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.

Dietary Vitamin K and Association with Hepatic Vitamin K Status in a Yup'ik Study Population from Southwestern Alaska

“…As reported previously, inheritance of the CYP4F2*3 allele was associated with long‐term (PIVKA‐II) vitamin K status in our study population . CYP4F2 has been shown to act as an ω‐hydroxylase to VK1 and MK4, and the V433M coding variant defining the *3 allele is associated with a higher warfarin dose requirement of ≈1 mg d –1[ ] and a reduced risk of a major bleeding event in patients receiving warfarin therapy chronically .…”

“…a) Data for this group of 659 study participants is a subset of the larger cohort previously reported …”

“…Many Yup'ik people in southwest Alaska incorporate a subsistence‐based diet that is high in marine animals, fish, and local tundra greens into their lifestyle. We recently reported that consumption of foods rich in ω3 PUFAs is associated with hemostasis biomarkers . Specifically, high PUFA consumption was associated with reduced platelet activation, as indicated by lower plasma sP‐selectin concentrations compared to control.…”

“…Because of its relatively long half‐life (≈60 h), plasma PIVKA‐II concentration is considered a better measure of past long‐term vitamin K status, with values ≥2 ng mL –1 taken as an indicator of subclinical deficiency of vitamin K . An important variable influencing vitamin K status in humans is the CYP4F2*3 allele, which is associated with decreased enzyme function and increased vitamin K concentrations, because CYP4F2 initiates catabolism of the vitamin …”

“…Investigators from the University of Alaska Fairbanks, Center for Alaska Native Health Research have been working in partnership with members of the Yup'ik communities in the YK Delta since 2001. As part of this ongoing health research collaboration, we initiated a multi‐faceted NIH‐funded study in 2010 to identify genetic and environmental sources of inter‐individual differences in warfarin response, with the goal of providing basic knowledge to the population and to their health care providers (principally the Yukon Kuskokwim Health Corporation) and of informing future decisions on the use of precision medicine tests to improve the health of the population …”