HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma.

Abstract:

: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.

authors

Zein J,Gaston B,Bazeley P,DeBoer MD,Igo RP Jr,Bleecker ER,Meyers D,Comhair S,Marozkina NV,Cotton C,Patel M,Alyamani M,Xu W,Busse WW,Calhoun WJ,Ortega V,Hawkins GA,Castro M,Chung KF,Fahy JV,Fitzpatrick AM,Israel

doi

10.1073/pnas.1918819117

subject

Has Abstract

pub_date

2020-01-28 00:00:00

pages

2187-2193

issue

4

eissn

0027-8424

issn

1091-6490

pii

1918819117

journal_volume

117

pub_type

临床试验,杂志文章
  • Interlocus variation of genetic distance and the neutral mutation theory.

    abstract::Theoretical distributions of genetic distance between reproductively isolated taxa are derived by means of computer simulation, taking into account mutation and random genetic drift. The distributions obtained are in good agreement with the observed distributions of interracial and interspecific genetic distances for ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.72.7.2758

    authors: Nei M,Tateno Y

    更新日期:1975-07-01 00:00:00

  • Phosphorylation of actin Tyr-53 inhibits filament nucleation and elongation and destabilizes filaments.

    abstract::Dictyostelium actin was shown to become phosphorylated on Tyr-53 late in the developmental cycle and when cells in the amoeboid stage are subjected to stress but the phosphorylated actin had not been purified and characterized. We have separated phosphorylated and unphosphorylated actin and shown that Tyr-53 phosphory...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0606321103

    authors: Liu X,Shu S,Hong MS,Levine RL,Korn ED

    更新日期:2006-09-12 00:00:00

  • Type II regulatory subunits are not required for the anchoring-dependent modulation of Ca2+ channel activity by cAMP-dependent protein kinase.

    abstract::Preferential phosphorylation of specific proteins by cAMP-dependent protein kinase (PKA) may be mediated in part by the anchoring of PKA to a family of A-kinase anchor proteins (AKAPs) positioned in close proximity to target proteins. This interaction is thought to depend on binding of the type II regulatory (RII) sub...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.20.11067

    authors: Burton KA,Johnson BD,Hausken ZE,Westenbroek RE,Idzerda RL,Scheuer T,Scott JD,Catterall WA,McKnight GS

    更新日期:1997-09-30 00:00:00

  • Starch grain and phytolith evidence for early ninth millennium B.P. maize from the Central Balsas River Valley, Mexico.

    abstract::Questions that still surround the origin and early dispersals of maize (Zea mays L.) result in large part from the absence of information on its early history from the Balsas River Valley of tropical southwestern Mexico, where its wild ancestor is native. We report starch grain and phytolith data from the Xihuatoxtla ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 历史文章,杂志文章

    doi:10.1073/pnas.0812525106

    authors: Piperno DR,Ranere AJ,Holst I,Iriarte J,Dickau R

    更新日期:2009-03-31 00:00:00

  • Chemotaxis of sperm cells.

    abstract::We develop a theoretical description of sperm chemotaxis. Sperm cells of many species are guided to the egg by chemoattractants, a process called chemotaxis. Motor proteins in the flagellum of the sperm generate a regular beat of the flagellum, which propels the sperm in a fluid. In the absence of a chemoattractant, s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0703530104

    authors: Friedrich BM,Jülicher F

    更新日期:2007-08-14 00:00:00

  • Sperm-specific protein kinase A catalytic subunit Calpha2 orchestrates cAMP signaling for male fertility.

    abstract::An unusual cAMP signaling system mediates many of the events that prepare spermatozoa to meet the egg. Its components include the atypical, bicarbonate-stimulated, sperm adenylyl cyclase and a cAMP-dependent protein kinase (PKA) with the unique catalytic subunit termed Calpha(2) or C(s). We generated mice that lack Ca...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0405580101

    authors: Nolan MA,Babcock DF,Wennemuth G,Brown W,Burton KA,McKnight GS

    更新日期:2004-09-14 00:00:00

  • Evolutionary repurposing of a sulfatase: A new Michaelis complex leads to efficient transition state charge offset.

