Browsing by Author "Xu, Weiling"

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    Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes
    (Nature, 2021-05-27) Baratchian, Mehdi; McManus, Jeffrey M.; Berk, Mike P.; Nakamura, Fumihiko; Mukhopadhyay, Sanjay; Xu, Weiling; Erzurum, Serpil; Drazba, Judy; Peterson, John; Klein, Eric A.; Gaston, Benjamin; Sharifi, Nima; Pediatrics, School of Medicine
    The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
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    Comparison of whole genome sequencing and targeted sequencing for mitochondrial DNA
    (Elsevier, 2021) Chen, Ruoying; Aldred, Micheala A.; Xu, Weiling; Zein, Joe; Bazeley, Peter; Comhai, Suzy A. A.; Meyers, Deborah A.; Bleecker, Eugene R.; Liu, Chunyu; Erzurum, Serpil C.; Hu, Bo; NHLBI Severe Asthma Research Program (SARP); Medicine, School of Medicine
    Mitochondrial dysfunction has emerged to be associated with a broad spectrum of diseases, and there is an increasing demand for accurate detection of mitochondrial DNA (mtDNA) variants. Whole genome sequencing (WGS) has been the dominant sequencing approach to identify genetic variants in recent decades, but most studies focus on variants on the nuclear genome. Whole genome sequencing is also costly and time consuming. Sequencing specifically targeted for mtDNA is commonly used in the diagnostic settings and has lower costs. However, there is a lack of pairwise comparisons between these two sequencing approaches for calling mtDNA variants on a population basis. In this study, we compared WGS and mtDNA-targeted sequencing (targeted-seq) in analyzing mitochondrial DNA from 1499 participants recruited into the Severe Asthma Research Program (SARP). Our study reveals that targeted-sequencing and WGS have comparable capacity to determine genotypes and to call haplogroups and homoplasmies on mtDNA. However, there exists a large variability in calling heteroplasmies, especially for low-frequency heteroplasmies, which indicates that investigators should be cautious about heteroplasmies acquired from different sequencing methods. Further research is highly desired to improve variant detection methods for mitochondrial DNA.
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    HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma
    (National Academy of Sciences, 2020-01-28) Zein, Joe; Gaston, Benjamin; Bazeley, Peter; DeBoer, Mark D.; Igo, Robert P., Jr; Bleecker, Eugene R.; Meyers, Deborah; Comhair, Suzy; Marozkina, Nadzeya V.; Cotton, Calvin; Patel, Mona; Alyamani, Mohammad; Xu, Weiling; Busse, William W.; Calhoun, William J.; Ortega, Victor; Hawkins, Gregory A.; Castro, Mario; Chung, Kian Fan; Fahy, John V.; Fitzpatrick, Anne M.; Israel, Elliot; Jarjour, Nizar N.; Levy, Bruce; Mauger, David T.; Moore, Wendy C.; Noel, Patricia; Peters, Stephen P.; Teague, W. Gerald; Wenzel, Sally E.; Erzurum, Serpil C.; Sharifi, Nima; Medicine, School of Medicine
    Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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    Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations
    (medRxiv, 2023-12-05) Xu, Weiling; Hong, Yun Soo; Hu, Bo; Comhair, Suzy A. A.; Janocha, Allison J.; Zein, Joe G.; Chen, Ruoying; Meyers, Deborah A.; Mauger, David T.; Ortega, Victor E.; Bleecker, Eugene R.; Castro, Mario; Denlinger, Loren C.; Fahy, John V.; Israel, Elliot; Levy, Bruce D.; Jarjour, Nizar N.; Moore, Wendy C.; Wenzel, Sally E.; Gaston, Benjamin; Liu, Chunyu; Arking, Dan E.; Erzurum, Serpil C.; National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program (SARP) and TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Pediatrics, School of Medicine
    Rationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation. Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations. Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations. Measures and main results: In UK Biobank, asthmatics (n = 29,768) have lower mtDNA-CN compared to non-asthmatics (n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46×10-5). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (FENO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007). Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.
