Association analysis between an epigenetic risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Exploratory Clinical Trial of a Depression Diagnostic Software That Integrates Stress Biomarkers and Composite Psychometrics.

OBJECTIVE: This study evaluated the clinical effectiveness of Minds.NAVI, a depression screening kit combining psychometric measures and stress hormone biomarkers, in a prospective clinical trial. The objective was to assess its potential as a depression screening tool and investigate the associations between psychological assessments, salivary hormone staging, and depression severity. METHODS: Thirty-five participants with major depressive disorder and 12 healthy controls (HCs) were included. The Minds.NAVI software, utilizing the PROtective and Vulnerable factors battEry Test (PROVE) and salivary cortisol/dehydroepiandrosterone (DHEA) analysis, was employed. The PROVE test is a comprehensive self-report questionnaire that assesses depressive symptoms, suicide risk, attachment style, adverse childhood experiences, mentalization capacity, and resilience. In addition, salivary cortisol and DHEA levels were measured to evaluate the functional stage of the hypothalamic-pituitary-adrenal (HPA) axis. RESULTS: Minds.NAVI exhibited 100% sensitivity, 91.7% specificity, and 97.9% accuracy in distinguishing depression from HCs within an exploratory small group. Salivary stress hormone phases showed changes with depression stage (p=0.030), and the proportion of patients with "adrenal exhaustion stage" was higher in the moderate/severe depression group (p=0.038). Protective/vulnerable factors differed significantly between controls and depressed groups (p<0.001). Cortisol awakening response inversely correlated with depressive symptom severity (r=-0.31, p=0.034). CONCLUSION: This study suggested possible clinical effectiveness of Minds.NAVI, a depression screening tool that integrates psychometric measures and stress hormone biomarkers. The findings support the potential association between depression, chronic stress, and HPA axis hyporesponsiveness.

Association analysis between an epigenetic alcohol risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Preoperative Serum Copeptin Can Predict Delayed Hyponatremia after Pituitary Surgery in the Absence of Arginine Vasopressin Deficiency.

BACKGRUOUND: Delayed postoperative hyponatremia (DPH) is the most common cause of readmission after pituitary surgery. In this study, we aimed to evaluate the cutoff values of serum copeptin and determine the optimal timing for copeptin measurement for the prediction of the occurrence of DPH in patients who undergo endoscopic transsphenoidal approach (eTSA) surgery and tumor resection. METHODS: This was a prospective observational study of 73 patients who underwent eTSA surgery for pituitary or stalk lesions. Copeptin levels were measured before surgery, 1 hour after extubation, and on postoperative days 1, 2, 7, and 90. RESULTS: Among 73 patients, 23 patients (31.5%) developed DPH. The baseline ratio of copeptin to serum sodium level showed the highest predictive performance (area under the curve [AUROC], 0.699), and its optimal cutoff to maximize Youden's index was 2.5×10-11, with a sensitivity of 91.3% and negative predictive value of 92.0%. No significant predictors were identified for patients with transient arginine vasopressin (AVP) deficiency. However, for patients without transient AVP deficiency, the copeptin-to-urine osmolarity ratio at baseline demonstrated the highest predictive performance (AUROC, 0.725). An optimal cutoff of 6.5×10-12 maximized Youden's index, with a sensitivity of 92.9% and a negative predictive value of 94.1%. CONCLUSION: The occurrence of DPH can be predicted using baseline copeptin and its ratio with serum sodium or urine osmolarity only in patients without transient AVP deficiency after pituitary surgery.

Comprehensive evaluation of smoking exposures and their interactions on DNA methylation.

BACKGROUND: Smoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (<1 year), persistence of differential methylation from in utero smoking exposure, and effects of environmental tobacco smoke (ETS). METHODS: We meta-analysed data from up to 15,014 adults across 5 cohorts with DNA methylation measured in blood using Illumina's EPIC array for current smoking (2560 exposed), quit < 1 year (500 exposed), in utero (286 exposed), and ETS exposure (676 exposed). We also evaluated the interaction of current smoking with sex or diet (fibre, folate, and vitamin C). FINDINGS: Using false discovery rate (FDR < 0.05), 65,857 CpGs were differentially methylated in relation to current smoking, 4025 with recent quitting, 594 with in utero exposure, and 6 with ETS. Most current smoking CpGs attenuated within a year of quitting. CpGs related to in utero exposure in adults were enriched for those previously observed in newborns. Differential methylation by current smoking at 4-71 CpGs may be modified by sex or dietary intake. Nearly half (35-50%) of differentially methylated CpGs on the 450 K array were associated with blood gene expression. Current smoking and in utero smoking CpGs implicated 3049 and 1067 druggable targets, including chemotherapy drugs. INTERPRETATION: Many smoking-related methylation sites were identified with Illumina's EPIC array. Most signals revert to levels observed in never smokers within a year of cessation. Many in utero smoking CpGs persist into adulthood. Smoking-related druggable targets may provide insights into cancer treatment response and shared mechanisms across smoking-related diseases. FUNDING: Intramural Research Program of the National Institutes of Health, Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, Chief Scientist Office of the Scottish Government Health Directorates and the Scottish Funding Council, Medical Research Council UK and the Wellcome Trust.

