Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population-based cohort study in Taiwan, 2004 to 2015.

While associations between maternal infections during pregnancy and childhood leukemia in offspring have been extensively studied, the evidence for other types of childhood cancers is limited. Additionally, antibiotic exposure during pregnancy could potentially increase the risk of childhood cancers. Our study investigates associations between maternal infections and antibiotic prescriptions during pregnancy and the risk of childhood cancer in Taiwan. We conducted a population-based cohort study using the Taiwan Maternal and Child Health Database (TMCHD), linked with national health and cancer registries. The study included 2 267 186 mother-child pairs, and the median follow-up time was 7.96 years. Cox proportional hazard models were utilized to estimate effects. Maternal infections during pregnancy were associated with a moderate increase in the risk of childhood hepatoblastoma (adjusted hazard ratio [HR] = 1.34; 95% confidence interval [CI]: 0.90-1.98) and a weaker increase in the risk of childhood acute lymphoblastic leukemia (ALL) (adjusted HR = 1.15; 95% CI: 0.99-1.35). Antibiotic prescriptions during pregnancy were also associated with an elevated risk of childhood ALL (adjusted HR = 1.30; 95% CI: 1.04-1.63), particularly with tetracyclines (adjusted HR = 2.15; 95% CI: 1.34-3.45). Several specific antibiotics were also associated with an increased risk of hepatoblastoma and medulloblastoma. Children exposed in utero to antibiotic prescription or both infections and antibiotics during pregnancy were at higher risk of developing ALL. Our findings suggest that there are associations between maternal infections, antibiotic use during pregnancy and the risk of several childhood cancers in addition to ALL and highlight the importance of further research in this area.

Effects of hypertension and use of antihypertensive drugs in pregnancy on the risks of childhood cancers in Taiwan.

BACKGROUND: Childhood cancers are associated with high mortality and morbidity, and some maternal prescription drug use during pregnancy has been implicated in cancer risk. There are few studies on the effects of hypertension, preeclampsia, and the use of antihypertensives in pregnancy on children's cancer risks. OBJECTIVE: This population-based cohort study analyzed the relationship between hypertension, preeclampsia, and antihypertensives taken during pregnancy and the risks of childhood cancers in the offspring. METHODS: Data on all children born in Taiwan between 2004 and 2015 (N = 2,294,292) were obtained from the Maternal and Child Health Database. This registry was linked with the National Health Insurance Database and Cancer Registry to get the records of maternal use of diuretics or other antihypertensives in pregnancy and records of children with cancer diagnosed before 13 years. We used Cox proportional hazard modeling to estimate the influence of maternal health conditions and antihypertensive drug exposure on the risks of developing childhood cancers. RESULTS: Offspring of mothers with hypertension (chronic or gestational) had a higher risk of acute lymphocytic lymphoma [hazard ratio (HR) = 1.87, 95% Confidence Interval (CI) 1.32 - 2.65] and non-Hodgkin's lymphoma (HR = 1.96, 95% CI 1.34 - 2.86). We estimated only a weak increased cancer risk in children whose mothers used diuretics (HR = 1.16, 95% CI 0.77 - 1.74) or used antihypertensives other than diuretics (HR = 1.15, 95% CI 0.86 - 1.54) before birth. CONCLUSIONS: In this cohort study, children whose mothers had chronic and gestational hypertension had an increased risk of developing childhood cancer.

