (cis-eQTL, expression quantitative trait locus), and many cis-eQTLs have implications for human disease. Less is known regarding the effects of genetic variation on expression of distant genes (trans-eQTLs) and their biological mechanisms. In this work, we use genome-wide data on SNPs and array-based expression measures from mononuclear cells obtained from a population-based cohort of 1,799 Bangladeshi individuals to characterize cis- and trans-eQTLs and determine if observed trans-eQTL associations are mediated by expression of transcripts in cis with the SNPs showing trans-association, using Sobel tests of mediation. We observed 434 independent trans-eQTL associations at a false-discovery rate of 0.05, and 189 of these trans-eQTLs were also cis-eQTLs (enrichment P<0.0001). Among these 189 trans-eQTL associations, 39 were significantly attenuated after adjusting for a cis-mediator based on Sobel P<10-5. We attempted to replicate 21 of these mediation signals in two European cohorts, and while only 7 trans-eQTL associations were present in one or both cohorts, 6 showed evidence of cis-mediation. Analyses of simulated data show that complete mediation will be observed as partial mediation in the presence of mediator measurement error or imperfect LD between measured and causal variants. Our data demonstrates that trans-associations can become significantly stronger or switch directions after adjusting for a potential mediator. Using simulated data, we demonstrate that this phenomenon is expected in the presence of strong cis-trans confounding and when the measured cis-transcript is correlated with the true (unmeasured) mediator. In conclusion, by applying mediation analysis to eQTL data, we show that a substantial fraction of observed trans-eQTL associations can be explained by cis-mediation. Future studies should focus on understanding the mechanisms underlying widespread cis-mediation and their relevance to disease biology, as well as using mediation analysis to improve eQTL discovery.

Relationship between arsenic skin lesions and the age of natural menopause.

BACKGROUND: Chronic exposure to arsenic is associated with neoplastic, cardiovascular, endocrine, neuro-developmental disorders and can have an adverse effect on women's reproductive health outcomes. This study examined the relationship between arsenic skin lesions (a hallmark sign of chronic arsenic poisoning) and age of natural menopause (final menopausal period) in populations with high levels of arsenic exposure in Bangladesh. METHODS: We compared menopausal age in two groups of women--with and without arsenic skin lesions; and presence of arsenic skin lesions was used as an indicator for chronic arsenic exposure. In a cross-sectional study, a total of 210 participants were randomly identified from two ongoing studies--participants with arsenic skin lesions were identified from an ongoing clinical trial and participants with no arsenic skin lesions were identified from an ongoing cohort study. Mean age of menopause between these two groups were calculated and compared. Multivariable linear regression was used to estimate the relationship between the status of the arsenic skin lesions and age of natural menopause in women. RESULTS: Women with arsenic skin lesions were 1.5 years younger (p <0.001) at the time of menopause compared to those without arsenic skin lesions. After adjusting with contraceptive use, body mass index, urinary arsenic level and family history of premature menopause, the difference between the groups' age at menopause was 2.1 years earlier (p <0.001) for respondents with arsenic skin lesions. CONCLUSIONS: The study showed a statistically significant association between chronic exposure to arsenic and age at menopause. Heavily exposed women experienced menopause two years earlier than those with lower or no exposure.

Arsenic and lung disease mortality in Bangladeshi adults.

BACKGROUND: Chronic arsenic exposure through drinking water is a public health problem affecting millions of people worldwide, including at least 30 million in Bangladesh. We prospectively investigated the associations of arsenic exposure and arsenical skin lesion status with lung disease mortality in Bangladeshi adults. METHODS: Data were collected from a population-based sample of 26,043 adults, with an average of 8.5 years of follow-up (220,157 total person-years). There were 156 nonmalignant lung disease deaths and 90 lung cancer deaths ascertained through October 2013. We used Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals (CIs) for lung disease mortality. RESULTS: Creatinine-adjusted urinary total arsenic was associated with nonmalignant lung disease mortality, with persons in the highest tertile of exposure having a 75% increased risk for mortality (95% CI = 1.15-2.66) compared with those in the lowest tertile of exposure. Persons with arsenical skin lesions were at increased risk of lung cancer mortality (hazard ratio = 4.53 [95% CI = 2.82-7.29]) compared with those without skin lesions. CONCLUSIONS: This prospective investigation of lung disease mortality, using individual-level arsenic measures and skin lesion status, confirms a deleterious effect of ingested arsenic on mortality from lung disease. Further investigations should evaluate effects on the incidence of specific lung diseases, more fully characterize dose-response, and evaluate screening and biomedical interventions to prevent premature death among arsenic-exposed populations, particularly among those who may be most susceptible to arsenic toxicity.

