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

Author
item XU, JIAYI - Cornell University
item GADDIS, NATHAN - Rti International, Usa
item BARTZ, TRACI - University Of Washington
item HOU, RUIXUE - University Of North Carolina
item MANICHAIKUL, ANI - University Of Virginia
item PANKRATZ, NATHAN - University Of Minnesota
item SMITH, ALBERT - University Of Michigan
item SUN, FANGUI - Boston University School Of Public Health
item TERZIKHAN, NATALIE - Ghent University
item MARKUNAS, CHRISTINA - Rti International, Usa
item PATCHEN, BONNIE - Cornell University
item SCHU, MATTHEW - Rti International, Usa
item BEYDOUN, MAY - Johns Hopkins School Of Public Health
item BRUSSELLE, GUY - Ghent University
item EIRIKSDOTTIR, GUDNY - Icelandic Heart Association
item ZHOU, XIA - University Of Minnesota
item WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)
item GRAFF, MARIAELISA - University Of North Carolina
item HARRIS, TAMARA - National Institute On Aging (NIA, NIH)
item IKRAM, M - Erasmus Medical Center
item JACOBS JR, DAVID - University Of Minnesota
item LAUNER, LENORE - National Institute On Aging (NIA, NIH)
item LEMAITRE, ROZENN - University Of Washington
item O'CONNOR, GEORGE - Boston University Medical School
item OELSNER, ELIZABETH - Columbia University - New York
item PSATY, BRUCE - University Of Washington
item RAMACHANDRAN, VASAN - Boston University Medical School
item ROHDE, REBECCA - University Of North Carolina
item RICH, STEPHEN - University Of Virginia
item ROTTER, JEROME - Harbor-Ucla Medical Center
item SESHADRI, SUDHA - Boston University
item SMITH, LEWIS - Northwestern University
item TEIMEIER, HENNING - Erasmus Medical Center
item TSAI, MICHAEL - University Of Minnesota
item UITTERLINDEN, ANDRE - Erasmus Medical Center
item VORUGANTI, V - University Of North Carolina
item XU, HANFEI - Boston University School Of Public Health
item ZILHÃO, NUNO - Icelandic Heart Association
item FORNAGE, MYRIAM - University Of Texas Health Science Center
item ZILLIKENS, M - Netherlands Genomics Initiative
item LONDON, STEPHANIE - National Institute Of Environmental Health Sciences (NIEHS, NIH)
item BARR, R - Columbia University - New York
item DUPUIS, JOSÉE - Boston University School Of Public Health
item GHARIB, SINA - University Of Washington
item GUDNASON, VILMUNDUR - Icelandic Heart Association
item LAHOUSSE, LIES - Erasmus Medical Center
item NORTH, KARI - University Of North Carolina
item STEFFEN, LYN - University Of Minnesota
item CASSANO, PATRICIA - Cornell University
item HANCOCK, DANA - Rti International, Usa

Submitted to: American Journal of Respiratory and Critical Care Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/7/2018
Publication Date: 9/10/2018
Citation: Xu, J., Gaddis, N.C., Bartz, T.M., Hou, R., Manichaikul, A.W., Pankratz, N., Smith, A.V., Sun, F., Terzikhan, N., Markunas, C.A., Patchen, B.K., Schu, M., Beydoun, M.A., Brusselle, G.G., Eiriksdottir, G., Zhou, X., Wood, A.C., Graff, M., Harris, T.B., Ikram, M.A., Jacobs Jr, D.R., Launer, L.J., Lemaitre, R.N., O'Connor, G., Oelsner, E.C., Psaty, B.M., Ramachandran, V.S., Rohde, R.R., Rich, S.S., Rotter, J.I., Seshadri, S., Smith, L.J., Teimeier, H., Tsai, M.Y., Uitterlinden, A.G., Voruganti, V.S., Xu, H., Zilhão, N.R., Fornage, M., Zillikens, M.C., London, S.J., Barr, R.G., Dupuis, J., Gharib, S.A., Gudnason, V., Lahousse, L., North, K.E., Steffen, L.M., Cassano, P.A., Hancock, D.B. 2018. Omega-3 fatty acids and genome-wide interaction analyses reveal DPP10-pulmonary function association. American Journal of Respiratory and Critical Care Medicine. https://doi.org/10.1164/rccm.201802-0304OC.
DOI: https://doi.org/10.1164/rccm.201802-0304OC

Interpretive Summary: Obesity is associated with inflammation and a significant co-morbidity is decreased pulmonary health. Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could help adults with chronic inflammation and decreased pulmonary health. However, few population-based studies have looked at the relationships between n-3 PUFAs and pulmonary function. In addition, although smokers have higher inflammation burden on average, no studies have examined if smoking modifies these relationships. Moreover, pulmonary function measures are heritable, with over 100 genetic markers identified through genome-wide association studies. Yet, to date no studies have examined the evidence for interactions between genetic variants and n-3 PUFAs on pulmonary function. Typically, studies looking at the effects ofn-3 PUFAs with disease risk use self-reported questionnaires of PUFA intake, which can introduce reporting bias and thus not provide a good assessment. To address this, we examined the relationships between biomarkers of n-3 PUFA intake in the blood and pulmonary function tests (PFTs). We used data from seven cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, which included 16,134 participants. First we established relationships between n-3 PUFA biomarkers and pulmonary function tests. Then, we tested genome-wide interactions between genetic variants and the n-3 PUFA biomarkers on PFT measures. Results showed a greater beneficial effect of n-3 PUFAs biomarkers, especially one of them (docosahexaenoic acid or DHA), on pulmonary function in current smokers. In addition, a specific genetic marker (DPP10) was related with forced vital capacity. This relationship was not found in standard genome-wide analyses. It was only discovered after incorporating the environmental variable of n-3 PUFA biomarker levels. The results of this study are important as they contribute to the evidence base needed to provide targeted dietary advice for COPD prevention.

Technical Abstract: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV1], forced vital capacity [FVC], and [FEV1/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 single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs. DPA and DHA were positively associated with FEV1 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 (P2df=9.4X10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency~80%) was associated with lower FVC (PSNP=2.1X10**-9; BetaSNP= -161.0mL), and the association was attenuated by higher DHA levels (PSNPXDHA interaction=2.1X10**-7; BetaSNPXDHA interaction=36.2mL). 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.