Plasma protein signatures of adult asthma.

BACKGROUND: Adult asthma is complex and incompletely understood. Plasma proteomics is an evolving technique that can both generate biomarkers and provide insights into disease mechanisms. We aimed to identify plasma proteomic signatures of adult asthma. METHODS: Protein abundance in plasma was measured in individuals from the Agricultural Lung Health Study (ALHS) (761 asthma, 1095 non-case) and the Atherosclerosis Risk in Communities study (470 asthma, 10,669 non-case) using the SOMAScan 5K array. Associations with asthma were estimated using covariate adjusted logistic regression and meta-analyzed using inverse-variance weighting. Additionally, in ALHS, we examined phenotypes based on both asthma and seroatopy (asthma with atopy (n = 207), asthma without atopy (n = 554), atopy without asthma (n = 147), compared to neither (n = 948)). RESULTS: Meta-analysis of 4860 proteins identified 115 significantly (FDR<0.05) associated with asthma. Multiple signaling pathways related to airway inflammation and pulmonary injury were enriched (FDR<0.05) among these proteins. A proteomic score generated using machine learning provided predictive value for asthma (AUC = 0.77, 95% CI = 0.75-0.79 in training set; AUC = 0.72, 95% CI = 0.69-0.75 in validation set). Twenty proteins are targeted by approved or investigational drugs for asthma or other conditions, suggesting potential drug repurposing. The combined asthma-atopy phenotype showed significant associations with 20 proteins, including five not identified in the overall asthma analysis. CONCLUSION: This first large-scale proteomics study identified over 100 plasma proteins associated with current asthma in adults. In addition to validating previous associations, we identified many novel proteins that could inform development of diagnostic biomarkers and therapeutic targets in asthma management.

Occupational farm work activities influence workers' indoor home microbiome.

BACKGROUND: Farm work entails a heterogeneous mixture of exposures that vary considerably across farms and farmers. Farm work is associated with various health outcomes, both adverse and beneficial. One mechanism by which farming exposures can impact health is through the microbiome, including the indoor home environment microbiome. It is unknown how individual occupational exposures shape the microbial composition in workers' homes. OBJECTIVES: We investigated associations between farm work activities, including specific tasks and pesticide use, and the indoor microbiome in the homes of 468 male farmers. METHODS: Participants were licensed pesticide applicators, mostly farmers, enrolled in the Agricultural Lung Health Study from 2008 to 2011. Vacuumed dust from participants' bedrooms underwent whole-genome shotgun sequencing for indoor microbiome assessment. Using questionnaire data, we evaluated 6 farm work tasks (processing of either hay, silage, animal feed, fertilizer, or soy/grains, and cleaning grain bins) and 19 pesticide ingredients currently used in the past year, plus 7 banned persistent pesticide ingredients ever used. RESULTS: All 6 work tasks were associated with increased microbial diversity levels, with a positive dose-response for the total number of tasks performed (P = 0.001). All tasks were associated with altered microbial compositions (weighted UniFrac P = 0.001) and with higher abundance of specific microbes, including soil-based commensal microbes such as Haloterrigena. Among the 19 pesticides, current use of glyphosate and past use of lindane were associated with increased microbial diversity (P = 0.02-0.04). Ten currently used pesticides and all 7 banned pesticides were associated with altered microbial composition (P = 0.001-0.04). Six pesticides were associated with differential abundance of certain microbes. DISCUSSION: Different farm activities and exposures can uniquely impact the dust microbiome inside homes. Our work suggests that changes to the home microbiome could serve as one pathway for how occupational exposures impact the health of workers and their cohabitating family members, offering possible future intervention targets.