Genome-wide association study of smoking behaviours among Bangladeshi adults.

BACKGROUND: The high prevalence of tobacco use in some developing nations, including Bangladesh, poses several public health challenges for these populations. Smoking behaviour is determined by genetic and environmental factors; however, the genetic determinants of smoking behaviour have not been previously examined in a Bangladeshi or South Asian population. We performed a genome-wide association study (GWAS) of tobacco smoking behaviour among a population-based sample of 5354 (2035 ever smokers and 3319 never smokers) men and women in Bangladesh. METHODS: Genome-wide association analyses were conducted for smoking initiation (ever vs never smokers), smoking quantity (cigarettes per day), age of smoking initiation, and smoking cessation (former vs current smokers). Sex-stratified associations were performed for smoking initiation. RESULTS: We observed associations for smoking initiation in the SLC39A11 region at 17q21.31 (rs2567519, p=1.33×10⁻7) among men and in the SLCO3A1 region at 15q26 (rs12912184, p=9.32×10⁻8) among women. CONCLUSIONS: These findings suggest possible underlying mechanisms related to solute carrier transporter genes, which transport neurotransmitters, nutrients, heavy metals and other substrates into cells, for smoking initiation in a South Asian population in a sex-specific pattern. Genetic markers could have potential translational implications for the prevention or treatment of tobacco use and addiction in South Asian populations and warrant further exploration.

Baseline comorbidities in a skin cancer prevention trial in Bangladesh.

BACKGROUND: Epidemiologic research suggests that increased cancer risk due to chronic arsenic exposure persists for several decades even after the exposure has terminated. Observational studies suggest that antioxidants exert a protective effect on arsenical skin lesions and cancers among those chronically exposed to arsenic through drinking water. This study reports on the design, methods and baseline analyses from the Bangladesh Vitamin E and Selenium Trial (BEST), a population-based chemoprevention study conducted among adults in Bangladesh with visible arsenic toxicity. MATERIALS AND METHODS: Bangladesh Vitamin E and Selenium Trial is a 2 × 2 full factorial, double-blind, randomized controlled trial of 7000 adults having manifest arsenical skin lesions evaluating the efficacy of 6-year supplementation with alpha-tocopherol (100 mg daily) and L-selenomethionine (200 µg daily) for the prevention of nonmelanoma skin cancer. RESULTS: In cross-sectional analyses, we observed significant associations of skin lesion severity with male gender (female prevalence odds ratio (POR) = 0.87; 95% CI = 0.79-0.96), older age (aged 36-45 years, POR = 1.27; 95% CI = 1.13-1.42; aged 46-55 years, POR = 1.44; 95% CI = 1.27-1.64 and aged 56-65 years, POR = 1.50; 95% CI = 1.26-1.78 compared with aged 25-35 years), hypertension (POR = 1.29; 95% CI = 1.08-1.55), diabetes (POR = 2.13; 95% CI = 1.32-3.46), asthma (POR = 1.55; 95% CI = 1.03-2.32) and peptic ulcer disease (POR = 1.20; 95% CI = 1.07-1.35). CONCLUSIONS: We report novel associations between arsenical skin lesions with several common chronic diseases. With the rapidly increasing burden of preventable cancers in developing countries, efficient and feasible chemoprevention study designs and approaches, such as employed in BEST, may prove both timely and potentially beneficial in conceiving cancer chemoprevention trials in Bangladesh and beyond.

Increased childhood mortality and arsenic in drinking water in Matlab, Bangladesh: a population-based cohort study.