    abstract::The recruitment and evolutionary optimization of promiscuous enzymes is key to the rapid adaptation of organisms to changing environments. Our understanding of the precise mechanisms underlying enzyme repurposing is, however, limited: What are the active-site features that enable the molecular recognition of multiple ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1607817115

    authors: Miton CM,Jonas S,Fischer G,Duarte F,Mohamed MF,van Loo B,Kintses B,Kamerlin SCL,Tokuriki N,Hyvönen M,Hollfelder F

    更新日期:2018-07-31 00:00:00

  • Rate of quaternary structure change in hemoglobin measured by modulated excitation.

    abstract::Using a novel technique of modulated photo-dissociation of carbon monoxide from hemoglobin, we have obtained the rates for conversion between the two quaternary states, R, and T, at 3-fold ligation. Our measurements at pH 7 and 22 degrees give rates of 780 +/- 40 sec-1 for going from R to T, and 2500 +/- 200 sec-1 fro...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.73.12.4497

    authors: Ferrone FA,Hopfield JJ

    更新日期:1976-12-01 00:00:00

  • Regulation of Cl- transport in T84 cell clones expressing a mutant regulatory subunit of cAMP-dependent protein kinase.

    abstract::Cl- channels in the apical membranes of salt-secreting epithelia are activated by both cAMP and Ca2+ second-messenger systems, and dysfunctions in their hormonal regulation have been demonstrated in patients with cystic fibrosis. We have transfected the epithelial cell line T84 with an expression vector containing a m...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.22.8975

    authors: Rogers KV,Goldman PS,Frizzell RA,McKnight GS

    更新日期:1990-11-01 00:00:00

  • Rb is dispensable for self-renewal and multilineage differentiation of adult hematopoietic stem cells.

    abstract::Stem cells have been identified as essential for maintaining multiple organ systems, including the hematopoietic system. The distinct cell fates of self-renewal and differentiation of hematopoietic stem cells (HSCs) depend on cell division. Recently, several negative regulators of the cell cycle, such as the cyclin-de...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0603389103

    authors: Walkley CR,Orkin SH

    更新日期:2006-06-13 00:00:00

  • Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro.

    abstract::Progressive amyloid deposition in senile plaques and cortical blood vessels may play a central role in the pathogenesis of Alzheimer disease. We have used x-ray diffraction and electron microscopy to study the molecular organization and morphology of macromolecular assemblies formed by three synthetic peptides homolog...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.19.6953

    authors: Kirschner DA,Inouye H,Duffy LK,Sinclair A,Lind M,Selkoe DJ

    更新日期:1987-10-01 00:00:00

  • Dual-color fluorescence imaging distinguishes tumor cells from induced host angiogenic vessels and stromal cells.

    abstract::We have developed a simple yet powerful technique for delineating the morphological events of tumor-induced angiogenesis and other tumor-induced host processes with dual-color fluorescence. The method clearly images implanted tumors and adjacent stroma, distinguishing unambiguously the host and tumor-specific componen...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2436101100

    authors: Yang M,Li L,Jiang P,Moossa AR,Penman S,Hoffman RM

    更新日期:2003-11-25 00:00:00

  • Regulation of V(D)J recombination: a dominant role for promoter positioning in gene segment accessibility.

    abstract::Antigen receptor gene assembly is regulated by transcriptional promoters and enhancers, which control the accessibility of gene segments to a lymphocyte-specific V(D)J recombinase. However, it remained unclear whether accessibility depends on the process of transcription itself or chromatin modifications that accompan...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.182166699

    authors: Sikes ML,Meade A,Tripathi R,Krangel MS,Oltz EM

    更新日期:2002-09-17 00:00:00

  • Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma.

    abstract::Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and deve...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1202490109

    authors: Mann KM,Ward JM,Yew CC,Kovochich A,Dawson DW,Black MA,Brett BT,Sheetz TE,Dupuy AJ,Australian Pancreatic Cancer Genome Initiative.,Chang DK,Biankin AV,Waddell N,Kassahn KS,Grimmond SM,Rust AG,Adams DJ,Jenkins NA,Copela