Non-linear association between long-term air pollution exposure and risk of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) has become a global epidemic, and air pollution has been identified as a potential risk factor. This study aims to investigate the non-linear relationship between ambient air pollution and MASLD prevalence. METHOD: In this cross-sectional study, participants undergoing health checkups were assessed for three-year average air pollution exposure. MASLD diagnosis required hepatic steatosis with at least 1 out of 5 cardiometabolic criteria. A stepwise approach combining data visualization and regression modeling was used to determine the most appropriate link function between each of the six air pollutants and MASLD. A covariate-adjusted six-pollutant model was constructed accordingly. RESULTS: A total of 131,592 participants were included, with 40.6% met the criteria of MASLD. "Threshold link function," "interaction link function," and "restricted cubic spline (RCS) link functions" best-fitted associations between MASLD and PM2.5, PM10/CO, and O3 /SO2/NO2, respectively. In the six-pollutant model, significant positive associations were observed when pollutant concentrations were over: 34.64 µg/m3 for PM2.5, 57.93 µg/m3 for PM10, 56 µg/m3 for O3, below 643.6 µg/m3 for CO, and within 33 and 48 µg/m3 for NO2. The six-pollutant model using these best-fitted link functions demonstrated superior model fitting compared to exposure-categorized model or linear link function model assuming proportionality of odds. CONCLUSION: Non-linear associations were found between air pollutants and MASLD prevalence. PM2.5, PM10, O3, CO, and NO2 exhibited positive associations with MASLD in specific concentration ranges, highlighting the need to consider non-linear relationships in assessing the impact of air pollution on MASLD.

All-Cause and Cause-Specific Mortality in Parents After the Death of a Child in Taiwan: A Population-Based Cohort Study.

OBJECTIVE: Research from Western countries suggests that there is an increase in mortality in parents bereaved by the death of a child. Few studies have investigated this issue in a non-Western context. We explored the impact of the death of a child on parental mortality in Taiwan. METHOD: By linking population-based national registers, we followed the 2004-2014 birth cohort ( N = 2,083,972) up until 2016. A total of 11,755 child deaths were identified. For each deceased child, four living children matched on age and sex were randomly selected; their parents were the comparison group. We used Cox proportional hazards regression models to compare the mortality risk of bereaved parents with the comparison group up until 2017. RESULTS: Overall mortality risk was increased in parents who experienced the death of a child; the risk was higher in bereaved mothers (adjusted hazard ratio = 4.91, 95% confidence interval = 3.96-6.09) than fathers (adjusted hazard ratio = 1.82, 95% confidence interval = 1.55-2.13). The risk did not differ according to the sex of the child, but parents whose children died of unexpected causes (i.e., suicide/accidents/violence) were at greater risk than those dying of other causes. Risk was higher when the child was older than 1 year at the time of death than for deaths before age 1 year. CONCLUSIONS: Parents who lost a child were at increased mortality risk in this East Asian population. Special attention should be paid to the health of bereaved parents and explore the pathways leading to their risk.

Maternal anemia and the risk of childhood cancer: A population-based cohort study in Taiwan.

BACKGROUND: Childhood cancer may be related to maternal health in pregnancy. Maternal anemia is a common condition in pregnancy, especially in low-income countries, but the association between maternal anemia and childhood cancer has not been widely studied. OBJECTIVE: To examine the potential relation between maternal anemia during pregnancy and childhood cancers in a population-based cohort study in Taiwan. METHODS: We examined the relationship between maternal anemia and childhood cancer in Taiwan (N = 2160 cancer cases, 2,076,877 noncases). Cases were taken from the National Cancer Registry, and noncases were selected from birth records. Using national health registries, we obtained maternal anemia diagnoses. We estimated the risks for childhood cancers using Cox proportional hazard analysis. RESULTS: There was an increased risk of cancers in children born to mothers with nutritional anemia (hazard ratio (HR): 1.32, 95% CI 0.99, 1.76). Iron deficiency anemia (HR: 1.30, 95% CI 0.97-1.75) carried an increased risk, while non-nutritional anemias were not associated with childhood cancer risk. CONCLUSION: Our results provide additional support for screening for anemia during pregnancy. Adequate nutrition and vitamin supplementation may help to prevent some childhood cancer.

Maternal diabetes and childhood cancer risks in offspring: two population-based studies.

