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IMPORTANCE: Olfactory dysfunction is among the earliest signs of many age-related neurodegenerative diseases and has been associated with increased mortality in older adults; however, its genetic basis remains largely unknown. OBJECTIVE: To identify the genetic loci associated with olfactory dysfunction in the general population. DESIGN SETTING AND PARTIICIPANTS: This genome-wide association study meta-analysis (GWMA) included participants of European ancestry (N = 22,730) enrolled in four different large population-based studies, followed by a multi-ancestry GWMA including participants of African ancestry (N = 1,030). The data analysis was performed from March 2023 through June 2024. EXPOSURES: Genome-wide single nucleotide polymorphisms. MAIN OUTCOMES AND MEASURES: Olfactory dysfunction was the outcome and assessed using a 12-item smell identification test. RESULTS: GWMA revealed a novel genome-wide significant locus (tagged by rs11228623 at 11q12) associated with olfactory dysfunction. Gene-based analysis revealed a high enrichment for olfactory receptor genes in this region. Phenome-wide association studies demonstrated associations between genetic variants related to olfactory dysfunction and blood cell counts, kidney function, skeletal muscle mass, cholesterol levels and cardiovascular disease. Using individual-level data, we also confirmed and quantified the strength of these associations on a phenotypic level. Moreover, employing two-sample Mendelian Randomization analyses, we found evidence for causal associations between olfactory dysfunction and these phenotypes. CONCLUSIONS: These findings provide novel insights into the genetic architecture of the sense of smell and highlight its importance for many aspects of human health.
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Background: Brain imaging studies may provide etiologic insight into observed links between lung function and dementia and stroke. Objective: We evaluated associations of lung function measures with brain MRI markers of vascular and neurodegenerative disease in the ARIC Neurocognitive Study, as few studies have examined the associations. Methods: Lung function was measured at participants' midlife in 1990-1992 (mean ageâ=â56±5 years) and later-life in 2011-2013 (mean ageâ=â76±5 years), and brain MRI was performed in 2011-2013. Linear regression models were used to examine the associations of lung function with brain and white matter hyperintensity (WMH) volumes, and logistic regression models were used for cerebral infarcts and microbleeds, adjusting for potential confounders. Results: In cross-sectional analysis (i.e., examining later-life lung function and MRI markers, nâ=â1,223), higher forced-expiratory volume in one second (FEV1) and forced vital capacity (FVC) were associated with larger brain and lower WMH volumes [e.g., 8.62 (95% CI:2.54-14.71) cm3 greater total brain volume per one-liter higher FEV1]. No association was seen with microbleeds in the overall sample, but higher FVC was associated with lower odds of microbleeds in never-smokers and higher odds in ever-smokers. In the cross-temporal analysis (i.e., associations with midlife lung function, nâ=â1,787), higher FVC levels were significantly associated with lower later-life brain volumes. Conclusions: Our results support modest associations of better lung function with less neurodegenerative and cerebrovascular pathology, although findings for microbleeds were unexpected in ever-smokers.
Subject(s)
Brain , Magnetic Resonance Imaging , Humans , Male , Female , Aged , Middle Aged , Cross-Sectional Studies , Brain/diagnostic imaging , Brain/pathology , Atherosclerosis/diagnostic imaging , Lung/diagnostic imaging , Lung/physiopathology , Lung/pathology , Respiratory Function Tests , Vital Capacity , Aged, 80 and overABSTRACT
Study Objectives: Retinal microvascular pathology (RMP) and obstructive sleep apnea (OSA) are both cardiovascular disease risk factors. Limited data exists on their interrelationship. We tested the hypotheses that OSA and nocturnal hypoxemia would be associated with RMP and vessel calibers. Methods: We conducted a quasi-cross-sectional analysis of 1625 participants in the Atherosclerosis Risk in Communities Sleep Heart Health Study. Participants completed in-home polysomnography monitoring (1996-1998) and were categorized by OSA severity (apnea-hypopnea index: <5, 5-14.9, and ≥15) and proportion of total sleep time with oxygen saturationâ <â 90% (T90). Retinal photography (1993-1995) was used to assess RMP and measure vascular diameters (central retinal arteriolar equivalent [CRAE] and central retinal venular equivalent [CRVE]). Logistic and linear models were adjusted for demographics, behaviors, and BMI. Results: Of the participants, 19% had OSA (AHIâ >â 15) and 4% had RMP. Severe OSA was not associated with RMP [OR (95% CI): 1.08 (0.49 to 2.38)] or CRAE in adjusted models. OSA severity showed a positive linear relationship with CRVE; adjusted mean CRVE for those with OSA was 195.8 µm compared to 193.2 µm for those without OSA (Ptrendâ =â 0.03). T90 was strongly associated with CRVE, but not with RMP or CRAE. Adjusted mean CRVE for T90â ≥â 5% was 199.0 and 192.9 for T90â <â 1% (ptrendâ <â 0.0001). Conclusions: OSA and T90 were not associated with RMP or CRAE. However, both OSA and T90â ≥â 5% were associated with wider venules, which may be early and indicative changes of increased inflammation and future risk of stroke and CHD.
