Omega-3 fatty acids and genome-wide interaction analyses reveal DPP10–pulmonary function association

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 (a-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV 1 , FVC, and FEV 1 /FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs Results: DPA and DHA were positively associated with FEV 1 and FVC (P, 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320—an intronic DPP10 SNP—with FVC when incorporating an interaction with DHA, and the finding was replicated (P 2df = 9.4 3 10 29 across discovery and replication cohorts). The rs11693320-A allele (frequency, z80%) was associated with lower FVC (P SNP = 2.1 3 10 29 ; b SNP = 2161.0 ml), and the association was attenuated by higher DHA levels (P SNP 3DHA interaction = 2.1 3 10 27 ; b SNP 3DHA interaction = 36.2 ml). 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.

Original languageEnglish (US)
Pages (from-to)631-642
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Volume199
Issue number5
DOIs
StatePublished - Mar 1 2019

Bibliographical note

Funding Information:
This CHS (Cardiovascular Health Study) research was supported by NHLBI contracts HHSN268201800001C, HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and by NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through grant 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 NIH. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Omega-3 fatty acid measurements were made possible by NHLBI (grant R01HL085710).

Funding Information:
This work in the Framingham Heart Study was supported by NHLBI’s Framingham Heart Study contracts N01HC25195 and HHSN268201500001I.

Funding Information:
of this work was supported by a Research Foundation–Flanders (FWO) grant G035014N.

Funding Information:
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. Part

Funding Information:
The CARDIA (Coronary Artery Risk Development in Young Adults) Study is conducted and supported by NHLBI contracts in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. Genotyping was funded as part of the NHLBI Candidate-Gene Association Resource (contract N01HC65226) and the NHGRI Gene Environment Association Studies (GENEVA) (cooperative agreements U01HG004729, U01HG04424, and U01HG004446). Collection of plasma polyunsaturated fatty acids was supported by NHLBI grant R01HL084099.

Funding Information:
Supported by NIH grant R21HL125574 funded by the NHLBI and the NIH Office of Dietary Supplements (multiple Principal Investigators [PIs]: P.A.C. and D.B.H.). P.A.C. and D.B.H. 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 the following: the Fellow Program at RTI International (to N.C.G., C.A.M., M.S., and D.B.H.); NHLBI grant R01HL077612 (PI: R.G.B.); and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project number Z01ES043012; PI: S.J.L.). The infrastructure for the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium is supported in part by NHLBI grant R01HL105756. Additional financial support information can be found before the REFERENCES.

Funding Information:
The MESA (Multi-Ethnic Study of Atherosclerosis) and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by NHLBI contracts HHSN268201500003I, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, National Center for Advancing Translational Sciences grants UL1TR000040, UL1TR001079, UL1TR001420, UL1TR001881, and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491. Funding for SHARe genotyping was provided by NHLBI contract N02HL64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and the Massachusetts Institute of Technology (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The MESA Lung study was supported by grants R01HL077612, RC1HL100543, and R01HL093081 from the NHLBI.

Funding Information:
Financial Support: The AGES (Age, Gene/Environment Susceptibility)—Reykjavik Study has been funded by NIH contracts N01AG12100 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.

Publisher Copyright:
Copyright © 2019 by the American Thoracic Society.

Keywords

  • FEV
  • FVC
  • Genome-wide association study
  • Omega-3 fatty acids
  • Smoking

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