BACKGROUND: The effect of maternal diabetes on childhood cancer has not been widely studied. METHODS: We examined this in two population-based studies in Denmark (N = 6420 cancer cases, 160,484 controls) and Taiwan (N = 2160 cancer cases, 2,076,877 non-cases) using logistic regression and Cox proportional hazard regression adjusted for birth year, child's sex, maternal age and birth order. RESULTS: Gestational diabetes in Denmark [odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.71-1.35] or type II and gestational diabetes in Taiwan (type II: hazard ratio (HR) = 0.81, 95% CI: 0.63-1.05; gestational diabetes: HR = 1.06, 95% CI: 0.92-1.22) were not associated with cancer (all types combined). In Denmark, maternal type I diabetes was associated with the risk of glioma (OR = 2.33, 95% CI: 1.04-5.22), while in Taiwan, the risks of glioma (HR = 1.59, 95% CI: 1.01-2.50) were elevated among children whose mothers had gestational diabetes. There was a twofold increased risk for hepatoblastoma with maternal type II diabetes (HR = 2.02, 95% CI: 1.02-4.00). CONCLUSIONS: Our results suggest that maternal diabetes is an important risk factor for certain types of childhood cancers, emphasising the need for effective interventions targeting maternal diabetes to prevent serious health effects in offspring.

Psychometric properties of a novel instrument for evaluating indoor air pollution health literacy in adults.

This study aimed to develop and validate the psychometric properties of a novel instrument that measures Indoor Air Pollution Health Literacy (IAPHL). The qualitative phase was conducted to design questions based on the conceptual model of the European Health Literacy Survey Questionnaire. We developed a 38-item instrument covering 12 constructs, that is, four information competencies within three health domains to assess IAPHL. A cross-sectional online video survey of 647 adults aged 20 years and above in Taiwan was conducted. Various measures of validity and reliability coefficients were assessed to indicate the psychometric properties of the IAPHL instrument. The content validity indices for relevance, importance, and clarity of the 38 questions were 0.97, 0.96, and 0.89, respectively. The model fit indices obtained from the confirmatory factor analysis supported the acceptable structures of the theoretically hypothetical 12-factor model (standardized root mean square residual = 0.055; root mean square error of approximation = 0.065). Internal consistency for the instrument showed a Cronbach's alpha of 0.96. The IAPHL instrument developed in this study showed satisfactory validity and reliability and can be used in future fieldwork.

Outdoor air pollutants exposure associated with pulmonary function and EBC pH value in atopic asthmatic and non-asthmatic children.

OBJECTIVE: Air pollution is associated with the prevalence of respiratory diseases. This study aimed to evaluate the impacts of outdoor air pollutants and indoor Dermatophagoides pteronyssinus 1 (Der p 1) exposure on levels of fractional exhaled nitric oxide (FeNO), exhaled breath condensate (EBC) pH, and pulmonary function in atopic children. METHODS: This study recruited 59 atopic mild-to-moderate asthmatic children and 23 atopic non-asthmatic children. Data on personal characteristics, FeNO, EBC pH, and pulmonary function were collected. Group 1 allergens of Der p 1 were measured on the tops of mattresses and on bedroom floors in the children's homes, and outdoor air pollutant concentrations were estimated from air quality monitoring stations, using the ordinary kriging method. RESULTS: Exposure levels of outdoor air pollutants, except for particulate matter (PM)2.5, for the recruited children met outdoor air quality standards set by the Taiwan Environmental Protection Agency. The lag effect of outdoor PM10 exposure was negatively associated with the forced expiratory volume in one second (FEV1) [(Lag 1: ß=-0.771, p = 0.028), and O3 (Lag 1-7: ß=-2.02, p = 0.04, Lag 1-28: ß=-3.213, p = 0.029)]. Median pulmonary function parameters differed significantly in forced vital capacity (FVC) (p = 0.004) and FEV1 (p = 0.024) values between atopic asthmatic and non-asthmatic children. No association was found between the FeNO/EBC pH level and exposure to Der p 1 allergen and air pollutants in the recruited children. CONCLUSIONS: Outdoor PM10 and O3 exposure was associated with reduction in FEV1 in atopic asthmatic and non-asthmatic children.

