Zhanghua Chen

Chronic effects of air pollution on respiratory health in Southern California children: findings from the Southern California Children’s Health Study

Outdoor air pollution is one of the leading contributors to adverse respiratory health outcomes in urban areas around the world. Children are highly sensitive to the adverse effects of air pollution due to their rapidly growing lungs, incomplete immune and metabolic functions, patterns of ventilation and high levels of outdoor activity. The Childrens Health Study (CHS) is a continuing series of longitudinal studies that first began in 1993 and has focused on demonstrating the chronic impacts of air pollution on respiratory illnesses from early childhood through adolescence. A large body of evidence from the CHS has documented that exposures to both regional ambient air and traffic-related pollutants are associated with increased asthma prevalence, new-onset asthma, risk of bronchitis and wheezing, deficits of lung function growth, and airway inflammation. These associations may be modulated by key genes involved in oxidative-nitrosative stress pathways via gene-environment interactions. Despite successful efforts to reduce pollution over the past 40 years, air pollution at the current levels still brings many challenges to public health. To further ameliorate adverse health effects attributable to air pollution, many more toxic pollutants may require regulation and control of motor vehicle emissions and other combustion sources may need to be strengthened. Individual interventions based on personal susceptibility may be needed to protect childrens health while control measures are being implemented.

Ambient Air Pollutants Have Adverse Effects on Insulin and Glucose Homeostasis in Mexican Americans

OBJECTIVE Recent studies suggest that air pollution plays a role in type 2 diabetes (T2D) incidence and mortality. The underlying physiological mechanisms have yet to be established. We hypothesized that air pollution adversely affects insulin sensitivity and secretion and serum lipid levels. RESEARCH DESIGN AND METHODS Participants were selected from BetaGene (n = 1,023), a study of insulin resistance and pancreatic β-cell function in Mexican Americans. All participants underwent DXA and oral and intravenous glucose tolerance tests and completed dietary and physical activity questionnaires. Ambient air pollutant concentrations (NO2, O3, and PM2.5) for short- and long-term periods were assigned by spatial interpolation (maximum interpolation radius of 50 km) of data from air quality monitors. Traffic-related air pollution from freeways (TRAP) was estimated using the dispersion model as NOx. Variance component models were used to analyze individual and multiple air pollutant associations with metabolic traits. RESULTS Short-term (up to 58 days cumulative lagged averages) exposure to PM2.5 was associated with lower insulin sensitivity and HDL-to-LDL cholesterol ratio and higher fasting glucose and insulin, HOMA-IR, total cholesterol, and LDL cholesterol (LDL-C) (all P ≤ 0.036). Annual average PM2.5 was associated with higher fasting glucose, HOMA-IR, and LDL-C (P ≤ 0.043). The effects of short-term PM2.5 exposure on insulin sensitivity were largest among obese participants. No statistically significant associations were found between TRAP and metabolic outcomes. CONCLUSIONS Exposure to ambient air pollutants adversely affects glucose tolerance, insulin sensitivity, and blood lipid concentrations. Our findings suggest that ambient air pollutants may contribute to the pathophysiology in the development of T2D and related sequelae.

Effects of Childhood Asthma on the Development of Obesity among School-aged Children

Rationale: Asthma and obesity often occur together in children. It is unknown whether asthma contributes to the childhood obesity epidemic. Objectives: We aimed to investigate the effects of asthma and asthma medication use on the development of childhood obesity. Methods: The primary analysis was conducted among 2,171 nonobese children who were 5‐8 years of age at study enrollment in the Southern California Childrens Health Study (CHS) and were followed for up to 10 years. A replication analysis was performed in an independent sample of 2,684 CHS children followed from a mean age of 9.7 to 17.8 years. Measurements and Main Results: Height and weight were measured annually to classify children into normal, overweight, and obese categories. Asthma status was ascertained by parent‐ or self‐reported physician‐diagnosed asthma. Cox proportional hazards models were fitted to assess associations of asthma history with obesity incidence during follow‐up. We found that children with a diagnosis of asthma at cohort entry were at 51% increased risk of developing obesity during childhood and adolescence compared with children without asthma at baseline (hazard ratio, 1.51; 95% confidence interval, 1.08‐2.10) after adjusting for confounders. Use of asthma rescue medications at cohort entry reduced the risk of developing obesity (hazard ratio, 0.57; 95% confidence interval, 0.33‐0.96). In addition, the significant association between a history of asthma and an increased risk of developing obesity was replicated in an independent CHS sample. Conclusions: Children with asthma may be at higher risk of obesity. Asthma rescue medication use appeared to reduce obesity risk independent of physical activity.