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OBJECTIVE: Quantitative olfactory assessment has demonstrated clinical utility for the evaluation of a range of neurologic, psychiatric, and sinonasal conditions. Here, we provide age, sex, race, and education-specific normative data for the 12-item Sniffin Sticks Odor Identification Test (SSOIT-12) in older Black and White U.S. adults without preclinical or clinical dementia or sinonasal disease. METHOD: A sample of 2,224 Atherosclerosis Risk in Communities study participants aged 66-89 years were included. A normative regression equation was developed using a linear model for the association of age, sex, race, and education with odor identification score. Regression-based normative mean scores and percentiles were generated by age, sex, race, and education groups. RESULTS: Participants (mean age = 74 years, 59% women, 20% Black, 48% > high school education) had a mean SSOIT-12 score of 9.8. Age, sex, race, and education were all associated with odor identification performance (all ps < .05). A linear regression model for the predicted SSOIT-12 score was developed for use with an individual's actual SSOIT-12 score in order to calculate the Z-score and corresponding percentile for a specific age, sex, race, and education group. Data are also reported in tabular format. CONCLUSIONS: Our study provides SSOIT-12 normative data obtained from a large population of White and Black older adults without preclinical or clinical dementia or sinonasal disease living in the USA. These findings can aid clinicians in assessing the degree of olfactory loss, establishing concordance with a person's perception of olfactory difficulties and quantitatively monitoring changes in olfactory performance over time.
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BACKGROUND AND OBJECTIVES: Research on olfaction and brain neuropathology may help understand brain regions associated with normal olfaction and dementia pathophysiology. To identify early regional brain structures affected in poor olfaction, we examined cross-sectional associations of microstructural integrity of the brain with olfaction in the Atherosclerosis Risk in Communities Neurocognitive Study. METHODS: Participants were selected from a prospective cohort study of community-dwelling adults; selection criteria included the following: evidence of cognitive impairment, participation in a previous MRI study, and a random sample of cognitively normal participants. Microstructural integrity was measured by 2 diffusion tensor imaging (DTI) measures, fractional anisotropy (FA) and mean diffusivity (MD), and olfaction by a 12-item odor identification test at the same visit. Higher FA and MD values indicate better and worse microstructural integrity, respectively, and higher odor identification scores indicate better olfaction. We used brain region-specific linear regression models to examine associations between DTI measures and olfaction, adjusting for potential confounders. RESULTS: Among 1,418 participants (mean age 76 ± 5 years, 41% male, 21% Black race, 59% with normal cognition), the mean olfaction score was 9 ± 2.3. Relevant to olfaction, higher MD in the medial temporal lobe (MTL) regions, namely the hippocampus (ß -0.79 [95% CI -0.94 to -0.65] units lower olfaction score per 1 SD higher MD), amygdala, entorhinal area, and some white matter (WM) tracts connecting to these regions, was associated with olfaction. We also observed associations with MD and WM FA in multiple atlas regions that were not previously implicated in olfaction. The associations between MD and olfaction were particularly stronger in the MTL regions among individuals with mild cognitive impairment (MCI) compared with those with normal cognition (e.g., ßhippocampus -0.75 [95% CI -1.02 to -0.49] and -0.44 [95% CI -0.63 to -0.26] for MCI and normal cognition, respectively, p interaction = 0.004). DISCUSSION: Neuronal microstructural integrity in multiple brain regions, particularly the MTL (the regions known to be affected in early Alzheimer disease), is associated with odor identification ability. Differential associations in the MTL regions among cognitively normal individuals compared with those with MCI may reflect the earlier vs later effects of the dementia pathogenesis. It is likely that some of the associated regions may not have any functional relevance to olfaction.