A national survey of ambient air pollution health literacy among adult residents of Taiwan.

OBJECTIVE: To investigate the level of and covariates associated with ambient air pollution health literacy (AAPHL) among adult residents of Taiwan. METHODS: With a cross-sectional study design, we conducted telephone interviews using a Chinese version AAPHL scale, which consisted of 24 items assessing 12 subdomains of AAPHL formed by 4 information processing competence matrices (i.e., access, understand, appraise, and apply) and 3 health contexts (i.e., healthcare, disease prevention, and health promotion). The AAPHL was with the lowest and highest score at 1 to 4, respectively. Between September and November 2020, a sample of 1017 and 280 adults was successfully interviewed via home phones and mobile phones, respectively. We employed multiple linear regression models to identify covariates significantly associated with overall and 4 matric-specific AAPHL scores. RESULTS: The mean and standard deviation (±SD) of overall AAPHL score was considered as moderate at 2.90 (±0.56), with the highest and lowest metric-specific score for "apply" (3.07 ± 0.59) and "appraise" (2.75 ± 0.66). Lower education was significantly associated with a lower overall score; and living with children < 12 years and single were both significantly associated with higher overall scores. We also noted a significant geographic variation in overall score in which people living in the east/remote islands had highest scores. CONCLUSIONS: People in Taiwan had only moderate level of AAPHL; and covariates including education, living arrangement, marital status, and area of living were significantly associated with AAPHL. These covariates should be considered in future educational interventions aiming to improve the AAPHL in the community.

Residential greenness and birth outcomes: Evaluating the mediation and interaction effects of particulate air pollution.

BACKGROUND: The few studies that examined the association between residential greenness and birth outcomes have produced inconsistent results, and the underlying mechanisms of these associations remain unclear. OBJECTIVES: We examined the mediation and interaction effects of particulate matter (PM) air pollution on the relationship between greenness exposure during the first and third trimesters of pregnancy and birth outcomes, including preterm birth (PTB), term low birth weight (TLBW), small for gestational age (SGA), birth weight (BW), and head circumference (HC). METHODS: We conducted a retrospective cohort study on 16,184 singleton live births between 2010 and 2012 in Taiwan. Residential greenness was estimated based on the normalized difference vegetation index (NDVI), and the PM information during the first and third trimesters was estimated through hybrid kriging land use regression and ordinary kriging interpolation methods. Multiple regression analyses were performed to evaluate the associations between greenness exposure and birth outcomes. We estimated the mediating effects of PM associated with greenness exposure on birth outcomes through causal mediation analyses. We also examined the potential multiplicative and additive interactions between greenness exposure and PM and their effects on birth outcomes. RESULTS: The first trimester NDVI exposure was associated with reduced risks for PTB, TLBW, and SGA, which had an adjusted OR (aOR) of 0.93 (95% CI: 0.89-0.97), 0.91 (95% CI: 0.83-0.99), and 0.95 (95% CI: 0.91-1.00), respectively, per 0.1 unit increase in multi-pollutant models. The causal mediation analysis showed that PM mediated approximately 5-19% of the association between first and third trimester greenness and PTB and mediated approximately 15-37% of the association between greenness and SGA. We identified multiplicative interactions in log scale between first trimester PM10 and NDVI exposure for SGA (aORinteraction = 0.92, p = 0.03) and HC (estimateinteraction = 1.47, p = 0.04). CONCLUSIONS: This study revealed beneficial associations between residential greenness and birth outcomes, including PTB, TLBW, and SGA. The associations were partly mediated by a reduction in exposure to PM air pollution. SUMMARY: The beneficial effects of greenness on PTB and SGA are partly mediated by a reduction in exposure to PM air pollution.