BACKGROUND: Arsenic in drinking water was associated with increased risk of all-cause, cancer, and cardiovascular death in adults. However, the extent to which exposure is related to all-cause and deaths from cancer and cardiovascular condition in young age is unknown. Therefore, we prospectively assessed whether long-term and recent arsenic exposures are associated with all-cause and cancer and cardiovascular mortalities in Bangladeshi childhood population. METHODS AND FINDINGS: We assembled a cohort of 58406 children aged 5-18 years from the Health and Demographic Surveillance System of icddrb in Bangladesh and followed during 2003-2010. There were 185 non-accidental deaths registered in-about 0.4 million person-years of observation. We calculated hazard ratios for cause-specific death in relation to exposure at baseline (µg/L), time-weighted lifetime average (µg/L) and cumulative concentration (µg-years/L). After adjusting covariates, hazard ratios (HRs) for all-cause childhood deaths comparing lifetime average exposure 10-50.0, 50.1-150.0, 150.1-300.0 and ≥300.1µg/L were 1.37 (95% confidence interval [CI], 0.74-2.57), 1.44 (95% CI, 0.88-2.38), 1.22 (95% CI, 0.75-1.98) and 1.88 (95% CI, 1.14-3.10) respectively. Significant increased risk was also observed for baseline (P for trend = 0.023) and cumulative exposure categories (P for trend = 0.036). Girls had higher mortality risk compared to boys (HR for girls 1.79, 1.21, 1.64, 2.31; HR for boys 0.52, 0.53, 1.14, 0.99) in relation to baseline exposure. For all cancers and cardiovascular deaths combined, multivariable adjusted HRs amounted to 1.53 (95% CI 0.51-4.57); 1.29 (95% CI 0.43-3.87); 2.18 (95%CI 1.15-4.16) for 10.0-50.0, 50.1-150.0, and ≥150.1, comparing lowest exposure as reference (P for trend = 0.009). Adolescents had higher mortality risk compared to children (HRs = 1.53, 95% CI 1.03-2.28 vs. HRs = 1.30, 95% CI 0.78-2.17). CONCLUSIONS: Arsenic exposure was associated with substantial increased risk of deaths at young age from all-cause, and cancers and cardiovascular conditions. Girls and adolescents (12-18 years) had higher risk compared to boys and child.

Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8)) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10(-12)) and neighboring gene C10orf32 (P = 10(-44)), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide.

Gender and age differences in mixed metal exposure and urinary excretion.

BACKGROUND: Little is known about the variation in exposure to toxic metals by age and gender and other potential modifying factors. We evaluated age and gender differences by measurements of metal/element concentrations in urine in a rural population in Matlab, Bangladesh, in three age groups: 8-12 (N=238), 14-15 (N=107) and 30-88 (N=710) years of age, living in an area with no point sources of metal exposure but where elevated water arsenic concentrations are prevalent. RESULTS: We found marked differences in urine concentrations of metals and trace elements by gender, age, tobacco use, socioeconomic and nutritional status. Besides a clearly elevated urinary arsenic concentration in all age groups (medians 63-85 µg As/L), and despite the low degree of contamination from industries and traffic, the urine concentrations of toxic metals such as cadmium and lead were clearly elevated, especially in children (median 0.31 µg Cd/L and 2.9 µg Pb/L, respectively). In general, women had higher urinary concentrations of toxic metals, especially Cd (median 0.81 µg/L) compared to men (0.66 µg/L) and U (median 10 ng/L in women, compared to 6.4 ng/L in men), while men had higher urinary concentrations of the basic and essential elements Ca (69 mg/L in men, 30-50 years, compared to 52 mg/L in women), Mg (58 mg/L in men compared to 50 mg/L in women), Zn (182 µg/L in men compared to 117 µg/L in women) and Se (9.9 µg/L in men compared to 8.7 µg/L in women). Manganese was consistently higher in females than in males in all age groups, suggesting a biological difference between females and males in Mn metabolism. Increasing socioeconomic status decreased the toxic metal exposure significantly in children and especially in men. Poor iron status was detected in 17% of children, adolescents and women, but only in 6% of men. Also zinc deficiency was more prevalent in females than in males. CONCLUSIONS: Women and children seemed to be more at risk for toxic metal exposure than men and at the same time more vulnerable to micronutrient deficiency. Higher concentrations of the toxic metals in urine in women are likely to reflect an increased gastrointestinal absorption of these metals at micronutrient deficiency, such as low body iron stores and Zn deficiency. Higher urinary concentrations of the essential elements in men likely reflect a better nutritional status. There is a need for information on exposure, lifestyle and socioeconomic factors, stratified by gender and age, for the purpose of conducting balanced risk assessment and management that considers such differences.

Impact of smoking and chewing tobacco on arsenic-induced skin lesions.