Zaluzanin C Alleviates Inflammation and Lipid Accumulation in Kupffer Cells and Hepatocytes by Regulating Mitochondrial ROS.

Zaluzanin C (ZC), a sesquiterpene lactone isolated from Laurus nobilis L., has been reported to have anti-inflammatory and antioxidant effects. However, the mechanistic role of ZC in its protective effects in Kupffer cells and hepatocytes has not been elucidated. The purpose of this study was to elucidate the efficacy and mechanism of action of ZC in Kupffer cells and hepatocytes. ZC inhibited LPS-induced mitochondrial ROS (mtROS) production and subsequent mtROS-mediated NF-κB activity in Kupffer cells (KCs). ZC reduced mRNA levels of pro-inflammatory cytokines (Il1b and Tnfa) and chemokines (Ccl2, Ccl3, Ccl4, Cxcl2 and Cxcl9). Tumor necrosis factor (TNF)-α-induced hepatocyte mtROS production was inhibited by ZC. ZC was effective in alleviating mtROS-mediated mitochondrial dysfunction. ZC enhanced mitophagy and increased mRNA levels of fatty acid oxidation genes (Pparα, Cpt1, Acadm and Hadha) and mitochondrial biosynthetic factors (Pgc1α, Tfam, Nrf1 and Nrf2) in hepatocytes. ZC has proven its anti-lipid effect by improving lipid accumulation in hepatocytes by enhancing mitochondrial function to facilitate lipid metabolism. Therefore, our study suggests that ZC may be an effective compound for hepatoprotection by suppressing inflammation and lipid accumulation through regulating mtROS.

Occupational Farm Work Activities Influence Workers' Indoor Home Microbiome.

Background: Farm work entails a heterogeneous mixture of exposures that vary considerably across farms and farmers. Farm work is associated with various health outcomes, both adverse and beneficial. One mechanism by which farming exposures can impact health is through the microbiome, including the indoor built environment microbiome. It is unknown how individual occupational exposures shape the microbial composition in workers' homes. Objectives: We investigated associations between farm work activities, including specific tasks and pesticide use, and the indoor microbiome in the homes of 468 male farmers. Methods: Participants were licensed pesticide applicators, mostly farmers, enrolled in the Agricultural Lung Health Study from 2008-2011. Vacuumed dust from participants' bedrooms underwent whole-genome shotgun sequencing for indoor microbiome assessment. Using questionnaire data, we evaluated 6 farm work tasks (processing of either hay, silage, animal feed, fertilizer, or soy/grains, and cleaning grain bins) and 19 pesticide ingredients currently used in the past year, plus 7 persistent banned pesticide ingredients ever used. Results: All 6 work tasks were associated with increased within-sample microbial diversity, with a positive dose-response for the sum of tasks (p=0.001). All tasks were associated with altered overall microbial compositions (weighted UniFrac p=0.001) and with higher abundance of specific microbes, including soil-based microbes such as Haloterrigena. Among the 19 pesticides, only current use of glyphosate and past use of lindane were associated with increased within-sample diversity (p=0.02-0.04). Ten currently used pesticides and all 7 banned pesticides were associated with altered microbial composition (p=0.001-0.04). Six pesticides were associated with differential abundance of certain microbes. Discussion: Specific farm activities and exposures can impact the dust microbiome inside homes. Our work suggests that occupational farm exposures could impact the health of workers and their families through modifying the indoor environment, specifically the microbial composition of house dust, offering possible future intervention targets.

Metagenomics reveals novel microbial signatures of farm exposures in house dust.

Indoor home dust microbial communities, important contributors to human health, are shaped by environmental factors, including farm-related exposures. Advanced metagenomic whole genome shotgun sequencing (WGS) improves detection and characterization of microbiota in the indoor built-environment dust microbiome, compared to conventional 16S rRNA amplicon sequencing (16S). We hypothesized that the improved characterization of indoor dust microbial communities by WGS will enhance detection of exposure-outcome associations. The objective of this study was to identify novel associations of environmental exposures with the dust microbiome from the homes of 781 farmers and farm spouses enrolled in the Agricultural Lung Health Study. We examined various farm-related exposures, including living on a farm, crop versus animal production, and type of animal production, as well as non-farm exposures, including home cleanliness and indoor pets. We assessed the association of the exposures on within-sample alpha diversity and between-sample beta diversity, and the differential abundance of specific microbes by exposure. Results were compared to previous findings using 16S. We found most farm exposures were significantly positively associated with both alpha and beta diversity. Many microbes exhibited differential abundance related to farm exposures, mainly in the phyla Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. The identification of novel differential taxa associated with farming at the genera level, including Rhodococcus, Bifidobacterium, Corynebacterium, and Pseudomonas, was a benefit of WGS compared to 16S. Our findings indicate that characterization of dust microbiota, an important component of the indoor environment relevant to human health, is heavily influenced by sequencing techniques. WGS is a powerful tool to survey the microbial community that provides novel insights on the impact of environmental exposures on indoor dust microbiota. These findings can inform the design of future studies in environmental health.

