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  1. Article ; Online: Exploiting meta-analysis of genome-wide interaction with serum 25-hydroxyvitamin D to identify novel genetic loci associated with pulmonary function.

    Seo, Jungkyun / Gaddis, Nathan C / Patchen, Bonnie K / Xu, Jiayi / Barr, R Graham / O'Connor, George / Manichaikul, Ani W / Gharib, Sina A / Dupuis, Josée / North, Kari E / Cassano, Patricia A / Hancock, Dana B

    The American journal of clinical nutrition

    2024  Volume 119, Issue 5, Page(s) 1227–1237

    Abstract: Background: Higher 25-hydroxyvitamin D (25(OH)D) concentrations in serum has a positive association with pulmonary function. Investigating genome-wide interactions with 25(OH)D may reveal new biological insights into pulmonary function.: Objectives: ... ...

    Abstract Background: Higher 25-hydroxyvitamin D (25(OH)D) concentrations in serum has a positive association with pulmonary function. Investigating genome-wide interactions with 25(OH)D may reveal new biological insights into pulmonary function.
    Objectives: We aimed to identify novel genetic variants associated with pulmonary function by accounting for 25(OH)D interactions.
    Methods: We included 211,264 participants from the observational United Kingdom Biobank study with pulmonary function tests (PFTs), genome-wide genotypes, and 25(OH)D concentrations from 4 ancestral backgrounds-European, African, East Asian, and South Asian. Among PFTs, we focused on forced expiratory volume in the first second (FEV
    Results: Our GWAS meta-analyses, accounting for interaction with 25(OH)D, revealed 30 genetic variants significantly associated with FEV
    Conclusion: Genetic variant associations with lung function can be modified by 25(OH)D, and smoking history can further modify variant×25(OH)D interactions. These results expand the known genetic architecture of pulmonary function and add evidence that gene-environment interactions, including with 25(OH)D and smoking, influence lung function.
    MeSH term(s) Humans ; Genome-Wide Association Study ; Vitamin D/analogs & derivatives ; Vitamin D/blood ; Lung/physiology ; Female ; Respiratory Function Tests ; Male ; Genetic Loci ; Middle Aged ; United Kingdom ; Polymorphism, Single Nucleotide ; Aged ; Forced Expiratory Volume ; Vital Capacity/genetics
    Chemical Substances 25-hydroxyvitamin D (A288AR3C9H) ; Vitamin D (1406-16-2)
    Language English
    Publishing date 2024-03-12
    Publishing country United States
    Document type Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 280048-2
    ISSN 1938-3207 ; 0002-9165
    ISSN (online) 1938-3207
    ISSN 0002-9165
    DOI 10.1016/j.ajcnut.2024.03.007
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  2. Article ; Online: Genetically predicted serum vitamin D and COVID-19: a Mendelian randomisation study.

    Patchen, Bonnie K / Clark, Andrew G / Gaddis, Nathan / Hancock, Dana B / Cassano, Patricia A

    BMJ nutrition, prevention & health

    2021  Volume 4, Issue 1, Page(s) 213–225

    Abstract: Objectives: To investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection.: Design: Two-sample Mendelian randomisation study.: Setting: Summary data from genome-wide analyses in the population- ... ...

