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Large Meta-Analysis in the CHARGE Consortium Provides Evidence For an Association of Serum Vitamin D With Pulmonary Function

Jiayi Xu, Traci M. Bartz, Geetha Chittoor, Gudny Eiriksdottir, Ani W. Manichaikul, Fangui Sun, Natalie Terzikhan, Xia Zhou, Sarah L. Booth, Guy G. Brusselle, Ian H. de Boer, Myriam Fornage, Alexis C. Frazier-Wood, Mariaelisa Graff, Vilmundur Gudnason, Tamara B. Harris, Albert Hofman, Ruixue Hou, Denise K. Houston, David R. Jacobs Jr., Stephen B. Kritchevsky, Jeanne Latourelle, Rozenn N. Lemaitre, Pamela L. Lutsey, George O’Connor, Elizabeth C. Oelsner, James S. Pankow, Bruce M. Psaty, Rebecca R. Rohde, Stephen S. Rich, Jerome I. Rotter, Lewis J. Smith, Bruno H. Stricker, V. Saroja Voruganti, Thomas J. Wang, M. Carola Zillikens, R. Graham Barr, Josée Dupuis, Sina A. Gharib, Lies Lahousse, Stephanie J. London, Kari E. North, Albert V. Smith, Lyn M. Steffen, Dana B. Hancock, Patricia A. Cassano
doi: https://doi.org/10.1101/144717
Jiayi Xu
1Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
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Traci M. Bartz
2Department of Biostatistics, University of Washington, Seattle, Washington, United States
3Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States
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Geetha Chittoor
4Department of Biomedical and Translational Informatics, Geisinger, Danville, Pennsylvania, United States
17Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
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Gudny Eiriksdottir
5Icelandic Heart Association, Kopavogur, Iceland
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Ani W. Manichaikul
6Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, United States
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Fangui Sun
7Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States
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Natalie Terzikhan
8Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
9Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
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Xia Zhou
10Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States
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Sarah L. Booth
11Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, United States
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Guy G. Brusselle
8Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
9Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
12Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
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Ian H. de Boer
13Department of Medicine, University of Washington, Seattle, Washington, United States
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Myriam Fornage
14Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, United States
15Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States
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Alexis C. Frazier-Wood
16Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas, United States
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Mariaelisa Graff
17Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
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Vilmundur Gudnason
5Icelandic Heart Association, Kopavogur, Iceland
18University of Iceland, Reykjavik, Iceland
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Tamara B. Harris
19Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States
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Albert Hofman
9Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
20Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging, Leiden, the Netherlands
21Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States
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Ruixue Hou
22Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina, United States
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Denise K. Houston
23Sticht Center on Aging, Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States
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David R. Jacobs Jr.
10Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States
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Stephen B. Kritchevsky
23Sticht Center on Aging, Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States
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Jeanne Latourelle
24The Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts, United States
25Department of Neurology, Boston University, Boston, Massachusetts, United States
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Rozenn N. Lemaitre
3Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States
13Department of Medicine, University of Washington, Seattle, Washington, United States
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Pamela L. Lutsey
10Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States
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George O’Connor
24The Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts, United States
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Elizabeth C. Oelsner
26Department of Medicine, Columbia University, New York, New York, United States
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James S. Pankow
10Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States
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Bruce M. Psaty
3Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, United States
13Department of Medicine, University of Washington, Seattle, Washington, United States
27Department of Epidemiology, University of Washington, Seattle, Washington, United States
28Department of Health Services, University of Washington, Seattle, Washington, United States
29Kaiser Permanente Washington Health Research Institute, Seattle, Washington, United States
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Rebecca R. Rohde
17Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
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Stephen S. Rich
6Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, United States
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Jerome I. Rotter
30Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, California, United States
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Lewis J. Smith
31Division of Pulmonary and Critical Care, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
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Bruno H. Stricker
9Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
20Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging, Leiden, the Netherlands
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V. Saroja Voruganti
22Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina, United States
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Thomas J. Wang
32Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States
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M. Carola Zillikens
20Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging, Leiden, the Netherlands
33Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
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R. Graham Barr
26Department of Medicine, Columbia University, New York, New York, United States
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Josée Dupuis
7Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States
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Sina A. Gharib
13Department of Medicine, University of Washington, Seattle, Washington, United States
34Center for Lung Biology, University of Washington, Seattle, Washington, United States
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Lies Lahousse
8Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
9Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
35Department of Bioanalysis, Ghent University, Ghent, Belgium
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Stephanie J. London
36Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, United States
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Kari E. North
17Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
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Albert V. Smith
5Icelandic Heart Association, Kopavogur, Iceland
18University of Iceland, Reykjavik, Iceland
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Lyn M. Steffen
10Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States
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Dana B. Hancock
37Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina, United States
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Patricia A. Cassano
1Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
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ABSTRACT

