LTC4 synthase polymorphism modifies efficacy of botanical seed oil combination in asthma

Abstract

Botanical seed oils reduce the generation of leukotrienes in patients with asthma. Our objective was to determine the efficacy of a botanical seed oil combination against airflow obstruction in asthma, and to determine the pharmacogenomic effect of the leukotriene C4 synthase (LTC4S) polymorphism A-444C. We conducted a randomized, double-blind, placebo-controlled, cross-over clinical trial in mild to moderate asthmatics to determine the change in FEV1 after 6 weeks of therapy with borage and echium seed oils versus corn oil placebo. We also examined the effect of the variant LTC4S -444C allele on the change in lung function. We did not identify a difference in FEV1 in the study cohort as a whole (n = 28), nor in the group of A homozygotes. In the C allele carriers (n = 9), FEV1 improved by 3% after treatment with borage and echium seed oils and declined by 4% after placebo corn oil (p = 0.02). All 9 C allele carriers demonstrated an improvement in their FEV1 on active treatment compared to placebo as compared to only 7 out of 19 A allele homozygotes (p = 0.007). We observed transient differences in ex vivo leukotriene generation from circulating basophils and granulocytes. We did not observe significant differences in urinary LTE4 levels. We conclude that compared to corn oil, a combination of borage and echium seed oils improves airflow obstruction in mild to moderate asthmatics who carry the variant allele in the LTC4S gene (A-444C). Botanical oil supplementation may have therapeutic potential in asthma if used in a personalized manner.

Trial registration: This trial was registered at http://www.clinicaltrials.gov as NCT00806442.

Keywords: Asthma; Borage oil; Echium oil; LTC4 synthase; Leukotrienes.

Figures

Figure 1

Pathways for metabolism of omega-6 (left) and omega-3 (right) fatty acids in humans. The synthesis of long chain PUFAs from the essential dietary medium chain PUFAs, α-linolenic acid (ω-3) and linoleic acid (ω-6). The fatty acids derived from borage oil (linoleic and gamma-linoleic acids, both ω-6) and echium (stearidonic, ω-3; linoleic and gamma-linoleic acids, both ω-6) would be expected to enter the pathways as indicated.

Figure 2

Study enrollment and randomization flow sheet.

Figure 3

Change in FEV1% predicted in participants from both genotype groups after 6 weeks of therapy with drug and placebo. Horizontal bars represent group means.

Figure 4

Effect of 6 weeks of dietary supplementation with borage and echium seed oils on FEV1compared to corn oil placebo in 28 mild to moderate asthmatics. The letters on the X axis demonstrate their leukotriene C4 synthase promoter polymorphism status (A-444C, rs730012).

Figure 5

Effects of dietary supplementation with borage and echium seed oils on 5-LO pathway product formation by ionophore-stimulated peripheral blood granulocyte fractions from stable asthmatic subjects with AA and AC/CCLTC4Sgenotypes. a. Sum of total 5-LO pathway products (5-HETE, all-trans-LTB4, LTB4, and cys-LTs) generated per 1 × 106 ionophore-stimulated granulocytes in each indicated genotype after 3 and 6 weeks of treatment on each arm. b. Non-cys LTs (5-HETE, all-trans-LTB4, LTB4) c. cys-LTs (LTC4, LTD4, and LTE4) were measured for the same samples.

Figure 6

Study design. Illustrates study visits and periods of run-in, treatment, and wash-out. GLA = gamma-linolenic acid; SDA = stearidonic acid; Placebo = corn oil; B = blood draw for measurement of biochemical outcomes; C = provision and review of diary cards; G = blood draw for genomic analysis; L = measurement of lung function by spirometry; P = pregnancy test; S = safety monitoring.