Gestational risk factors and childhood cancers: A cohort study in Taiwan.

Gestational risk factors such as birth weight, gestational age and parity have been repeatedly found to be related to pediatric cancers, but few reports have emerged from Asian countries. Here we report on demographic and gestational factors in a Taiwanese cohort. Our study included all children born in Taiwan 2004-2014 for whom there was a birth record (n = 2,079,037), of which 1900 children had been diagnosed with cancer prior to age 12. We conducted multivariable hazard regression to examine associations between demographic and gestational factors with cancer. Greater parity (family with 2+ older children) was related to acute myeloid leukemia [Hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.31, 3.55), central nervous system tumors (HR = 1.67, CI: 1.13, 2.48) and neuroblastoma (HR = 1.67, CI: 1.07, 2.63). Hepatoblastoma cases had a higher risk of low birth weight (<2,500 g; HR = 3.01, CI: 1.85, 4.91), very preterm birth (<33 weeks gestation; HR = 13.71, CI: 7.45, 25.23), plural pregnancies (HR = 2.37, CI: 1.10, 5.14) and both small (HR = 2.13, CI: 1.23, 3.67) and large (HR = 1.83, CI: 1.01, 3.32) for gestational age. Germ cell tumors were more common among children born in rural areas (HR = 1.63, CI: 1.02, 2.60). Despite that Taiwan has lower rates of both high and low birthweight compared to other developed nations, we observed several similar associations to those reported in Western Countries. Further research should examine unique exposures in Taiwan that may be contributing to higher incidence of certain cancer types.

Better Self-report Health Status and Provider-Patient Communication in Dental Service Can Improve the Patient Experience: A Cross-year Comparison from the NHI Survey.

Several factors, including healthcare outcomes and quality, influence patients' expectations of healthcare services. Currently, as patients have more understanding about dental care services, patient satisfaction is essential for continually improving the services being provided. The purpose of this study is to analyze the multiyear annual National Health Insurance (NHI) patient experience survey in Taiwan to explore the factors associated with the satisfaction rate from 2012-2016. This study used the annual NHI survey to explore patients' experiences of receiving medical service in dental care from 2012 to 2016. There were over 40 major items in the survey each year; however, we only selected suitable items that followed the Andersen model. We ran a logistics regression testing the relationship between the covariates and the items related to satisfaction in outcomes in different years. Patients who received health education from a provider in most time, self-reported better health status, felt that cost of care was not expensive, did not wait too long for counseling time and found it easy to make an appointment, had two to ten times greater satisfaction in outcomes compared with those who did not (OR: 1.83-10.06). Individuals working in the healthcare industry should implement communication strategies to improve patients' experience in the care process by including easy-to-understand explanations or sharing decision-making with patients. Furthermore, in patient experience surveys in dental care, less attention should be paid to whether patients can provide meaningful quality measures and more attention to ways in which patient experiences can be improved. This can be achieved by providing easy-to-understand explanations, giving patients an opportunity to express their concerns, and by sharing decision-making with patients.

Spina bifida and pediatric cancers.

Spina bifida has been reported to co-occur with pediatric cancer, but comprehensive evaluations remained elusive. We investigated this co-occurrence in two large, population-based studies in Taiwan (N = 1900 cancer cases, 2,077,137 controls) and Denmark (N = 5508 cases, 137,700 controls). Analyses in Denmark were restricted to the period before prenatal diagnostics became available (2004) and pregnancy terminations of fetuses with birth defects became more common. Using national patient and cancer registries, we linked spina bifida and cancer diagnoses among cases and non-cases. The risk of spina bifida among all cancer cases was increased and similar in Denmark [odds ratio (OR)=8.4, 95% confidence interval (CI) 5.1-13.8] and Taiwan (OR = 8.5, 95% CI 4.0-17.8), particularly for central nervous system (CNS) tumors (Denmark: OR = 16.3, 95% CI 8.1-33.0; Taiwan: OR = 26.6, 95% CI 8.5, 83.1), including benign CNS tumors (Denmark: OR = 41.5, 95% CI 21.2, 81.4). These findings suggest the need for comprehensive investigation of shared risk factors in the link between spina bifida and pediatric cancer.