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for the association of serum 25-hydroxyvitamin D [25(OH)D] and pulmonary function. We conducted the largest cross-sectional meta-analysis of the 25(OH)D– pulmonary function association to date, based on nine European ancestry (EA) cohorts (n=22,838) and five African ancestry (AA) cohorts (n=4,290) in the CHARGE Consortium. Data were analyzed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean (SD) serum 25(OH)D was 68 (29) nmol/L for EAs and 49 (21) nmol/L for AAs. For each 1 nmol/L higher 25(OH)D, forced expiratory volume in the first second (FEV1) was higher by 1.1 mL in EAs (95% CI: 0.9,1.3; P=2.5×10-21) and 1.8 mL (95% CI: 1.1,2.5; P=1.6×10-7) in Aas (Prace difference=0.06), and forced vital capacity (FVC) was higher by 1.3 mL in EAs (95% CI: 1.0,1.6; P=1.1×10-20) and 1.5 mL (95% CI: 0.8,2.3; P=1.2×10-4) in AAs (Prace difference=0.56). Among EAs, the 25(OH)D–FVC association was stronger in smokers: per 1nmol/L higher 25(OH)D, FVC was higher by 1.7 mL (95% CI: 1.1,2.3) for current smokers and 1.7 mL (95% CI: 1.2,2.1) for former smokers, compared to 0.8 mL (95% CI: 0.4,1.2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EAs, a stronger association was observed for smokers compared to never smokers, which supports the importance of vitamin D in vulnerable populations.

Cohort Funding This work was supported by National Institutes of Health (NIH) grant number R21 HL125574 funded by the National Heart, Lung, and Blood Institute (NHLBI) and the NIH Office of Dietary Supplements (ODS) (co-Principal Investigators [co-PIs]: DBH and PAC). The corresponding author (PAC) had full access to the data for the meta-analysis, and had final responsibility for the decision to submit for publication. No funding source had any role in the analysis of the data, the writing of the manuscript, or the decision to submit it. This work was also supported in part by R01HL077612 (PI: RGB) and by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (ZO1 ES043012, PI: SJL). SJL is supported by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences. Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756.

The Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.

The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. 25(OH)D measurements were conducted with the support of R01 HL103706 from the NHLBI and R01 HL103706-S1 from the NIH ODS. The authors thank the staff and participants of the ARIC study for their important contributions.

This Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Vitamin D measurements were made possible by NHLBI (R01HL084443-01A2).

This work in Framingham Heart Study was supported by NHLBI’s Framingham Heart Study contract (N01-HC-25195 and HHSN268201500001I). Vitamin D measurements in the Framingham study were made possible by NIA (R01 AG14759 to SLB.).

The Health Aging and Body Composition cohort study was supported by NIA contracts N01AG62101, N01AG2103, and N01AG62106, NIA grant R01-AG028050, NINR grant R01-NR012459, and in part by the Intramural Research Program of the NIA, NIH. This research was further supported by RC1AG035835, and the serum vitamin D assays were supported by R01AG029364.

The Multi-Ethnic Study of Atherosclerosis (MESA) study is conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from NHLBI, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001881 from NCRR, and DK063491 from the NIDDK. The MESA Lung study was supported by grants R01 HL077612, RC1 HL100543 and R01 HL093081 from NHLBI. Support for the Mineral Metabolite dataset was provided by grant HL096875.

The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands; the Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Dutch Ministry of Education, Culture, and Science; the Dutch Ministry for Health, Welfare, and Sports; the European Commission (DG XII), and the Municipality of Rotterdam. LL was a postdoctoral fellow of the Research Foundation—Flanders (FWO) in Brussels, Belgium. Part of this work was supported by a FWO-grant G035014N. DSM Nutritional Products AG, Kaiseraugst, Switzerland, sponsored the Vitamin D serum analyses. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists.

The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005).