Self-Reported Physical Activity Is Associated With β-Cell Function in Mexican American Adults

OBJECTIVE To examine the association between self-reported physical activity (PA) and diabetes-related quantitative traits. RESEARCH DESIGN AND METHODS The observational cohort was 1,152 Mexican American adults with dual-energy X-ray absorptiometry, oral and intravenous glucose tolerance tests, and self-reported dietary and PA questionnaires. PA was categorized into three mutually exclusive groups according to the U.S. Department of Health and Human Services PA guidelines for Americans: low (vigorous <75 min/week and moderate <150 min/week), moderate (vigorous ≥75 min/week or moderate ≥150 min/week), and high (vigorous ≥75 min/week and moderate ≥150 min/week). Trends in PA groups were tested for association with metabolic traits in a cross-sectional analysis. RESULTS The participants’ mean age was 35 years (range, 18–66 years), mean BMI was 29.6 kg/m2, and 73% were female. Among them, 501 (43%), 448 (39%), and 203 (18%) were classified as having low, moderate, and high PA, respectively. After adjustment for age, a higher PA was significantly associated with lower 2-h glucose, fasting insulin, and 2-h insulin and greater β-cell function (P = 0.001, 0.0003, 0.0001, and 0.004, respectively). The association did not differ significantly by sex. Results were similar after further adjustment for age, sex, BMI, or percent body fat. CONCLUSIONS An increasing level of PA is associated with a better glucose and insulin profile and enhanced β-cell function that is not explained by differences in BMI or percent body fat. Our results suggest that PA can be beneficial to β-cell function and glucose regulation independent of obesity.

Joint Effects of Known Type 2 Diabetes Susceptibility Loci in Genome-Wide Association Study of Singapore Chinese: The Singapore Chinese Health Study

Background Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study. Methods 2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r2>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ±100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis. Results Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69–2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72×10−14). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs. Conclusions While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment interactions complicate the genetic architecture of this disease.

Longitudinal Associations Between Ambient Air Pollution with Insulin Sensitivity, β-Cell Function, and Adiposity in Los Angeles Latino Children.

Evidence suggests that ambient air pollution (AAP) exposure may contribute to the development of obesity and type 2 diabetes. The objective of this study was to determine whether exposure to elevated concentrations of nitrogen dioxide (NO2) and particulate matter with aerodynamic diameter <2.5 (PM2.5) had adverse effects on longitudinal measures of insulin sensitivity (SI), β-cell function, and obesity in children at high risk for developing diabetes. Overweight and obese Latino children (8–15 years; n = 314) were enrolled between 2001 and 2012 from Los Angeles, CA, and followed for an average of 3.4 years (SD 3.1 years). Linear mixed-effects models were fitted to assess relationships between AAP exposure and outcomes after adjusting for covariates including body fat percent. Higher NO2 and PM2.5 were associated with a faster decline in SI and a lower SI at age 18 years, independent of adiposity. NO2 exposure negatively affected β-cell function, evidenced by a faster decline in disposition index (DI) and a lower DI at age 18 years. Higher NO2 and PM2.5 exposures over follow-up were also associated with a higher BMI at age 18 years. AAP exposure may contribute to development of type 2 diabetes through direct effects on SI and β-cell function.