Metagenomics reveals novel microbial signatures of farm exposures in house dust.

Indoor home dust microbial communities, important contributors to human health outcomes, are shaped by environmental factors, including farm-related exposures. Detection and characterization of microbiota are influenced by sequencing methodology; however, it is unknown if advanced metagenomic whole genome shotgun sequencing (WGS) can detect novel associations between environmental exposures and the indoor built-environment dust microbiome, compared to conventional 16S rRNA amplicon sequencing (16S). This study aimed to better depict indoor dust microbial communities using WGS to investigate novel associations with environmental risk factors from the homes of 781 farmers and farm spouses enrolled in the Agricultural Lung Health Study. We examined various farm-related exposures, including living on a farm, crop versus animal production, and type of animal production, as well as non-farm exposures, including home cleanliness and indoor pets. We assessed the association of the exposures on within-sample alpha diversity and between-sample beta diversity, and the differential abundance of specific microbes by exposure. Results were compared to previous findings using 16S. We found most farm exposures were significantly positively associated with both alpha and beta diversity. Many microbes exhibited differential abundance related to farm exposures, mainly in the phyla Actinobacteria, Bacteroidetes, Firmicutes , and Proteobacteria . The identification of novel differential taxa associated with farming at the genera level, including Rhodococcus, Bifidobacterium, Corynebacterium , and Pseudomonas , was a benefit of WGS compared to 16S. Our findings indicate that characterization of dust microbiota, an important component of the indoor environment relevant to human health, is heavily influenced by sequencing techniques. WGS is a powerful tool to survey the microbial community that provides novel insights on the impact of environmental exposures on indoor dust microbiota, and should be an important consideration in designing future studies in environmental health.

Early-life farm exposures and eczema among adults in the Agricultural Lung Health Study.

Background: Several studies conducted in Europe have suggested a protective association between early-life farming exposures and childhood eczema or atopic dermatitis; few studies have examined associations in adults. Objectives: To investigate associations between early-life exposures and eczema among 3217 adult farmers and farm spouses (mean age 62.8 years) in a case-control study nested within an US agricultural cohort. Methods: We used sampling-weighted logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for associations between early-life exposures and self-reported doctor-diagnosed eczema (273 cases) and polytomous logistic regression to estimate ORs (95%CIs) for a 4-level outcome combining information on eczema and atopy (specific IgE≥0.35). Additionally, we explored genetic and gene-environment associations with eczema. Results: Although early-life farming exposures were not associated with eczema overall, several early-life exposures were associated with a reduced risk of having both eczema and atopy. Notably, results suggest stronger protective associations among individuals with both eczema and atopy than among those with either atopy alone or eczema alone. For example, ORs (95%CIs) for having a mother who did farm work while pregnant were 1.01 (0.60-1.69) for eczema alone and 0.80 (0.65-0.99) for atopy alone, but 0.54 (0.33-0.80) for having both eczema and atopy. A genetic risk score based on previously identified atopic dermatitis variants was strongly positively associated with eczema, and interaction testing suggested protective effects of several early-life farming exposures only in individuals at lower genetic risk. Conclusions: In utero and childhood farming exposures are associated with decreased odds of having eczema with atopy in adults.

Serum copeptin levels at day two after pituitary surgery and ratio to baseline predict postoperative central diabetes insipidus.