Subject(s)
Atherosclerosis , Dementia , White Matter , Male , Humans , Adult , Aged , Aged, 80 and over , Female , Diffusion Tensor Imaging/methods , Smell , Cross-Sectional Studies , Prospective Studies , Independent Living , Brain/diagnostic imaging , Brain/pathology , White Matter/diagnostic imaging , White Matter/pathology , Dementia/pathology , Atherosclerosis/diagnostic imaging , Atherosclerosis/epidemiology , AnisotropyABSTRACT
Olfactory function has significant implications for human health, but few risk factors for olfactory decline have been identified. We examined the factors associated with olfactory status and decline over five years in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. A 12-item odor identification test was used to assess olfaction in 6053 participants in 2011-2013 (ARIC visit 5, mean age: 75.6, 41% male, 23% Black race) and in 3235 participants in 2016-2017 (visit 6). We used Poisson regression models to examine cross-sectional associations of a range of potential factors with the total odor identification errors (mean errors: 2.8 ± 2.4) in visit 5 participants. We used mixed-effect Poisson regression to examine associations with olfactory decline between visits 5 and 6. We also examined associations with visit 5 anosmia prevalence (847 cases, 14%) and incident anosmia between the two visits (510 cases, 16%) using Poisson models. Older age, male sex, lower education, Black race, APOE ε4 alleles, and diabetes were associated with higher odor identification errors and higher anosmia prevalence, and greater physical activity and hypertension with better olfaction. Age, male sex, lower education, Black race, APOE ε4 allele, and vitamin B12 levels were associated with incident anosmia over 5 years. Older age was associated with faster olfactory decline. Future studies with longer follow-ups are warranted.
Subject(s)
Atherosclerosis , Smell , Male , Humans , Aged , Child, Preschool , Female , Anosmia , Apolipoprotein E4 , Cross-Sectional StudiesABSTRACT
We examined the associations between lung function and incident dementia and cognitive decline in 12,688 participants in the ARIC Study who provided lung function measurements in 1990-1992. Cognitive tests were administered up to 7 times, and dementia was ascertained through 2019. We used shared parameter models to jointly fit proportional hazard models and linear mixed-effect models to estimate lung-function-associated dementia rate and cognitive change, respectively. Higher forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were associated with reduced dementia (n = 2,452 persons developed dementia); hazard ratios per 1-L increase in FEV1 and FVC were 0.79 (95% confidence interval (CI): 0.71, 0.89) and 0.81 (95% CI: 0.74, 0.89), respectively. Each 1-L increase in FEV1 and FVC was associated with a 0.08-standard deviation (SD) (95% CI: 0.05, 0.12) and a 0.05-SD (95% CI: 0.02, 0.07) attenuation of 30-year cognitive decline, respectively. A 1% increase in FEV1/FVC ratio was associated with 0.008-SD (95% CI: 0.004, 0.012) less cognitive decline. We observed statistical interaction between FEV1 and FVC, suggesting that cognitive declines depended on values of specific FEV1 and FVC (as compared with FEV1, FVC, or FEV1/FVC ratio models that suggested linear incremental associations). Our findings may have important implications for reducing the burden of cognitive decline that is attributable to environmental exposures and associated lung function impairment.
Subject(s)
Atherosclerosis , Cognitive Dysfunction , Dementia , Humans , Lung , Forced Expiratory Volume , Atherosclerosis/epidemiology , Cognitive Dysfunction/epidemiology , Dementia/epidemiology , Dementia/etiologyABSTRACT
At visit 3 (1993-1995) of the ARIC Study, 1.5T brain MRI was completed in 1,881 stroke-free participants (Mean ageâ=â62.9±4.9, 50% Black). Cox regression examined associations between infarct group [infarct-free (referent; nâ=â1,611), smaller only (<3âmm; nâ=â50), larger only (≥3âmm but <20âmm; nâ=â185), both (nâ=â35)] and up to 25-year incident dementia (nâ=â539). Participants with both infarcts were over 2.5 times more likely to develop dementia [HRâ=â2.61; 95% CIâ=â1.44, 4.72]. Smaller only (HRâ=â1.22; 95% CIâ=â0.70, 2.13) and larger only (HRâ=â1.27; 95% CIâ=â0.92, 1.74) groups showed associations with wide confidence intervals, unsupported statistically. A late midlife infarct profile including smaller and larger infarcts may represent particular vulnerability to dementia risk.