    Abstract Objectives: To investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection.
    Design: Two-sample Mendelian randomisation study.
    Setting: Summary data from genome-wide analyses in the population-based UK Biobank and SUNLIGHT Consortium, applied to meta-analysed results of genome-wide analyses in the COVID-19 Host Genetics Initiative.
    Participants: 17 965 COVID-19 cases including 11 085 laboratory or physician-confirmed cases, 7885 hospitalised cases and 4336 severe respiratory cases, and 1 370 547 controls, primarily of European ancestry.
    Exposures: Genetically predicted variation in serum vitamin D status, instrumented by genome-wide significant single nucleotide polymorphisms (SNPs) associated with serum vitamin D or risk of vitamin D deficiency/insufficiency.
    Main outcome measures: Susceptibility to and severity of COVID-19 infection, including severe respiratory infection and hospitalisation.
    Results: Mendelian randomisation analysis, sufficiently powered to detect effects comparable to those seen in observational studies, provided little to no evidence for an effect of genetically predicted serum vitamin D on susceptibility to or severity of COVID-19 infection. Using SNPs in loci related to vitamin D metabolism as genetic instruments for serum vitamin D concentrations, the OR per SD higher serum vitamin D was 1.04 (95% CI 0.92 to 1.18) for any COVID-19 infection versus population controls, 1.05 (0.84 to 1.31) for hospitalised COVID-19 versus population controls, 0.96 (0.64 to 1.43) for severe respiratory COVID-19 versus population controls, 1.15 (0.99 to 1.35) for COVID-19 positive versus COVID-19 negative and 1.44 (0.75 to 2.78) for hospitalised COVID-19 versus non-hospitalised COVID-19. Results were similar in analyses using SNPs with genome-wide significant associations with serum vitamin D (ie, including SNPs in loci with no known relationship to vitamin D metabolism) and in analyses using SNPs with genome-wide significant associations with risk of vitamin D deficiency or insufficiency.
    Conclusions: These findings suggest that genetically predicted differences in long-term vitamin D nutritional status do not causally affect susceptibility to and severity of COVID-19 infection, and that associations observed in previous studies may have been driven by confounding. These results do not exclude the possibility of low-magnitude causal effects or causal effects of acute responses to therapeutic doses of vitamin D.
    Language English
    Publishing date 2021-05-04
    Publishing country England
    Document type Journal Article
    ISSN 2516-5542
    ISSN (online) 2516-5542
    DOI 10.1136/bmjnph-2021-000255
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  3. Article ; Online: Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study

    Patchen, Bonnie K / Clark, Andrew G / Gaddis, Nathan M / Hancock, Dana B / Cassano, Patricia A

    medRxiv

    Abstract: Objectives: To investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection. Design: Two-sample Mendelian randomization study. Setting: Summary data from genome-wide analyses in the population-based UK ... ...

    Abstract Objectives: To investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection. Design: Two-sample Mendelian randomization study. Setting: Summary data from genome-wide analyses in the population-based UK Biobank and SUNLIGHT Consortium, applied to meta-analyzed results of genome-wide analyses in the COVID-19 Host Genetics Initiative. Participants: 17,965 COVID-19 cases including 11,085 laboratory or physician confirmed cases, 7,885 hospitalized cases, and 4,336 severe respiratory cases, and 1,370,547 controls, primarily of European ancestry. Exposures: Genetically predicted variation in serum vitamin D status, based on genome-wide significant single nucleotide polymorphisms (SNPs) associated with serum vitamin D or risk of vitamin D deficiency/insufficiency. Main outcome measures: Susceptibility to and severity of COVID-19 infection, including severe respiratory infection and hospitalization. Results: Mendelian randomization analysis, powered to detect moderate effects comparable to those seen in observational studies, provided little to no evidence for an effect of genetically predicted serum vitamin D on susceptibility to or severity of COVID-19 infection. Using SNPs in loci related to vitamin D metabolism as proxies for serum vitamin D concentration, the odds ratio for a standard deviation increase in serum vitamin D was 1.04 (95% confidence interval 0.92 to 1.18) for any COVID-19 infection versus population controls, 1.05 (0.84-1.31) for hospitalized COVID-19 versus population controls, 0.96 (0.64 to 1.43) for severe respiratory COVID-19 versus population controls, 1.15 (0.99 to 1.35) for COVID-19 positive versus COVID-19 negative, and 1.44 (0.75 to 2.78) for hospitalized COVID-19 versus non-hospitalized COVID-19. Results were similar in analyses that used all SNPs with genome-wide significant associations with serum vitamin D (i.e., including SNPs in loci with no known relationship to vitamin D metabolism) and in analyses using SNPs with genome-wide significant associations with risk of vitamin D deficiency or insufficiency. Conclusions: These findings suggest that genetically predicted differences in long-term vitamin D nutritional status do not causally affect susceptibility to and severity of COVID-19 infection, and that associations observed in previous studies may have been driven by confounding. These results do not exclude the possibility of low-magnitude causal effects, nor do they preclude potential causal effects of acute responses to therapeutic doses of vitamin D. Future directions include extension of this work to non-European ancestry populations, and high-risk populations, for example persons with comorbid disease.
    Keywords covid19
    Language English
    Publishing date 2021-02-01
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2021.01.29.21250759
    Database COVID19

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  4. Article: Investigating associations of omega-3 fatty acids, lung function decline, and airway obstruction.