PURPOSE: Central diabetes insipidus is a complication that may occur after pituitary surgery and has been difficult to predict. This study aimed to identify the cutoff levels of serum copeptin and its optimal timing for predicting the occurrence of central diabetes insipidus in patients who underwent transsphenoidal surgery. METHODS: This was a prospective observational study of patients who underwent transsphenoidal surgery for pituitary gland or stalk lesions. Copeptin levels were measured before surgery, 1 h after extubation, and on postoperative days 1, 2, 7, and 90. RESULTS: Among 73 patients, 14 (19.2%) and 13 (17.8%) patients developed transient and permanent central diabetes insipidus, respectively. There was no significant difference in copeptin levels before surgery and 1 h after extubation; copeptin levels on postoperative days 1, 2, 7, and 90 were significantly lower in patients with permanent central diabetes insipidus than in those without central diabetes insipidus. Copeptin measurement on postoperative day 2 exhibited the highest performance for predicting permanent central diabetes insipidus among postoperative days 1, 2, and 7 (area under the curve [95% confidence interval] = 0.754 [0.632-0.876]). Serum copeptin level at postoperative day 2(< 3.1 pmol/L) showed a sensitivity of 92.3% and a negative predictive value of 97.1%. The ratio of copeptin at postoperative day 2 to baseline (< 0.94) presented a sensitivity of 84.6% and a negative predictive value of 94.9%. The copeptin levels > 3.4 and 7.5 pmol/L at postoperative day 2 and 7 may have ruled out the occurrence of CDI with a negative predictive value of 100%. CONCLUSION: The copeptin level at postoperative day 2 and its ratio to baseline can predict the occurrence of permanent central diabetes insipidus after pituitary surgery.

Residential Wood Burning and Pulmonary Function in the Agricultural Lung Health Study.

BACKGROUND: In low- and middle-income countries, burning biomass indoors for cooking or heating has been associated with poorer lung function. In high-income countries, wood, a form of biomass, is commonly used for heating in rural areas with increasing prevalence. However, in these settings the potential impact of chronic indoor woodsmoke exposure on pulmonary function is little studied. OBJECTIVE: We evaluated the association of residential wood burning with pulmonary function in case-control study of asthma nested within a U.S. rural cohort. METHODS: Using sample weighted multivariable linear regression, we estimated associations between some and frequent wood burning, both relative to no exposure, in relation to forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), their ratio (FEV1/FVC), and fractional exhaled nitric oxide (FeNO). We examined effect modification by smoking or asthma status. RESULTS: Among all participants and within smoking groups, wood burning was not appreciably related to pulmonary function. However, in individuals with asthma (n=1,083), frequent wood burning was significantly associated with lower FEV1 [ß: -164mL; 95% confidence interval (CI): -261, -66mL], FVC (ß: -125mL; 95% CI: -230, -20mL), and FEV1/FVC (ß: -2%; 95% CI: -4, -0.4%), whereas no appreciable association was seen in individuals without asthma (n=1,732). These differences in association by asthma were statistically significant for FEV1 (pinteraction=0.0044) and FEV1/FVC (pinteraction=0.049). Frequent wood burning was also associated with higher FeNO levels in all individuals (n=2,598; ß: 0.1 ln(ppb); 95% CI: 0.02, 0.2), but associations did not differ by asthma or smoking status. DISCUSSION: Frequent exposure to residential wood burning was associated with a measure of airway inflammation (FeNO) among all individuals and with lower pulmonary function among individuals with asthma. This group may wish to reduce wood burning or consider using air filtration devices. https://doi.org/10.1289/EHP10734.

Identification of genetic variants related to metabolic syndrome by next-generation sequencing.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of conditions associated with glucose intolerance, hypertension, abdominal obesity, dyslipidemia, and insulin resistance that increase the risk of cardiovascular diseases (CVD) and type 2 diabetes (T2D). Since MetS is known as a complex symptom with a high incidence of genetic factors, it is important to identify genetic variants for each clinical characteristic of MetS. METHODS: We performed targeted next-generation sequencing (NGS) to identify genetic variants related to obesity, blood glucose, triacylglycerol (TG), and high-density lipoprotein (HDL)-cholesterol level, and hypertension in 48 subjects with MetS and in 48 healthy subjects. RESULTS: NGS analysis revealed that 26 of 48 subjects (54.2%) with MetS had putative non-synonymous variants related to the clinical features of MetS. Of the subjects with MetS, 8 (16.7%) had variants in 4 genes (COL6A2, FTO, SPARC, and MTHFR) related to central obesity, 17 (35.4%) had variants in 6 genes (APOB, SLC2A2, LPA, ABCG5, ABCG8, and GCKR) related to hyperglycemia, 3 (6.3%) had variants in 4 genes (APOA1, APOC2, APOA4, and LMF1) related to hypertriglyceridemia, 8 (16.7%) had variants in 4 genes (ABCA1, CETP, SCARB1, and LDLR) related to low HDL-cholesterolemia, and 5 (10.4%) had variants in ADD1 related to hypertension. CONCLUSIONS: Our findings may contribute to broadening the genetic spectrum of risk variants related to the development of MetS.