Subject(s)
Atherosclerosis , Dementia , Stroke , Humans , Aged , Risk Factors , Dementia/diagnostic imaging , Dementia/epidemiology , Atherosclerosis/complications , Atherosclerosis/diagnostic imaging , Atherosclerosis/epidemiology , Magnetic Resonance ImagingABSTRACT
BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables. METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.
Subject(s)
Lung , Magnetic Resonance Imaging , Humans , Aged , Forced Expiratory Volume , Cross-Sectional Studies , Lung/diagnostic imaging , Brain/diagnostic imagingABSTRACT
Importance: Traumatic brain injury has been associated with short-term olfactory dysfunction, but the association of number of prior head injuries and head injury severity with both subjective and objective long-term olfactory function is less clear. Objective: To investigate the associations of prior head injury, number of prior head injuries, and head injury severity with subjective and psychophysical (objective) olfactory function in older adults and to examine concordance between subjective and objective olfactory function among individuals with and without head injury. Design, Setting, and Participants: This prospective cohort study included 5951 participants who attended Atherosclerosis Risk in Communities (ARIC) Study visit 5 (2011 through 2013). Data analysis was performed between November 2021 and May 2022. Exposures: Head injury was defined by self-report and International Classification of Diseases codes. Main Outcomes and Measures: Self-reported subjective olfactory dysfunction was assessed by the question, "Do you suffer from smell loss or a significantly decreased sense of smell?" Objective olfactory performance was assessed using the 12-item Sniffin' Sticks odor identification test. Results: Overall, the 5951 participants were a mean (SD) age of 75.6 (5.2) years, 3501 (58.8%) were female, 1356 (22.8%) were of Black race, and 1666 (28.0%) had a history of head injury. Participants with prior head injury were more likely than individuals without prior head injury to report subjective olfactory dysfunction (24% vs 20%; difference, 4%; 95% CI, 1% to 6%) and have objective anosmia (15% vs 13%; difference, 2%; 95% CI, 0.1% to 4%) but had lower concordance between subjective and objective assessment (72% vs 77%; difference, -5%; 95% CI, -8% to -3%). In logistic regression models adjusted for sociodemographics and medical comorbidities including cognitive status, participants with a history of prior head injury, particularly individuals with 2 or more prior head injuries and more severe head injuries, were more likely to self-report subjective olfactory dysfunction and were more likely to be found to have objective anosmia compared with participants with no history of head injury. Conclusions and Relevance: Findings of this cohort study provide evidence supporting the association between head injury and olfactory dysfunction, particularly among individuals who experienced multiple prior head injuries and among individuals with more severe head injury. The findings also suggest that individuals with prior head injury were more likely to both under-self-report and over-self-report deficits compared with objective olfactory testing; therefore, it may be important to consider objective olfactory testing in this patient population.
Subject(s)
Atherosclerosis , Craniocerebral Trauma , Olfaction Disorders , Aged , Anosmia , Cohort Studies , Craniocerebral Trauma/complications , Craniocerebral Trauma/epidemiology , Female , Humans , Male , Olfaction Disorders/epidemiology , Prospective Studies , SmellABSTRACT
OBJECTIVES: Pyrethroid insecticides have been linked with multiple health outcomes. One study reported an association with increased all-cause and cardiovascular mortality. Given the widespread use of pyrethroids, these findings warrant confirmation. We explored associations of permethrin/pyrethroid use with overall and cause-specific mortality among 50 665 licensed pesticide applicators in the Agricultural Health Study. METHODS: At enrolment (1993-1997), participants self-reported information on permethrin/pyrethroid use. Information on causes of death came from linkage with death registries through 2016. We used Cox proportional hazards models to estimate HRs and 95% CIs with adjustment for potential confounders. RESULTS: Over an average 21 years of follow-up, 19.6% (9,955) of the cohort died. We found no clear evidence that ever-use of permethrin/pyrethroid was associated with elevated overall mortality or with mortality from most causes examined. There was suggestive evidence, based on a small number of deaths among those exposed, for elevated pyrethroid-associated mortality from some neurological, respiratory and genitourinary diseases in the overall sample and from lung cancer among never-smokers. CONCLUSION: Although based on mortality, which is also affected by survival, rather than incidence, these findings are biologically plausible, and future investigations in other populations may be warranted.
