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Water-soluble inorganic (WSI) ions are major components of ambient air PM2.5 (particulate matter of diameter ≤2.5 μm); however, their potential health effects are understudied. On C57BL/6 mice, we quantified the effect of three major PM2.5 WSIs (NO3-, SO42-, and NH4+) on respiratory systems. Exposure scenarios include different WSI types, concentrations, animal development stages (young vs adult), and sex. The exposure effects were comprehensively assessed, with special focus on the respiratory function and tissue/cell level changes. Chronic PM2.5 NO3- exposure produced significant respiratory function decline, mainly presented as airflow obstruction. The decline was more profound in young mice than in adult mice. In young mice, exposure to 22 μg/m3 PM2.5 NO3- reduced FEV0.05 (forced expiratory volume in 0.05 s) by 11.3% (p = 9.6 × 10-3) and increased pulmonary neutrophil infiltration by 7.9% (p = 7.1 × 10-3). Causality tests identified that neutrophil infiltration was involved in the biological mechanism underlying PM2.5 NO3- toxicity. In contrast, the effects of PM2.5 SO42- were considerably weaker than NO3-. PM2.5 NO3- exposure was 3.4 times more potent than PM2.5 SO42- in causing reduction of the peak expiratory flow. PM2.5 NH4+ exposure had no statistically significant effects on the respiratory function. In summary, this study provided strong evidence on the adverse impacts of PM2.5 WSIs, where the impacts were most profound in young mice exposed to PM2.5 NO3-. If confirmed in humans, toxicity of PM2.5 WSI will have broad implications in environment health and policy making.

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell–mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4(+)/CD8(+) T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.

BACKGROUND: Ambient particulate matter (PM) exposure has been associated with respiratory function decline in epidemiological studies. We hypothesize that a possible underlying mechanism is the perturbation of airway microbiome by PM exposure. METHODS: During October 2016 – October 2017, on two human cohorts (n = 115 in total) in Shanghai China, we systematically collected three categories of data (1) respiratory functions, (2) airway microbiome from sputum and (3) ambient PM(2.5) (PM of ≤ 2.5 micron in diameter) – level in ambient air. We investigated the impact of PM(2.5) on airway microbiome as well as the link between airway microbiome and respiratory functions using mix linear regression models. RESULTS: The respiratory function of our primary interest includes forced vital capacity (FVC) and forced expiratory volume in 1st second (FEV(1)). FEV(1)/FVC, an important respiratory function trait and key diagnosis criterion of COPD, was significantly associated with airway bacteria load (p = 0.0038); and FEV(1) was associated with airway microbiome profile (p = 0.013). Further, airway microbiome was significantly influenced by PM(2.5) exposure (p = 4.48E-11). CONCLUSIONS: To our knowledge, for the first time, we demonstrated the impact of PM(2.5) on airway microbiome, and reported the link between airway microbiome and respiratory functions. The results expand our understanding on the scope of PM(2.5) exposure’s influence on human respiratory system, and pointed to novel etiological mechanism of PM(2.5) exposure induced diseases.

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss but whether recipient risk allele expression impacts kidney transplant outcomes is unclear. To test whether recipient APOL1 allelic variants independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data of donors and recipients from two kidney transplant cohorts, Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17). We estimated genetic ancestry (quantified as proportion of African ancestry or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we observed that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with increased risk of death-censored allograft loss (DCAL), independent of genetic ancestry (HR = 2.14; P = 0.006), and within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with increased risk of any T cell-mediated rejection (TCMR) event. Analysis of the CTOT cohort validated these associations. Ex vivo studies of peripheral blood mononuclear cells revealed unanticipated high APOL1 expression in activated CD4+/CD8+ T cells and natural killer cells. We detected enriched immune response gene pathways in G1/G2 allele carriers vs. non-carriers among patients on the kidney waitlist and healthy controls. Together our findings highlight a previously unrecognized contribution of recipient APOL1 risk alleles to renal allograft outcomes. This immunomodulatory role has broader implications for immune mediated injury to native kidneys.

Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown.We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH.We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI.Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.

Background Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown. Methods We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH. Results We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI. Conclusions Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.

AimsFibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test.Methods and resultsFemales with ‘multifocal’ FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%.ConclusionFMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

Major depressive disorder (MDD) affects ~20% of the world population and is characterized by strong sexual dimorphism with females being 2–3 times more likely to develop this disorder. Previously, we demonstrated that a combination therapy with dihydrocaffeic acid (DHCA) and malvidin-glucoside (Mal-gluc) to synergistically target peripheral inflammation and stress-induced synaptic maladaptation in the brain was effective in alleviating chronic social defeat stress (CSDS)-induced depression-like phenotype in male mice. Here, we test the combination therapy in a female CSDS model for depression and compared sex-specific responses to stress in the periphery and the central nervous system. Similar to male mice, the combination treatment is also effective in promoting resilience against the CSDS-induced depression-like behavior in female mice. However, there are sex-specific differences in peripheral immune responses and differential gene regulation in the prefrontal cortex to chronic stress and to the treatment. These data indicate that while therapeutic approaches to combat stress-related disorders may be effective in both sexes, the mechanisms underlying these effects differ, emphasizing the need for inclusion of both sexes in preclinical studies using animal models.

Background Impaired in utero fetal growth trajectory may have long term health consequences of the newborns and increase risk of adulthood metabolic diseases. Prenatal exposure to air pollution has been linked to fetal development restriction; however, the impact of exposure to ambient air pollutants on the entire course of intrauterine fetal development has not been comprehensively investigated. Methods During 2015–2018, two cohorts of mother-infant dyads (N = 678 and 227) were recruited in Shanghai China, from which three categories of data were systematically collected: (1) daily exposure to six air pollutants during pregnancy, (2) fetal biometry in the 2nd (gestational week 24, [GW24]) and 3rd trimester (GW36), and (3) neonatal outcomes at birth. We investigated the impact of prenatal exposure to air pollutant mixture on the trajectory of fetal development during the course of gestation, adjusting for a broad set of potential confounds. Results Prenatal exposure to PM2.5, PM10, SO2 and O3 significantly reduced fetal biometry at GW24, where SO2 had the most potent effect. For every 10 μg/m3 increment increase of daily SO2 exposure during the 1st trimester shortened femur length by 2.20 mm (p = 6.7E-21) translating to 5.3% reduction from the average of the study cohort. Prenatal air pollution exposure also decreased fetal biometry at GW36 with attenuated effect size. Comparing to the lowest exposed quartile, fetus in the highest exposed quartile had 6.3% (p = 3.5E-5) and 2.1% (p = 2.4E-3) lower estimated intrauterine weight in GW24 and GW36, respectively; however, no difference in birth weight was observed, indicating a rapid catch-up growth in the 3rd trimester. Conclusions To our knowledge, for the first time, we demonstrated the impact of prenatal exposure to ambient air pollutants on the course of intrauterine fetal development. The altered growth trajectory and rapid catch-up growth in associated with high prenatal exposure may lead to long-term predisposition for adulthood metabolic disorders.

Smoking is a major cause of respiratory conditions. To date, the genetic pleiotropy between smoking behavior and lung function/chronic obstructive pulmonary disease (COPD) have not been systematically explored. We leverage large data sets of smoking behavior, lung function and COPD, and addressed two questions, (1) whether the genetic predisposition of nicotine dependence influence COPD risk and lung function; and (2) the genetic pleiotropy follow causal or independent model. We found the genetic predisposition of nicotine dependence was associated with COPD risk, even after adjusting for smoking behavior, indicating genetic pleiotropy and independent model. Two known nicotine dependent loci (15q25.1 and 19q13.2) were associated with smoking adjusted lung function, and 15q25.1 reached genome-wide significance. At various suggestive p-value thresholds, the smoking adjusted lung function traits share association signals with cigarettes per day and former smoking, substantially greater than random chance. Empirical data showed the genetic pleiotropy between nicotine dependence and COPD or lung function. The basis of pleiotropic effect is rather complex, attributable to a large number of genetic variants, and many variants functions through independent model, where the pleiotropic variants directly affect lung function, not mediated by influencing subjects’ smoking behavior.

Background Increasing number of eQTL (Expression Quantitative Trait Loci) datasets facilitate genetics and systems biology research. Meta-analysis tools are in need to jointly analyze datasets of same or similar issue types to improve statistical power especially in trans-eQTL mapping. Meta-analysis framework is also necessary for ChrX eQTL discovery. Results We developed a novel tool, meta-eqtl, for fast eQTL meta-analysis of arbitrary sample size and arbitrary number of datasets. Further, this tool accommodates versatile modeling, eg. non-parametric model and mixed effect models. In addition, meta-eqtl readily handles calculation of chrX eQTLs. Conclusions We demonstrated and validated meta-eqtl as fast and comprehensive tool to meta-analyze multiple datasets and ChrX eQTL discovery. Meta-eqtl is a set of command line utilities written in R, with some computationally intensive parts written in C. The software runs on Linux platforms and is designed to intelligently adapt to high performance computing (HPC) cluster. We applied the novel tool to liver and adipose tissue data, and revealed eSNPs underlying diabetes GWAS loci.