Genetic Variants Associated with Elevated Plasma Ceramides in Individuals with Metabolic Syndrome.

Metabolic syndrome (MetS) is a complex condition of metabolic disorders and shows a steady onset globally. Ceramides are known as intracellular signaling molecules that influence key metabolism through various pathways such as MetS and insulin resistance. Therefore, it is important to identify novel genetic factors related to increased plasma ceramides in subjects with MetS. Here we first measured plasma ceramides levels in 37 subjects with MetS and in 38 healthy subjects by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Specifically, levels of C16 ceramide (Cer-16), C18 ceramide (Cer-18), C20 ceramide (Cer-20), C18 dihydroceramide (DhCer-18), C24 dihydroceramide (DhCer-24), and C24:1 dihydroceramide (DhCer-24:1) were significantly increased in MetS group (p < 5.0 × 10−2). We then performed single nucleotide polymorphism (SNP) genotyping to identify variants associated with elevated plasma ceramides in MetS group using Axiom® Korea Biobank Array v1.1 chip. We also performed linear regression analysis on genetic variants involved in ceramide synthesis and significantly elevated plasma ceramides and dihydroceramides. Ten variants (rs75397325, rs4246316, rs80165332, rs62106618, rs12358192, rs11006229, rs10826014, rs149162405, rs6109681, and rs3906631) across six genes (ACER1, CERS3, CERS6, SGMS1, SPTLC2, and SPTLC3) functionally involved in ceramide biosynthesis showed significant associations with the elevated levels of at least one of the ceramide species in MetS group at a statistically significant threshold of false discovery rate (FDR)-adjusted p < 5.0 × 10−2. Our findings suggest that the variants may be genetic determinants associated with increased plasma ceramides in individuals with MetS.

Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis.

Rationale: Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. Measurements and Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.

Gaseous air pollutants and DNA methylation in a methylome-wide association study of an ethnically and environmentally diverse population of U.S. adults.

Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR<0.05) at Cytosine-phosphate-Guanine (CpG) sites without among-strata heterogeneity (PCochran's Q > 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2 concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.

Opioid medication use and blood DNA methylation: epigenome-wide association meta-analysis.

Aim: To identify differential methylation related to prescribed opioid use. Methods: This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting. Results: Differential methylation (false discovery rate <0.05) was observed at six CpGs annotated to the following genes: KIAA0226, CPLX2, TDRP, RNF38, TTC23 and GPR179. Integrative epigenomic analyses linked implicated loci to regulatory elements in blood and/or brain. Additionally, 74 CpGs were differentially methylated in males or females. Methylation at significant CpGs correlated with gene expression in blood and/or brain. Conclusion: This study identified DNA methylation related to opioid medication use in general populations. The results could inform the development of blood methylation biomarkers of opioid use.

Trend Analysis of the Profiles of 12 Sexually Transmitted Disease Pathogens in the Republic of Korea in 2019.

BACKGROUND: Sexually transmitted diseases (STDs) are common infectious diseases in humans transmitted through unprotected sexual activities. In South Korea, despite the high annual incidence of STDs, detailed examinations of pathogen-specific factors and causes for delays in diagnosis and treatment are still lacking. Furthermore, STD prevalence patterns and important pathogen-specific factors remain unclear. Herein, we retrospectively analyzed the epidemiology of STDs in South Korea in 2019 by analyzing the association of pathogen-specific infection patterns with factors such as sex, age, region, and month. METHODS: We obtained the STD test results of 172,973 individuals from the Seoul Clinic Laboratory in 2019, most of whom had multiple infections; hence, 275,296 STD-positive cases were included in this analysis. Through deoxyribonucleic acid (DNA) amplification, they were categorized by pathogen type. Subsequently, they were further classified by month, region, and age while concurrently being stratified according to sex. RESULTS: Among the 12 pathogens detected in this study, Gardnerella vaginalis had the highest prevalence, with 92,490 cases in both sex groups; moreover, many of them were concurrently infected by two or more pathogens. The prevalence of STDs did not differ according to month or region. Conversely, the pathogen-specific prevalence rates significantly differed according to age. Older adults had higher prevalence rates of Chlamydia trachomatis, Trichomonas vaginalis, Candida albicans, and herpes simplex virus type 1 infections than younger adults. CONCLUSION: These pathogen-specific prevalence patterns provide information that helps to understand population vulnerability according to region and age and helps develop STD prevention and treatment strategies in South Korea.