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Omega-3 fatty acids and genome-wide interaction analyses reveal DPP10-pulmonary function association
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., ... Hancock, D. B. (2019). Omega-3 fatty acids and genome-wide interaction analyses reveal DPP10-pulmonary function association. American Journal of Respiratory and Critical Care Medicine, 199(5), 631-642. https://doi.org/10.1164/rccm.201802-0304OC
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 (FEV1, 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 SNPassociations and their interactions with n-3PUFAs.Results: 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 (P-2df = 9.4 x 10(-9) across discovery and replication cohorts). The rs11693320-A allele (frequency, similar to 80%) was associated with lower FVC (P-SNP = 2.1 x 10(-9); beta(SNP) = 2161.0 ml), and the association was attenuated by higher DHA levels (P-SNPxDHA interaction = 2.1x10(-7); beta(SNPxDHA 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.