Subject(s)
Insecticides , Occupational Exposure , Pesticides , Pyrethrins , Agriculture , Humans , Insecticides/adverse effects , Occupational Exposure/adverse effects , Permethrin/adverse effects , Pyrethrins/adverse effectsABSTRACT
Medicare Fee for Service (FFS) claims data, including inpatient (Part A) and outpatient (Part B) services, provide a valuable resource for research on older adults (≥65 year) in linked U.S. cohorts. Here we describe our experience linking the Agricultural Health Study cohort, including 47,501 licensed pesticide applicators and spouses from North Carolina (NC) and Iowa (IA) to Medicare claims data from 1999 to 2016. Given increased Part C (i.e., managed care/Medicare Advantage) enrollment during this period, and a resulting lack of available Part C claims data prior to 2015, we also explored potential for informative missingness. We compared those with partial or limited/no FFS to those with complete FFS coverage (i.e., ≥11 months per year parts AB, but not C, throughout Medicare enrollment) in relation to baseline farm size, general pesticide use, and mortality, in logistic regression models adjusted for age, sex, race, education, and smoking, and stratified by state. While 46,689 participants (98%) were linked to Medicare IDs, only 33,487 (70%) had complete FFS, 9353 (20%) had partial FFS (≥1 year FFS but not complete), and 3849 (8%) had limited/no FFS (Part A or Part C-only). Incomplete FFS was more common in NC, mostly due to Part C, and was associated with farm characteristics, pesticide use, and mortality. These findings indicate that, in addition to reduced sample size in analyses limited to complete FFS, missingness may not be random. The potential impact of incomplete FFS data and changes in coverage type need to be considered when planning linked analyses and interpreting results.
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BACKGROUND: Dream-enacting behavior is a characteristic feature of rapid eye movement sleep behavior disorder, the most specific prodromal marker of synucleinopathies. Pesticide exposure may be associated with dream-enacting behaviors, but epidemiological evidence is limited. OBJECTIVES: To examine high pesticide exposure events in relation to dream-enacting behaviors among farmers in the Agricultural Health Study. METHODS: We conducted multivariable logistic regression analyses to examine high pesticide exposure events reported from 1993 to 1997 in relation to dream-enacting behaviors assessed from 2013 to 2015 among 11,248 farmers (age 47 ± 11 years). RESULTS: A history of dream-enacting behaviors was reported by 939 (8.3%) farmers. Compared with farmers who did not report any high pesticide exposure event, those who reported were more likely to endorse dream-enacting behaviors 2 decades later (odds ratio = 1.75; 95% confidence interval [CI], 1.49-2.05). The association appeared stronger when there was a long delay in washing with soap and water after the event (2.63 [95% CI, 1.62-4.27] for waiting >6 hours vs. 1.71 [95% CI, 1.36-2.15] for washing within 30 minutes) and when the exposure involved the respiratory or digestive tract (2.04 [95% CI, 1.62-2.57] vs. 1.58 [95% CI, 1.29-1.93] for dermal contact only). In the analyses of specific pesticides involved, we found positive associations with two organochlorine insecticides (dichlorodiphenyltrichloroethane and lindane), four organophosphate insecticides (phorate, ethoprop, terbufos, and parathion), two herbicides (alachlor and paraquat), and fungicides as a group. CONCLUSIONS: This study provides the first epidemiological evidence that high pesticide exposures may be associated with a higher risk of dream-enacting behaviors. © 2022 International Parkinson and Movement Disorder Society.