High Calorie Intake Is Associated With Worsening Insulin Resistance and β-Cell Function in Hispanic Women After Gestational Diabetes Mellitus

OBJECTIVE To assess associations between dietary intake and rates of change in insulin resistance and β-cell function in Hispanic women with prior gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS Sixty-two nondiabetic Hispanic women with pregnancies complicated by GDM completed oral and intravenous glucose tolerance tests and bioelectrical impedance measurements of body fat every 12–15 months postpartum for up to 12 years. Self-reported dietary intake was collected at all visits by structured food frequency questionnaires developed for Hispanics. Mixed-effects models were used to assess the relationship between dietary intake and rates of change in metabolic outcomes during follow-up. RESULTS The median length of follow-up from the first postpartum evaluation was 8.0 years (interquartile range 4.5–10.8 years). At baseline, women were 32 ± 5.7 years old and had a median calorie intake of 2,091 kcal/day. Over the course of follow-up, dietary intake did not change significantly. Higher baseline calorie intake was associated with a faster decline in insulin sensitivity, measured by the insulin sensitivity index (SI) (P = 0.029), and β-cell compensation, measured by the disposition index (DI) (P = 0.027), over time. These associations remained after adjustment for baseline characteristics; changes in BMI, calorie intake, levels of physical activity; and additional pregnancies during the follow-up period. The median rates were −0.06 vs. −0.02 units/year for SI and −810 vs. −692 units/year for DI for women with baseline calorie intake above versus below the cohort median. CONCLUSIONS High calorie intake is associated with a faster decline in insulin sensitivity and β-cell compensation in Hispanic women who are at high risk for type 2 diabetes, independent of adiposity.

Exposure to traffic-related air pollution and the composition of the gut microbiota in overweight and obese adolescents

Background: Traffic‐related air pollution (TRAP) exposure has been linked to type 2 diabetes and metabolic dysfunction in humans. Animal studies suggest that air pollutants may alter the composition of the gut microbiota, which may negatively impact metabolic health through changes in the composition and/or function of the gut microbiome. Objectives: The primary aim of this study was to determine whether elevated TRAP exposure was correlated with gut bacterial taxa in overweight and obese adolescents from the Meta‐AIR (Metabolic and Asthma Incidence Research) study. The secondary aim was to examine whether gut microbial taxa correlated with TRAP were also correlated with risk factors for type 2 diabetes (e.g., fasting glucose levels). We additionally explored whether correlations between TRAP and these metabolic risk factors could be explained by the relative abundance of these taxa. Methods: Participants (17–19 years; n=43) were enrolled between 2014 and 2016 from Southern California. The CALINE4 line dispersion model was used to model prior year residential concentrations of nitrogen oxides (NOx) as a marker of traffic emissions. The relative abundance of fecal microbiota was characterized by 16S rRNA sequencing and spearman partial correlations were examined after adjusting for body fat percent. Results: Freeway TRAP was correlated with decreased Bacteroidaceae (r=−0.48; p=0.001) and increased Coriobacteriaceae (r=0.48; p<0.001). These same taxa were correlated with fasting glucose levels, including Bacteroidaceae (r=−0.34; p=0.04) and Coriobacteriaceae (r=0.41; p<0.01). Further, freeway TRAP was positively correlated fasting glucose (r=0.45; p=0.004) and Bacteroidaceae and Coriobacteriaceae explained 24% and 29% of the correlation between TRAP and fasting glucose levels. Conclusions: Increased TRAP exposure was correlated with gut microbial taxa and fasting glucose levels. Gut microbial taxa that were correlated with TRAP partially explained the correlation between TRAP and fasting glucose levels. These results suggest that exposure to air pollutants may negatively impact metabolic health via alterations in the gut microbiota. HIGHLIGHTSTraffic‐related air pollution (TRAP) was positively correlated with fasting glucose.TRAP exposure was correlated with specific gut microbial taxa.These taxa partially explained the correlation between TRAP and fasting glucose.TRAP exposure may negatively impact metabolic health via the gut microbiota.

Gene Coexpression Networks in Whole Blood Implicate Multiple Interrelated Molecular Pathways in Obesity in People with Asthma: Blood Gene Coexpression Networks of Asthma with Obesity

Asthmatic children who develop obesity through adolescence have poorer disease outcomes compared with those who do not. This study aimed to characterize the biology of childhood asthma complicated by adult obesity.

Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.