    Patchen, Bonnie K / Balte, Palavi / Bartz, Traci M / Barr, R Graham / Fornage, Myriam / Graff, Mariaelisa / Jacobs, David R / Kalhan, Ravi / Lemaitre, Rozenn N / O'Connor, George / Psaty, Bruce / Seo, Jungkyun / Tsai, Michael Y / Wood, Alexis C / Xu, Hanfei / Zhang, Jingwen / Gharib, Sina A / Manichaikul, Ani / North, Kari /
    Steffen, Lyn M / Dupuis, Josée / Oelsner, Elizabeth / Hancock, Dana B / Cassano, Patricia A

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have anti-inflammatory properties and may benefit lung health.: Objectives: Investigate associations of ... ...

    Abstract Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have anti-inflammatory properties and may benefit lung health.
    Objectives: Investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in adults of diverse races/ethnicities from general population cohorts.
    Methods: Complementary study designs: (1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV
    Measurements and main results: The longitudinal study found that higher omega-3 fatty acid concentrations were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for docosahexaenoic acid (DHA). One standard deviation higher DHA was associated with an attenuation of 1.8 mL/year for FEV
    Conclusions: The longitudinal and MR studies provide evidence supporting beneficial effects of higher circulating omega-3 fatty acids, especially DHA, on lung health.
    Language English
    Publishing date 2023-01-18
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.01.18.23284671
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  5. Article ; Online: Investigating Associations of Omega-3 Fatty Acids, Lung Function Decline, and Airway Obstruction.

    Patchen, Bonnie K / Balte, Pallavi / Bartz, Traci M / Barr, R Graham / Fornage, Myriam / Graff, Mariaelisa / Jacobs, David R / Kalhan, Ravi / Lemaitre, Rozenn N / O'Connor, George / Psaty, Bruce / Seo, Jungkyun / Tsai, Michael Y / Wood, Alexis C / Xu, Hanfei / Zhang, Jingwen / Gharib, Sina A / Manichaikul, Ani / North, Kari /
    Steffen, Lyn M / Dupuis, Josée / Oelsner, Elizabeth / Hancock, Dana B / Cassano, Patricia A

    American journal of respiratory and critical care medicine

    2023  Volume 208, Issue 8, Page(s) 846–857

    Abstract: Rationale: ...

    Abstract Rationale:
    MeSH term(s) Adult ; Humans ; Fatty Acids, Omega-3 ; Longitudinal Studies ; Lung ; Pulmonary Disease, Chronic Obstructive/genetics ; Airway Obstruction ; Docosahexaenoic Acids
    Chemical Substances Fatty Acids, Omega-3 ; Docosahexaenoic Acids (25167-62-8)
    Language English
    Publishing date 2023-07-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 0003-0805 ; 1073-449X
    ISSN (online) 1535-4970
    ISSN 0003-0805 ; 1073-449X
    DOI 10.1164/rccm.202301-0074OC
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  6. Article ; Online: Chronic rapamycin treatment causes diabetes in male mice.

    Schindler, Christine E / Partap, Uttara / Patchen, Bonnie K / Swoap, Steven J

    American journal of physiology. Regulatory, integrative and comparative physiology

    2014  Volume 307, Issue 4, Page(s) R434–43

    Abstract: Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin ...