    更新日期:2012-04-17 00:00:00

  • GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras-driven pancreatic tumorigenesis in mice.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini an...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1616060114

    authors: Shen J,Ha DP,Zhu G,Rangel DF,Kobielak A,Gill PS,Groshen S,Dubeau L,Lee AS

    更新日期:2017-05-16 00:00:00

  • Rox8 promotes microRNA-dependent yki messenger RNA decay.

    abstract::The Hippo pathway is an evolutionarily conserved regulator of organ growth and tumorigenesis. In Drosophila, oncogenic RasV12 cooperates with loss-of-cell polarity to promote Hippo pathway-dependent tumor growth. To identify additional factors that modulate this signaling, we performed a genetic screen utilizing the D...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2013449117

    authors: Guo X,Sun Y,Azad T,Janse van Rensburg HJ,Luo J,Yang S,Liu P,Lv Z,Zhan M,Lu L,Zhou Y,Ma X,Zhang X,Yang X,Xue L

    更新日期:2020-12-01 00:00:00

  • Biologically relevant mechanism for catalytic superoxide removal by simple manganese compounds.

    abstract::Nonenzymatic manganese was first shown to provide protection against superoxide toxicity in vivo in 1981, but the chemical mechanism responsible for this protection subsequently became controversial due to conflicting reports concerning the ability of Mn to catalyze superoxide disproportionation in vitro. In a recent ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1203051109

    authors: Barnese K,Gralla EB,Valentine JS,Cabelli DE

    更新日期:2012-05-01 00:00:00

  • Impairments in verb morphology after brain injury: a connectionist model.

    abstract::The formation of the past tense of verbs in English has been the focus of the debate concerning connectionist vs. symbolic accounts of language. Brain-injured patients differ with respect to whether they are more impaired in generating irregular past tenses (TAKE-TOOK) or past tenses for nonce verbs (WUG-WUGGED). Such...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.13.7592

    authors: Joanisse MF,Seidenberg MS

    更新日期:1999-06-22 00:00:00

  • Local maternal control of seed size by KLUH/CYP78A5-dependent growth signaling.

    abstract::Seed development in plants involves the coordinated growth of the embryo, endosperm, and maternal tissue. Several genes have been identified that influence seed size by acting maternally, such as AUXIN RESPONSE FACTOR2, APETALA2, and DA1. However, given the lack of gain-of-function effects of these genes on seed size,...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0907024106

    authors: Adamski NM,Anastasiou E,Eriksson S,O'Neill CM,Lenhard M

    更新日期:2009-11-24 00:00:00

  • Redirected infection of directly biotinylated recombinant adenovirus vectors through cell surface receptors and antigens.

    abstract::The inability of adenovirus to infect primitive hematopoietic cells presents an obstacle to the use of adenovirus vectors for gene transfer to these cell types. Therefore, expanding the tropism of adenovirus vectors to unique cell surface antigens would be an important development for gene therapy protocols. In this s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.16.8855

    authors: Smith JS,Keller JR,Lohrey NC,McCauslin CS,Ortiz M,Cowan K,Spence SE

    更新日期:1999-08-03 00:00:00

  • Atherosclerosis and hypertension induction by lead and cadmium ions: an effect prevented by calcium ion.

    abstract::In epidemiological studies, both positive and negative correlations have been found between cardiovascular disease and mortality and the presence of several inorganic ions in the drinking water. In an attempt to resolve this apparent disagreement, we exposed White Carneau pigeons to drinking water containing calcium (...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.10.6494

    authors: Revis NW,Zinsmeister AR,Bull R

    更新日期:1981-10-01 00:00:00

  • Development and regional expression of beta nerve growth factor messenger RNA and protein in the rat central nervous system.

    abstract::The presence of nerve growth factor (NGF) mRNA and protein in the rat central nervous system is documented. Blot-hybridization analysis showed an abundance of NGF mRNA in the hippocampus, cerebral cortex, and olfactory bulb. Enzyme immunoassay confirmed significant levels of a NGF-like protein in the hippocampus and c...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.3.817

    authors: Whittemore SR,Ebendal T,Lärkfors L,Olson L,Seiger A,Strömberg I,Persson H