Author Disclosure Dr. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.

All other authors have no conflicts of interest. There is no commercial support or financial interest from the tobacco industry for the research presented.

The study sponsors were not involved in study design, data collection, data analysis, data interpretation, report writing, or decisions to submit the paper for publication. PAC and DBH had final responsibility for the decision to submit for publication.

Online Supporting Material Supplemental table, figures, and methods are available.

25(OH)D
25-Hydroxyvitamin D
AA
African Ancestry
AGES
Age, Gene, Environment, Susceptibility Study—Reykjavik, Iceland
ARIC
Atherosclerosis Risk in Communities Study
CARDIA
Coronary Artery Risk Development in Young Adults Study
CHARGE
Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium
CHS
Cardiovascular Health Study
CLIA
Chemiluminescence Immunoassay
COPD
Chronic Obstructive Pulmonary Disease
EA
European Ancestry
FEV1
Forced Expiratory Volume in the First Second
FHS (Offspring)
Framingham Heart Study—Offspring Cohort
FHS (Gen3)
Framingham Heart Study—Generation 3 Cohort
FVC
Forced Vital Capacity
HABC
Health, Aging, and Body Composition Study
LC-MS/MS
Liquid Chromatography in Tandem with Mass Spectrometry
MESA
Multi-Ethnic Study of Atherosclerosis
NHANES
National Health and Nutrition Examination Survey
PFT
Pulmonary Function Test
RIA
Radioimmunoassay
RS
Rotterdam (Netherlands) Study
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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Large Meta-Analysis in the CHARGE Consortium Provides Evidence For an Association of Serum Vitamin D With Pulmonary Function
Jiayi Xu, Traci M. Bartz, Geetha Chittoor, Gudny Eiriksdottir, Ani W. Manichaikul, Fangui Sun, Natalie Terzikhan, Xia Zhou, Sarah L. Booth, Guy G. Brusselle, Ian H. de Boer, Myriam Fornage, Alexis C. Frazier-Wood, Mariaelisa Graff, Vilmundur Gudnason, Tamara B. Harris, Albert Hofman, Ruixue Hou, Denise K. Houston, David R. Jacobs Jr., Stephen B. Kritchevsky, Jeanne Latourelle, Rozenn N. Lemaitre, Pamela L. Lutsey, George O’Connor, Elizabeth C. Oelsner, James S. Pankow, Bruce M. Psaty, Rebecca R. Rohde, Stephen S. Rich, Jerome I. Rotter, Lewis J. Smith, Bruno H. Stricker, V. Saroja Voruganti, Thomas J. Wang, M. Carola Zillikens, R. Graham Barr, Josée Dupuis, Sina A. Gharib, Lies Lahousse, Stephanie J. London, Kari E. North, Albert V. Smith, Lyn M. Steffen, Dana B. Hancock, Patricia A. Cassano
bioRxiv 144717; doi: https://doi.org/10.1101/144717
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Large Meta-Analysis in the CHARGE Consortium Provides Evidence For an Association of Serum Vitamin D With Pulmonary Function
Jiayi Xu, Traci M. Bartz, Geetha Chittoor, Gudny Eiriksdottir, Ani W. Manichaikul, Fangui Sun, Natalie Terzikhan, Xia Zhou, Sarah L. Booth, Guy G. Brusselle, Ian H. de Boer, Myriam Fornage, Alexis C. Frazier-Wood, Mariaelisa Graff, Vilmundur Gudnason, Tamara B. Harris, Albert Hofman, Ruixue Hou, Denise K. Houston, David R. Jacobs Jr., Stephen B. Kritchevsky, Jeanne Latourelle, Rozenn N. Lemaitre, Pamela L. Lutsey, George O’Connor, Elizabeth C. Oelsner, James S. Pankow, Bruce M. Psaty, Rebecca R. Rohde, Stephen S. Rich, Jerome I. Rotter, Lewis J. Smith, Bruno H. Stricker, V. Saroja Voruganti, Thomas J. Wang, M. Carola Zillikens, R. Graham Barr, Josée Dupuis, Sina A. Gharib, Lies Lahousse, Stephanie J. London, Kari E. North, Albert V. Smith, Lyn M. Steffen, Dana B. Hancock, Patricia A. Cassano
bioRxiv 144717; doi: https://doi.org/10.1101/144717

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