    Abstract Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17β-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2 against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2 plays a protective role against the development of rapamycin-induced diabetes.
    MeSH term(s) Administration, Oral ; Animals ; Blood Glucose/drug effects ; Blood Glucose/metabolism ; Diabetes Mellitus/blood ; Diabetes Mellitus/chemically induced ; Diabetes Mellitus/pathology ; Diabetes Mellitus/prevention & control ; Diabetes Mellitus/urine ; Estradiol/administration & dosage ; Estrogen Replacement Therapy ; Female ; Glucose Intolerance/blood ; Glucose Intolerance/chemically induced ; Glycosuria/chemically induced ; Glycosuria/urine ; Male ; Mice ; Orchiectomy ; Ovariectomy ; Pancreas/drug effects ; Pancreas/metabolism ; Pancreas/pathology ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/toxicity ; Pyruvic Acid/metabolism ; Sex Factors ; Sirolimus/administration & dosage ; Sirolimus/toxicity ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; Testosterone/metabolism ; Time Factors
    Chemical Substances Blood Glucose ; Protein Kinase Inhibitors ; Testosterone (3XMK78S47O) ; Estradiol (4TI98Z838E) ; Pyruvic Acid (8558G7RUTR) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2014-06-25
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 603839-6
    ISSN 1522-1490 ; 0363-6119
    ISSN (online) 1522-1490
    ISSN 0363-6119
    DOI 10.1152/ajpregu.00123.2014
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  7. Article ; Online: Omega-3 Fatty Acids and Genome-Wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.

    Xu, Jiayi / Gaddis, Nathan C / Bartz, Traci M / Hou, Ruixue / Manichaikul, Ani W / Pankratz, Nathan / Smith, Albert V / Sun, Fangui / Terzikhan, Natalie / Markunas, Christina A / Patchen, Bonnie K / Schu, Matthew / Beydoun, May A / Brusselle, Guy G / Eiriksdottir, Gudny / Zhou, Xia / Wood, Alexis C / Graff, Mariaelisa / Harris, Tamara B /
    Ikram, M Arfan / Jacobs, David R / Launer, Lenore J / Lemaitre, Rozenn N / O'Connor, George T / Oelsner, Elizabeth C / Psaty, Bruce M / Vasan, Ramachandran S / Rohde, Rebecca R / Rich, Stephen S / Rotter, Jerome I / Seshadri, Sudha / Smith, Lewis J / Tiemeier, Henning / Tsai, Michael Y / Uitterlinden, André G / Voruganti, V Saroja / Xu, Hanfei / Zilhão, Nuno R / Fornage, Myriam / Zillikens, M Carola / London, Stephanie J / Barr, R Graham / Dupuis, Josée / Gharib, Sina A / Gudnason, Vilmundur / Lahousse, Lies / North, Kari E / Steffen, Lyn M / Cassano, Patricia A / Hancock, Dana B

    American journal of respiratory and critical care medicine

    2018  Volume 199, Issue 5, Page(s) 631–642

    Abstract: Rationale: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.: Objective: To investigate n-3 PUFA associations with spirometric measures of pulmonary function ... ...

    Abstract Rationale: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.
    Objective: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.
    Methods: Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV
    Results: DPA and DHA were positively associated with FEV
    Conclusions: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.
    MeSH term(s) Aged ; Biomarkers/blood ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/physiology ; Docosahexaenoic Acids/blood ; Eicosapentaenoic Acid/blood ; Fatty Acids, Omega-3/blood ; Fatty Acids, Unsaturated/blood ; Female ; Forced Expiratory Volume/genetics ; Genome-Wide Association Study ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Respiratory Physiological Phenomena/genetics ; Sex Factors ; Smoking/adverse effects ; Vital Capacity/genetics ; alpha-Linolenic Acid/blood
    Chemical Substances Biomarkers ; Fatty Acids, Omega-3 ; Fatty Acids, Unsaturated ; alpha-Linolenic Acid (0RBV727H71) ; Docosahexaenoic Acids (25167-62-8) ; Eicosapentaenoic Acid (AAN7QOV9EA) ; DPP10 protein, human (EC 3.4.14.-) ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (EC 3.4.14.-) ; docosapentaenoic acid (NS3OZT14QT)
    Language English
    Publishing date 2018-01-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 0003-0805 ; 1073-449X
    ISSN (online) 1535-4970
    ISSN 0003-0805 ; 1073-449X
    DOI 10.1164/rccm.201802-0304OC
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