Subject(s)
Insecticides , Occupational Exposure , Pesticides , Adult , Agriculture , Farmers , Humans , Middle Aged , Occupational Exposure/adverse effects , Pesticides/adverse effectsABSTRACT
Circulating magnesium has been associated with a lower risk of dementia, but the physiologic effects by which magnesium may prevent neurological insults remain unclear. We studied 1466 individuals (mean age 76.2 ± 5.3, 28.8% black, 60.1% female) free of prevalent stroke, with measured serum magnesium and with available MRI scans obtained in 2011-2013, participating in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Cross-sectional differences in frontal, temporal, parietal, and occipital lobe volume, along with deep grey matter, total brain, and white matter hyperintensity volume across serum magnesium (categorized into quintiles and per standard deviation increases) were assessed using multiple linear regression. We also examined associations of magnesium with the prevalence of cortical, subcortical, and lacunar infarcts using multiple logistic regression. After adjusting for demographics, biomarkers, medications, and cardiometabolic risk factors, higher circulating magnesium was associated with greater total brain volume and frontal, temporal, and parietal lobe volumes (volumes 0.14 to 0.19 standard deviations higher comparing Q5 to Q1). Elevated magnesium was also associated with lower odds of subcortical infarcts (OR (95%CI): 0.44 (0.25, 0.77) comparing Q5 to Q1) and lacunar infarcts (OR (95%CI): 0.40 (0.22, 0.71) comparing Q5 to Q1). Elevated serum magnesium was cross-sectionally associated with greater brain volumes and lower odds of subclinical cerebrovascular disease, suggesting beneficial effects on pathways related to neurodegeneration and cerebrovascular damage. Further exploration through prospective analyses is needed to assess increasing circulating magnesium as a potential neuroprotective intervention.
Subject(s)
Brain/pathology , Cerebrovascular Disorders/blood , Cerebrovascular Disorders/pathology , Magnesium/blood , Magnetic Resonance Imaging , Aged , Brain/diagnostic imaging , Cross-Sectional Studies , Female , Humans , Linear Models , Male , Odds Ratio , Organ SizeABSTRACT
BACKGROUND: Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides. OBJECTIVES: We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients. METHODS: The Agricultural Lung Health Study is a case-control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina's EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009-2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users. RESULTS: Using family-wise error rate (p<9×10-8) or false-discovery rate (FDR<0.05), we identified 162 differentially methylated CpGs across 8 of 9 currently marketed active ingredients (acetochlor, atrazine, dicamba, glyphosate, malathion, metolachlor, mesotrione, and picloram) and one banned organochlorine (heptachlor). Differentially methylated CpGs were unique to each active ingredient, and a dose-response relationship with lifetime days of use was observed for most. Significant CpGs were enriched for transcription motifs and 28% of CpGs were associated with whole blood cis-gene expression, supporting functional effects of findings. We corroborated a previously reported association between dichlorodiphenyltrichloroethane (banned in the United States in 1972) and epigenetic age acceleration. DISCUSSION: We identified differential methylation for several active ingredients in male farmers of European ancestry. These may serve as biomarkers of chronic exposure and could inform mechanisms of long-term health outcomes from pesticide exposure. https://doi.org/10.1289/EHP8928.
Subject(s)
Epigenome , Pesticides , Case-Control Studies , DNA Methylation , Humans , Lung , Male , Pesticides/toxicityABSTRACT
BACKGROUND: In epidemiologic studies where physician-based case adjudication is not feasible, Parkinson's disease (PD) case ascertainment is often limited to self-reports which may not be accurate. We evaluated strategies to identify PD cases in the Agricultural Health Study (AHS). METHODS: Doctor-diagnosed PD was self-reported on all cohort-wide surveys; potential cases were also identified from death certificates. Follow-up surveys asked about PD-related motor and non-motor symptoms. For PD confirmation, we collected additional diagnosis, symptom, and treatment data from 510 potential PD cases or their proxy (65% of those contacted) in a supplemental screener and obtained medical records for a subset (n = 65). We classified PD cases using established criteria and screener data. RESULTS: Of 510 potential PD cases, 75% were considered "probable" or "possible"; this proportion increased among participants diagnosed by a specialist (81.2%), taking PD medication (85.2%), or reporting ≥5 motor symptoms (86.8%) in a regular AHS survey. Of those with medical records, 93% (57 of 61) of probable or possible PD was confirmed. Never-smoking and non-motor and motor symptoms reported in prior AHS surveys were more common with probable/possible PD than unconfirmed PD. CONCLUSION: In this retrospective PD case ascertainment effort, we found that PD self-report with information on motor symptoms or medications may be a reasonable alternative for identifying PD cases when physician exam is not feasible. Because of intervening mortality, screeners could not be obtained from about one-third of those contacted. Thus, findings warrant replication.
Subject(s)
Death Certificates , Missed Diagnosis , Parkinson Disease/diagnosis , Parkinson Disease/epidemiology , Self Report , Adult , Aged , Aged, 80 and over , Case-Control Studies , Farmers/psychology , Female , Follow-Up Studies , Humans , Iowa/epidemiology , Male , Middle Aged , North Carolina/epidemiology , Parkinson Disease/drug therapy , Prospective Studies , Retrospective Studies , Risk Factors , Treatment OutcomeABSTRACT
BACKGROUND: Pesticides have been reported to be associated with malignant and non-malignant kidney disease. Few studies have examined the relationship between individual pesticides and kidney dysfunction. OBJECTIVE: We evaluated the associations of pesticide use with measured kidney function among male pesticide applicators in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study, a subcohort in the Agricultural Health Study. METHODS: Serum creatinine was measured in 1545 BEEA participants and estimated glomerular filtration rate (eGFR) was calculated with the chronic kidney disease epidemiology collaboration (CKD-EPI) equation. Using reported information on lifetime use of 41 pesticides, multivariable linear and logistic regression was used to examine associations with eGFR modeled continuously and with CKD (eGFR <60 mL/min/1.73 m2), respectively. Models were adjusted for possible confounding factors related to kidney function and correlated pesticides. RESULTS: Lower eGFR was observed among pesticide applicators who ever used the herbicides pendimethalin (-3.7%, 95% confidence interval (CI): 5.8%, -1.5%), atrazine (-3.7%, 95% CI: 6.9%, -0.4%), and dicamba (-2.8%, 95% CI: 5.3%, -0.2%) compared with never users of each pesticide. Ever use of pendimethalin (odds ratio (OR)=1.6, 95% CI: 1.1, 2.2) and atrazine (OR=1.8, 95% CI: 1.0, 3.0) was also associated with elevated odds of CKD, with an exposure-response association between intensity-weighted lifetime days of pendimethalin use and CKD among active farmers (N=1302; ptrend=0.04). Atrazine use within the last year was associated with lower eGFR and elevated odds of CKD when compared with never users, and we observed exposure-response associations with intensity-weighted lifetime days among recent users. Use of several other pesticides was associated with higher eGFR. DISCUSSION: These results suggest that two widely used herbicides, pendimethalin and atrazine, may be associated with altered kidney function among pesticide applicators. Our findings for these herbicides are consistent with observed associations with end-stage renal disease in the Agricultural Health Study.
Subject(s)
Occupational Exposure , Pesticides , Agriculture , Biomarkers , Farmers , Humans , Kidney , Male , Occupational Exposure/adverse effects , Pesticides/toxicityABSTRACT
BACKGROUND: Many pesticides are known to have thyroid-disrupting properties. However, few studies have evaluated the association between specific pesticide ingredients and risk of thyroid cancer. We investigated self-reported pesticide use and incident thyroid cancer in the Agricultural Health Study (AHS), a large cohort of occupationally-exposed male pesticide applicators. METHODS: The AHS is a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. At enrollment (1993-1997) and follow-up (1999-2005), participants reported use of 50 pesticides. We characterized exposure as ever use (44 pesticides with ≥5 exposed cases) and by cumulative intensity-weighted lifetime days (22 pesticides with ≥10 exposed cases), a metric that accounts for factors that influence exposure. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression for incident thyroid (n = 85 cases) cancer among male participants using follow-up through 2014/2015. RESULTS: Use of the fungicide metalaxyl (HR = 2.03, CI:1.16-3.52) and the organochlorine insecticide lindane (HR = 1.74, CI:1.06-2.84) was associated with increased risk of thyroid cancer. The herbicide chlorimuron-ethyl was inversely associated with risk when we restricted to papillary thyroid cancer, the most common subtype (HR = 0.52, CI:0.28-0.96). High use of the insecticide carbaryl (>median intensity-weighted days) was inversely associated with thyroid cancer (HR = 0.20, CI:0.08-0.53, ptrend = 0.001). CONCLUSIONS: In this large cohort study, we observed increased risk of thyroid cancer associated with use of metalaxyl and lindane, and an inverse association with carbaryl. More work is needed to understand the potential role of these chemicals in thyroid carcinogenesis.
Subject(s)
Agricultural Workers' Diseases , Occupational Exposure , Pesticides , Thyroid Neoplasms , Agricultural Workers' Diseases/chemically induced , Agricultural Workers' Diseases/epidemiology , Agriculture , Cohort Studies , Humans , Incidence , Iowa/epidemiology , Male , North Carolina/epidemiology , Pesticides/toxicity , Prospective Studies , Thyroid Neoplasms/chemically induced , Thyroid Neoplasms/epidemiologyABSTRACT
OBJECTIVES: Pesticide exposure may impair human olfaction, but empirical evidence is limited. We examined associations between occupational use of 50 specific pesticides and olfactory impairment, both self-reported, among 20 409 participants in the Agricultural Health Study, a prospective cohort of pesticide applicators (mostly farmers, 97% male). METHODS: We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between pesticide use at enrolment (1993-1997) and olfactory impairment reported two decades later (2013-2016), adjusting for baseline covariates. RESULTS: About 10% of participants reported olfactory impairment. The overall cumulative days of any pesticide use at enrolment were associated with a higher odds of reporting olfactory impairment (OR (highest vs lowest quartile): 1.17 (95% CI: 1.02 to 1.34), p-trend = 0.003). In the analyses of 50 specific pesticides, ever-use of 20 pesticides showed modest associations with olfactory impairment, with ORs ranging from 1.11 to 1.33. Of these, higher lifetime days of use of 12 pesticides were associated with higher odds of olfactory impairment compared with never use (p-trend ≤ 0.05), including two organochlorine insecticides (dichlorodiphenyltrichloroethane and lindane), two organophosphate insecticides (diazinon and malathion), permethrin, the fungicide captan and six herbicides (glyphosate, petroleum distillates, 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid and metribuzin), although many of these did not exhibit clear, monotonic exposure-response patterns. CONCLUSION: Overall, we found relatively broad associations between pesticides and olfactory impairment, involving many individual pesticides and covering several chemical classes, suggesting that pesticides could affect olfaction through multiple pathways. Future epidemiological studies with objective measurement of olfaction are required to confirm these findings.
ABSTRACT
BACKGROUND: Extensive literature suggests an association between general pesticide use and Parkinson's disease (PD). However, with few exceptions, little is known about associations between specific pesticides and PD. OBJECTIVE: We evaluated use of pesticides and incident PD in 38,274 pesticide applicators and 27,836 of their spouses in the Agricultural Health Study cohort followed over 20 years. METHODS: We used self-reported information on ever-use of 50 specific pesticides as of enrollment for both applicators and spouses, and considered intensity-weighted lifetime days (IWLD) reported at enrollment and through the first 5-year follow-up among applicators. We estimated covariate-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression. We also examined heterogeneity in associations by history of head injury and chemical resistant glove use. RESULTS: A total of 373 applicators and 118 spouses self-reported incident doctor-diagnosed PD. Ever-use of the insecticide terbufos (HR:1.31, 95%CI:1.02-1.68) and the herbicides trifluralin (HR:1.29, 95%CI: 0.99-1.70) and 2,4,5-T (HR:1.57, 95%CI:1.21-2.04) was associated with elevated PD risk. On the other hand, diazinon (HR:0.73, 95%CI: 0.58-0.94) and 2,4,5-TP (HR:0.39, 95%CI:0.25-0.62) were associated with reduced risk. We observed heterogeneity in ever-use associations by head injury and chemical-resistant glove use for some pesticides, with higher risk among those who reported a history of head injury, or who did not use gloves. PD risk was also elevated for applicators in the highest category of IWLD for dichlorvos, permethrin (animal use), and benomyl. CONCLUSIONS: We found evidence of increased PD risk for some pesticides. Our results also suggest higher susceptibility for pesticide-associated PD among individuals with head injury as well as protection with use of chemical resistant gloves, although further research is needed to understand the impact of head injury. Research on current and newer pesticides, including mechanisms relevant to PD, is important given widespread pesticide use.