Examining the Reserve Hypothesis in Parkinson's Disease: A Longitudinal Study.

BACKGROUND: Whether reserve plays a role in Parkinson's disease (PD) patients has received less attention than in dementia and has been mainly examined in relation with cognitive function. OBJECTIVE: To investigate whether reserve plays a role in the severity and progression of motor, cognitive, and nonmotor PD symptoms by examining whether education level (proxy of reserve) is associated with baseline performance and rate of progression. METHODS: We used data from a longitudinal cohort of PD patients (≤5-year disease duration at baseline) annually followed up to 5 years (n = 393; 41% women; mean age = 62.3 years, standard deviation = 10.0; mean disease duration = 2.6 years, standard deviation = 1.5). We examined the relationship of education with time to reach Hoehn and Yahr stage ≥3 using Cox regression and with baseline severity and progression of motor (Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts II and III, gait speed), cognitive (Mini-Mental State Examination), and nonmotor (depression, anxiety, nonmotor symptoms scale, quality of life) symptoms using mixed models. RESULTS: Education level was not associated with age at onset or diagnosis. Compared with the low-education group, the incidence of Hoehn and Yahr ≥3.0 was 0.42 times lower (95% confidence interval, 0.22-0.82, P = 0.012) in the high-education group. Higher education was associated with better baseline motor function (P < 0.001), but not with the rate of motor decline (P > 0.15). Similar results were observed for cognition. Education was not associated with nonmotor symptoms. CONCLUSIONS: Higher education is associated with better baseline motor/cognitive function in PD, but not with rate of decline, and with a lower risk of reaching Hoehn and Yahr ≥3 during the follow-up. Our observations are consistent with a passive reserve hypothesis for motor/cognitive symptoms. © 2019 International Parkinson and Movement Disorder Society.

Cancers Preceding Parkinson's Disease after Adjustment for Bias in a Danish Population-Based Case-Control Study.

Cancer patients are at lower risk of developing Parkinson's disease (PD) compared with the general population. One explanation is the negative association between smoking and PD, but PD risk is also lower for cancers not related to smoking. Another explanation is survival bias where death from cancer may act as a competing risk. We conducted a large population-based case-control study in Denmark and investigated whether cancer diagnosis reduced the risk of developing PD even after adjusting for important risk factors including smoking, physical activity, and lifetime oestrogen status. Using probabilistic bias analysis we quantified the influence of survival bias. We estimated negative point estimates (ORs) between cancers and PD for all cancers except skin, female breast, and ill-defined and unspecified 0.85 (95% CI 0.59-1.21); smoking-related cancers 0.75 (95% CI 0.45-1.23); and cancers not related to smoking 0.82 (95% CI 0.49-1.38) that are very similar to those previously reported for a much larger Danish register only based study, even though our confidence intervals include the null. These effect estimates shifted towards the null after accounting for survival bias but most bias-adjusted ORs remained below 1 within the range of priors considered in simulations. Overall, cancer patients have a lower risk of developing PD even after controlling for cancer-related lifestyles factors and correcting for survival bias.

Neighbourhood assets and early pregnancy cardiometabolic risk factors.