BACKGROUND: We recently reported that the main reason for the documented higher prevalence of arsenic-related skin lesions among men than among women is the result of less efficient arsenic metabolism. OBJECTIVE: Because smoking has been associated with less efficient arsenic methylation, we aimed to elucidate interactions between tobacco use and arsenic metabolism for the risk of developing skin lesions. METHODS: We used a population-based case-referent study that showed increased risk for skin lesions in relation to chronic arsenic exposure via drinking water in Bangladesh and randomly selected 526 of the referents (random sample of inhabitants > 4 years old; 47% male) and all 504 cases (54% male) with arsenic-related skin lesions to measure arsenic metabolites [methylarsonic acid (MA) and dimethylarsinic acid (DMA)] in urine using high-performance liquid chromatography (HPLC) and inductively coupled plasma mass spectrometry (ICPMS). RESULTS: The odds ratio for skin lesions was almost three times higher in the highest tertile of urinary %MA than in the lowest tertile. Men who smoked cigarettes and bidis (locally produced cigarettes; 33% of referents, 58% of cases) had a significantly higher risk for skin lesions than did nonsmoking men; this association decreased slightly after accounting for arsenic metabolism. Only two women smoked, but women who chewed tobacco (21% of referents, 43% of cases) had a considerably higher risk of skin lesions than did women who did not use tobacco. The odds ratio (OR) for women who chewed tobacco and who had < or = 7.9%MA was 3.8 [95% confidence interval (CI), 1.4-10] compared with women in the same MA tertile who did not use tobacco. In the highest tertile of %MA or %inorganic arsenic (iAs), women who chewed tobacco had ORs of 7.3 and 7.5, respectively, compared with women in the lowest tertiles who did not use tobacco. CONCLUSION: The increased risk of arsenic-related skin lesions in male smokers compared with nonsmokers appears to be partly explained by impaired arsenic methylation, while there seemed to be an excess risk due to interaction between chewing tobacco and arsenic metabolism in women.

Arsenic and cadmium in food-chain in Bangladesh--an exploratory study.

Arsenic contamination of tubewell water is a major public-health problem in Bangladesh. In the recent years, the use of shallow and deep tubewell water for irrigation and the use of excess amount of cheap fertilizers and pesticides containing cadmium pose a serious threat of contamination of arsenic and cadmium in food. In an exploratory study, arsenic and cadmium were measured in foods from Matlab, a rural area in Bangladesh, that is extensively affected by arsenic and the economy is agriculture-based. Raw and cooked food samples were collected from village homes (households, n=13) and analyzed to quantify concentrations of arsenic and cadmium using atomic absorption spectrophotometry. Washing rice with water before cooking reduced the concentration of arsenic in raw rice by 13-15%. Rice, when cooked with excess water discarded, showed a significant decrease in arsenic concentration compared to that cooked without discarding the water (p<0.001). In contrast, concentration of cadmium did not decrease in cooked rice after discarding water. Cooked rice with discarded water had significantly lower concentration of arsenic compared to raw rice (p=0.002). Raw rice had higher concentration of arsenic compared to raw vegetables (p<0.001); however, no such difference was found for cadmium. Compared to raw vegetables (e.g. arum), concentration of arsenic increased significantly (p=0.024) when cooked with arsenic-contaminated water. Thus, the practice of discarding excess water while cooking rice reduces the concentration of arsenic but not of cadmium in cooked rice. However, water generally not discarded when cooking vegetables to avoid loss of micronutrients consequently retains arsenic. The results suggest that arsenic and cadmium have entered the food-chain of Bangladesh, and the cooking practices influence the concentration of arsenic but not of cadmium in cooked food.

Arsenic in drinking water and adult mortality: a population-based cohort study in rural Bangladesh.

BACKGROUND: Arsenic is a potent human carcinogen and toxicant. Elevated concentration of arsenic in drinking water is a major public-health problem worldwide. We evaluated risks of adult mortality (due to cancer and cardiovascular and infectious diseases) in relation to arsenic exposure through drinking water. METHODS: A cohort analysis was applied to survival data prospectively collected during 1991-2000 in a health and demographic surveillance system in Matlab, Bangladesh, where tubewells were installed beginning in the early 1970s. A total of 115,903 persons aged 15 or more years on 1 January 1991 were available for analysis. In this period, 9015 people died and 22,488 were lost to follow-up. Arsenic exposure data were derived from a survey in 2002-2003 of past and current water use and arsenic concentrations in all tubewells. We estimated risk of excess mortality in relation to arsenic exposure, using proportional hazards models. RESULTS: Even at low levels (10-49 mug/L) of arsenic in drinking water, we observed increased risk of death due to all nonaccidental causes (hazard ratio = 1.16 [95% confidence interval = 1.06-1.26]). Increased risks at exposure of 50-149 microg/L were observed for death due to cancers (1.44 [1.06-1.95]), cardiovascular disease (1.16 [0.96-1.40]), and infectious diseases (1.30 [1.13-1.49]). We observed clear dose-response relationships for each of these causes. CONCLUSIONS: Arsenic exposure through drinking water has generated excess adult mortality after 20-30 years of exposure.