Omega-3 Fatty Acids and Genome-Wide Interaction Analyses Reveal DPP10-Pulmonary Function Association

Am J Respir Crit Care Med. 2019 Mar 1;199(5):631-642. doi: 10.1164/rccm.201802-0304OC.

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 (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 SNP associations and their interactions with n-3 PUFAs.

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 (P2df = 9.4 × 10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency, ∼80%) was associated with lower FVC (PSNP = 2.1 × 10-9; βSNP = -161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10-7; βSNP×DHA 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.

Keywords: FEV; FVC; genome-wide association study; omega-3 fatty acids; smoking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Biomarkers
  • Fatty Acids, Omega-3
  • Fatty Acids, Unsaturated
  • alpha-Linolenic Acid
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid
  • DPP10 protein, human
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • docosapentaenoic acid

Grant support