BACKGROUND: Prepregnancy cardiometabolic risk factors are associated with increased risks of adverse pregnancy outcomes. Neighbourhood features may reflect prepregnancy exposures that contribute to poor cardiometabolic health before pregnancy and may contribute to racial disparities in pregnancy outcomes. METHODS: Early pregnancy measurements from 1504 women enrolled in the Prenatal Exposures and Preeclampsia Prevention study were linked to a 2000 Census-based measure of neighbourhood socio-economic status and commercial data (food, alcohol, and retail density) during 1997-2001. Multilevel random-intercept linear regression was used to separately estimate the association between levels of neighbourhood assets (low, mid-low, mid-high, high) and C-reactive protein (CRP), systolic blood pressure (SBP), and body mass index (BMI) in cross-sectional analyses. Low neighbourhood assets have high-poverty/low-retail, whereas high neighbourhood assets have low-poverty/high-retail. Models were adjusted for individual-level factors (age and race), and we assessed effect modification by race. RESULTS: Low compared with high neighbourhood assets were associated with higher BMI (ß 1.95 kg/m2 , 95% CI 0.89, 3.00), after adjusting for individual-level covariates. After adjusting for BMI and other covariates, low compared with high assets were associated with higher CRP concentrations (ß 0.20 ng/mL, 95% CI 0.01, 0.39). Neighbourhood assets were not associated with SBP. Race did not modify the association between neighbourhood assets and cardiometabolic risk factors. CONCLUSIONS: Early pregnancy adiposity is related to neighbourhood features independent of individual factors. Further, inflammation beyond accounting for adiposity is related to neighbourhood features. Strategies that address neighbourhood assets during preconception and interconception may be promising approaches to improve prepregnancy health.

Pooled analysis of the HLA-DRB1 by smoking interaction in Parkinson disease.

OBJECTIVE: Inflammatory response plays an important role in Parkinson disease (PD). Previous studies have reported an association between human leukocyte antigen (HLA)-DRB1 and the risk of PD. There has also been growing interest in investigating whether inflammation-related genes interact with environmental factors such as smoking to influence PD risk. We performed a pooled analysis of the interaction between HLA-DRB1 and smoking in PD in 3 population-based case-control studies from Denmark and France. METHODS: We included 2,056 cases and 2,723 controls from 3 PD studies (Denmark, France) that obtained information on smoking through interviews. Genotyping of the rs660895 polymorphism in the HLA-DRB1 region was based on saliva or blood DNA samples. To assess interactions, we used logistic regression with product terms between rs660895 and smoking. We performed random-effects meta-analysis of marginal associations and interactions. RESULTS: Both carrying rs660895-G (AG vs AA: odds ratio [OR] = 0.81; GG vs AA: OR = 0.56; p-trend = 0.003) and ever smoking (OR = 0.56, p < 0.001) were inversely associated with PD. A multiplicative interaction was observed between rs660895 and smoking using codominant, additive (interaction parameter = 1.37, p = 0.005), and dominant (interaction parameter = 1.54, p = 0.001) genetic models without any heterogeneity (I² = 0.0%); the inverse association of rs660895-(AG+GG) with PD seen in never smokers (OR = 0.64, p < 0.001) disappeared among ever smokers (OR = 1.00, p = 0.99). Similar interactions were observed when we investigated light and heavy smokers separately. INTERPRETATION: Our study provides the first evidence that smoking modifies the previously reported inverse association of rs660895-G with PD, and suggests that smoking and HLA-DRB1 are involved in common pathways, possibly related to neuroinflammation. Ann Neurol 2017;82:655-664.

Gene-Environment Interaction in Parkinson's Disease: Coffee, ADORA2A, and CYP1A2.