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    Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2
    (Cold Spring Harbor Laboratory, 2020-10-14) Baratchian, Mehdi; McManus, Jeffrey M.; Berk, Mike; Nakamura, Fumihiko; Mukhopadhyay, Sanjay; Xu, Weiling; Erzurum, Serpil; Drazba, Judy; Peterson, John; Klein, Eric A.; Gaston, Ben; Sharifi, Nima; Pediatrics, School of Medicine
    The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide therapy. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
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    Urinary total conjugated 3-bromotyrosine, asthma severity, and exacerbation risk
    (American Physiological Society, 2022) Wang, Zeneng; Xu, Weiling; Comhair, Suzy A. A.; Fu, Xiaoming; Shao, Zhili; Bearden, Rebecca; Zein, Joe G.; Bleecker, Eugene R.; Castro, Mario; Denlinger, Loren C.; Fahy, John V.; Israel, Elliot; Levy, Bruce D.; Jarjour, Nizar N.; Moore, Wendy C.; Wenzel, Sally E.; Mauger, David T.; Gaston, Benjamin; Hazen, Stanley L.; Erzurum, Serpil C.; Pediatrics, School of Medicine
    Asthma is an inflammatory disease of the airways characterized by eosinophil recruitment, eosinophil peroxidase release, and protein oxidation through bromination, which following tissue remodeling results in excretion of 3-bromotyrosine. Predicting exacerbations and reducing their frequency is critical for the treatment of severe asthma. In this study, we aimed to investigate whether urinary total conjugated bromotyrosine can discriminate asthma severity and predict asthma exacerbations. We collected urine from participants with severe (n = 253) and nonsevere (n = 178) asthma, and the number of adjudicated exacerbations in 1-yr longitudinal follow-up was determined among subjects enrolled in the Severe Asthma Research Program, a large-scale National Institutes of Health (NIH)-funded consortium. Urine glucuronidated bromotyrosine and total conjugated forms were quantified by hydrolysis with either glucuronidase or methanesulfonic acid, respectively, followed by liquid chromatography-tandem mass spectrometry analyses of free 3-bromotyrosine. Blood and sputum eosinophils were also counted. The majority of 3-bromotyrosine in urine was found to exist in conjugated forms, with glucuronidated bromotyrosine representing approximately a third, and free bromotyrosine less than 1% of total conjugated bromotyrosine. Total conjugated bromotyrosine was poorly correlated with blood (r2 = 0.038) or sputum eosinophils (r2 = 0.0069). Compared with participants with nonsevere asthma, participants with severe asthma had significantly higher urinary total conjugated bromotyrosine levels. Urinary total conjugated bromotyrosine was independently associated with asthma severity, correlated with the number of asthma exacerbations, and served as a predictor of asthma exacerbation risk over 1-yr of follow-up.
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    Urinary total conjugated 3-bromotyrosine, asthma severity, and exacerbation risk
    (American Physiological Society, 2022-11) Wang, Zeneng; Xu, Weiling; Comhair, Suzy A. A.; Fu, Xiaoming; Shao, Zhili; Bearden, Rebecca; Zein, Joe G.; Bleecker, Eugene R.; Castro, Mario; Denlinger, Loren C.; Fahy, John V.; Israel, Elliot; Levy, Bruce D.; Jarjour, Nizar N.; Moore, Wendy C.; Wenzel, Sally E.; Mauger, David T.; Gaston, Benjamin; Hazen, Stanley L.; Erzurum, Serpil C.; Pediatrics, School of Medicine
    Asthma is an inflammatory disease of the airways characterized by eosinophil recruitment, eosinophil peroxidase release, and protein oxidation through bromination, which following tissue remodeling results in excretion of 3-bromotyrosine. Predicting exacerbations and reducing their frequency is critical for the treatment of severe asthma. In this study, we aimed to investigate whether urinary total conjugated bromotyrosine can discriminate asthma severity and predict asthma exacerbations. We collected urine from participants with severe (n = 253) and nonsevere (n = 178) asthma, and the number of adjudicated exacerbations in 1-yr longitudinal follow-up was determined among subjects enrolled in the Severe Asthma Research Program, a large-scale National Institutes of Health (NIH)-funded consortium. Urine glucuronidated bromotyrosine and total conjugated forms were quantified by hydrolysis with either glucuronidase or methanesulfonic acid, respectively, followed by liquid chromatography-tandem mass spectrometry analyses of free 3-bromotyrosine. Blood and sputum eosinophils were also counted. The majority of 3-bromotyrosine in urine was found to exist in conjugated forms, with glucuronidated bromotyrosine representing approximately a third, and free bromotyrosine less than 1% of total conjugated bromotyrosine. Total conjugated bromotyrosine was poorly correlated with blood (r2 = 0.038) or sputum eosinophils (r2 = 0.0069). Compared with participants with nonsevere asthma, participants with severe asthma had significantly higher urinary total conjugated bromotyrosine levels. Urinary total conjugated bromotyrosine was independently associated with asthma severity, correlated with the number of asthma exacerbations, and served as a predictor of asthma exacerbation risk over 1-yr of follow-up.