    更新日期:1986-02-01 00:00:00

  • Modulation of tissue growth heterogeneity by responses to mechanical stress.

    abstract::Morphogenesis often yields organs with robust size and shapes, whereas cell growth and deformation feature significant spatiotemporal variability. Here, we investigate whether tissue responses to mechanical signals contribute to resolve this apparent paradox. We built a model of growing tissue made of fiber-like mater...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1815342116

    authors: Fruleux A,Boudaoud A

    更新日期:2019-02-05 00:00:00

  • Sequence dependence of hydrogen exchange kinetics in DNA duplexes at the individual base pair level in solution.

    abstract::The kinetics for hydrogen exchange at individual base pairs in self-complementary deoxydodecanucleotide duplexes have been estimated from NMR saturation recovery measurements on the resolved imino protons as a function of temperature. The imino protons of dA . dT base pairs in the center of the fully alternating d(C-G...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.8.2184

    authors: Patel DJ,Ikuta S,Kozlowski S,Itakura K

    更新日期:1983-04-01 00:00:00

  • Promoter-regulatory region of the major immediate early gene of human cytomegalovirus.

    abstract::The DNA templates containing immediate early (IE) genes of human cytomegalovirus (CMV) were transcribed in vitro by using a HeLa cell extract. When IE region 1, 2, and 3 were used, transcription was detected qualitatively only from IE region 1. Transcription was detected with DNA representing IE region 2 when the IE r...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.3.659

    authors: Thomsen DR,Stenberg RM,Goins WF,Stinski MF

    更新日期:1984-02-01 00:00:00

  • Human lysosomes can be purified from diploid skin fibroblasts by free-flow electrophoresis.

    abstract::Human diploid fibroblasts underwent lysis when resuspended in isotonic sucrose. After preparation of a granular fraction by differential centrifugation, lysosomes were almost completely purified by free-flow electrophoresis. Electron micrographs of the final fraction of fibroblast lysosomes (about 25-fold purified) sh...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.10.6139

    authors: Harms E,Kern H,Schneider JA

    更新日期:1980-10-01 00:00:00

  • p85α deficiency protects β-cells from endoplasmic reticulum stress-induced apoptosis.

    abstract::In insulin resistant states such as type 2 diabetes, there is a high demand on the β-cell to synthesize and secrete insulin, which challenges the ability of the endoplasmic reticulum (ER) to synthesize and fold nascent proteins. This creates a state of ER stress that triggers a coordinated program referred to as the u...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1322564111

    authors: Winnay JN,Dirice E,Liew CW,Kulkarni RN,Kahn CR

    更新日期:2014-01-21 00:00:00

  • Repeat associated small RNAs vary among parents and following hybridization in maize.

    abstract::Small RNAs (sRNAs) are hypothesized to contribute to hybrid vigor because they maintain genome integrity, contribute to genetic diversity, and control gene expression. We used Illumina sequencing to assess how sRNA populations vary between two maize inbred lines (B73 and Mo17) and their hybrid. We sampled sRNAs from t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1202073109

    authors: Barber WT,Zhang W,Win H,Varala KK,Dorweiler JE,Hudson ME,Moose SP

    更新日期:2012-06-26 00:00:00

  • Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane.

    abstract::Despite being engineered to avoid renal clearance, many cationic polymer (polycation)-based siRNA nanoparticles that are used for systemic delivery are rapidly eliminated from the circulation. Here, we show that a component of the renal filtration barrier--the glomerular basement membrane (GBM)--can disassemble cation...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1200718109

    authors: Zuckerman JE,Choi CH,Han H,Davis ME

    更新日期:2012-02-21 00:00:00

  • Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8.

    abstract::The interaction of interleukin 8 (IL-8) with heparin was studied by using synthetic IL-8 analogs with C- and N-terminal truncations. Elimination of the N-terminal region preceding the first cysteine, which constitutes the IL-8 receptor binding site, did not affect the affinity to heparin-Sepharose. Affinity, however, ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.15.7158

    authors: Webb LM,Ehrengruber MU,Clark-Lewis I,Baggiolini M,Rot A

    更新日期:1993-08-01 00:00:00