BACKGROUND AND PURPOSE: Drinking caffeinated coffee has been reported to provide protection against Parkinson's disease (PD). Caffeine is an adenosine A2A receptor (encoded by the gene ADORA2A) antagonist that increases dopaminergic neurotransmission and Cytochrome P450 1A2 (gene: CYP1A2) metabolizes caffeine; thus, gene polymorphisms in ADORA2A and CYP1A2 may influence the effect coffee consumption has on PD risk. METHODS: In a population-based case-control study (PASIDA) in Denmark (1,556 PD patients and 1,606 birth year- and gender-matched controls), we assessed interactions between lifetime coffee consumption and 3 polymorphisms in ADORA2A and CYP1A2 for all subjects, and incident and prevalent PD cases separately using logistic regression models. We also conducted a meta-analysis combining our results with those from previous studies. RESULTS: We estimated statistically significant interactions for ADORA2A rs5760423 and heavy vs. light coffee consumption in incident (OR interaction = 0.66 [95% CI 0.46-0.94], p = 0.02) but not prevalent PD. We did not observe interactions for CYP1A2 rs762551 and rs2472304 in incident or prevalent PD. In meta-analyses, PD associations with daily coffee consumption were strongest among carriers of variant alleles in both ADORA2A and CYP1A2. CONCLUSION: We corroborated results from a previous report that described interactions between ADORA2A and CYP1A2 polymorphisms and coffee consumption. Our results also suggest that survivor bias may affect results of studies that enroll prevalent PD cases.

Gene-environment interactions linking air pollution and inflammation in Parkinson's disease.

Both air pollution exposure and systemic inflammation have been linked to Parkinson's disease (PD). In the PASIDA study, 408 incident cases of PD diagnosed in 2006-2009 and their 495 population controls were interviewed and provided DNA samples. Markers of long term traffic related air pollution measures were derived from geographic information systems (GIS)-based modeling. Furthermore, we genotyped functional polymorphisms in genes encoding proinflammatory cytokines, namely rs1800629 in TNFα (tumor necrosis factor alpha) and rs16944 in IL1B (interleukin-1ß). In logistic regression models, long-term exposure to NO2 increased PD risk overall (odds ratio (OR)=1.06 per 2.94µg/m3 increase, 95% CI=1.00-1.13). The OR for PD in individuals with high NO2 exposure (≧75th percentile) and the AA genotype of IL1B rs16944 was 3.10 (95% CI=1.14-8.38) compared with individuals with lower NO2 exposure (<75th percentile) and the GG genotype. The interaction term was nominally significant on the multiplicative scale (p=0.01). We did not find significant gene-environment interactions with TNF rs1800629. Our finds may provide suggestive evidence that a combination of traffic-related air pollution and genetic variation in the proinflammatory cytokine gene IL1B contribute to risk of developing PD. However, as statistical evidence was only modest in this large sample we cannot rule out that these results represent a chance finding, and additional replication efforts are warranted.

Prenatal air pollution exposure and ultrasound measures of fetal growth in Los Angeles, California.

BACKGROUND: Few previous studies examined the impact of prenatal air pollution exposures on fetal development based on ultrasound measures during pregnancy. METHODS: In a prospective birth cohort of more than 500 women followed during 1993-1996 in Los Angeles, California, we examined how air pollution impacts fetal growth during pregnancy. Exposure to traffic related air pollution was estimated using CALINE4 air dispersion modeling for nitrogen oxides (NOx) and a land use regression (LUR) model for nitrogen monoxide (NO), nitrogen dioxide (NO2) and NOx. Exposures to carbon monoxide (CO), NO2, ozone (O3) and particles <10µm in aerodynamic diameter (PM10) were estimated using government monitoring data. We employed a linear mixed effects model to estimate changes in fetal size at approximately 19, 29 and 37 weeks gestation based on ultrasound. RESULTS: Exposure to traffic-derived air pollution during 29 to 37 weeks was negatively associated with biparietal diameter at 37 weeks gestation. For each interquartile range (IQR) increase in LUR-based estimates of NO, NO2 and NOx, or freeway CALINE4 NOx we estimated a reduction in biparietal diameter of 0.2-0.3mm. For women residing within 5km of a monitoring station, we estimated biparietal diameter reductions of 0.9-1.0mm per IQR increase in CO and NO2. Effect estimates were robust to adjustment for a number of potential confounders. We did not observe consistent patterns for other growth endpoints we examined. CONCLUSIONS: Prenatal exposure to traffic-derived pollution was negatively associated with fetal head size measured as biparietal diameter in late pregnancy.