title: Dietary and genetic influences on hemostasis in a Yup'ik Alaska Native population.
abstract: Fish and marine animals are important components of the subsistence diet of Alaska Native people, resulting in a high ω3 PUFA intake. The historical record for circumpolar populations highlights a tendency for facile bleeding, possibly related to ω3 PUFA effects on platelet activation and/or vitamin K-dependent clotting factors. To evaluate these two scenarios in Yup'ik people of southwestern Alaska, we examined the association between dietary ω3 PUFA intake and activities of clotting factor II, V, fibrinogen, PT, INR, PTT, and sP-selectin in 733 study participants, using the nitrogen isotope ratio of red blood cells as a biomarker of ω3 PUFA consumption. sP-selectin alone correlated strongly and inversely with ω3 PUFA consumption. Approximately 36% of study participants exhibited PIVKA-II values above the threshold of 2 ng/ml, indicative of low vitamin K status. To assess genetic influences on vitamin K status, study participants were genotyped for common vitamin K cycle polymorphisms in VKORC1, GGCX and CYP4F2. Only CYP4F2*3 associated significantly with vitamin K status, for both acute (plasma vitamin K) and long-term (PIVKA-II) measures. These findings suggest: (i) a primary association of ω3 PUFAs on platelet activation, as opposed to vitamin K-dependent clotting factor activity, (ii) that reduced CYP4F2 enzyme activity associates with vitamin K status. We conclude that high ω3 PUFA intake promotes an anti-platelet effect and speculate that the high frequency of the CYP4F2*3 allele in Yup'ik people (~45%) evolved in response to a need to conserve body stores of vitamin K due to environmental limitations on its availability.
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Au
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Morayma
authors.initials: M
authors.lastname: Reyes
authors.affiliation: Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, Alaska, United States of America.
authors.forename: Bert B
authors.initials: BB
authors.lastname: Boyer
authors.affiliation: Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, Alaska, United States of America.
authors.forename: Scarlett E
authors.initials: SE
authors.lastname: Hopkins
authors.affiliation: Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, Alaska, United States of America.
authors.forename: Jynene
authors.initials: J
authors.lastname: Black
authors.affiliation: Center for Alaska Native Health Research, University of Alaska Fairbanks, Fairbanks, Alaska, United States of America.
authors.forename: Diane
authors.initials: D
authors.lastname: O'Brien
authors.affiliation: Public Health Genetics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Fohner
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Joe
authors.initials: J
authors.lastname: Yracheta
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Thornton
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Austin
authors.affiliation: Department of Medical Ethics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Wylie
authors.initials: W
authors.lastname: Burke
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Allan E
authors.identifier: http://orcid.org/0000-0001-9894-8753
authors.initials: AE
authors.lastname: Rettie
mesh_terms: D000293:Adolescent; D000328:Adult; D000413:Alaska; D000072957:Alaska Natives / Q000235:genetics*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000235:genetics; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000235:genetics; D003430:Cross-Sectional Studies; D000072470:Cytochrome P450 Family 4 / Q000235:genetics; D004032:Diet; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D006487:Hemostasis / Q000235:genetics*; D006801:Humans; D004930:Inuit / Q000235:genetics; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011498:Protein Precursors / Q000097:blood; D011516:Prothrombin; D014812:Vitamin K / Q000097:blood; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001779:Blood Coagulation Factors; D015525:Fatty Acids, Omega-3; D019007:P-Selectin; D011498:Protein Precursors; D014812:Vitamin K; C008208:acarboxyprothrombin; D011516:Prothrombin; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase