Pharmacogenetic discoveries and clinical associations in Alaska native populations

Pharmacogenetic discoveries and clinical associations in Alaska native populations

Kenneth E.THUMMEL

（Department of Pharmaceutics，University of Washington，Seattle，WA，USA）

A lack of knowledge about genetic variation in minority populations throughout the world limits the poten?tial uptake of genomic-based precision medicine in these often-underserved people.Extrapolation of pharmacoge?netic results derived from more extensively studied popu?lations to minority groups carries risk，as founder ef?fects，genetic drift and unique selective pressures can re?sult in the appearance of novel，functionally significant variants and the disappearance of ones common to a larger population.The NIH-funded Northwest-Alaska Pharmacogenetic Research Network was formed in 2010 with the goal of addressing the pharmacogenetic knowl?edge deficit in Alaska native（AN）and American Indian（AI）populations.A collaboration of investigators at the University of Washington，University of Montana，Univer?sity of Alaska-Fairbanks，Southcentral Foundation and Group Health Cooperative of Washington was formed to investigate genetic variation in key pharmacogenes and the resulting effect on drug disposition and response，with a focus on anticoagulation，antiplatelet and anticancer therapies.With regard to anticoagulation therapy，we sequenced and genotyped variation in theVKORC1，GGCX，CYP4F2，CYP4F11andCYP2C9genes in AN populations living in the interior and western Alaska. While no new variants in theVKORC1，GGCX，andCYP4Fgenes at frequencies≥1%were discovered，the reduced function-1639 variant in theVKORC1gene asso?ciated with a lower warfarin dose requirement was found at a relatively high frequency in the western AN population（78%），similar to that seen in some Asian populations（92%），but not so high in the interior AN population（54%）.The loss-of functionCYP4F2*3variant associated with a higher warfarin dose requirement was found at a frequency of 51%and 31%in the western and interior AN populations respectively，both higher than that found in most other world population（8%-29%）.Interestingly，in the western AN population，the reduced functionCYP4F2*3allele was associated with both short-term（plasma vitamin K concentration）and long-term（plasma PIVKA-Ⅱ concentration）measures of vitamin K status，which can affect anti-coagulation control in warfarin-treatedpatients because of its essential role in the synthesis ofⅡ-carboxylated clotting factors（eg，F(xiàn)actorⅡ）.CYP4F2 catabolizes vitamin K to inactive metabolites.Individuals carrying theCYP4F2*3allele were less likely to exhibit vitamin K insufficiency than those homozygous for the referenceCYP4F2*1allele.Moreover，the odds of longterm vitamin K insufficiency was lower in individuals reporting regular consumption of vitamin K rich foods than those who reported no consumption of those foods，and this risk factor was independent ofCYP4F2*3status. Inheritance of theCYP4F2*3allele may enhance the hepatic vitamin K reserve and reduce the risk of major，unexpected bleeding events in individuals receiving longterm warfarin therapy，as we reported in a non-native population receiving care from Group Health Coopera?tive.With respect to warfarin metabolism，we identified two novel coding variants（M1L and N218I）in theCYP2C9gene at frequencies of 6.3%and 3.8%in the western AN population and 1.4%and 5.4%in the interior AN population.In vitrostudies indicate that the M1L vari?ant will confer a complete loss ofCYP2C9function as a consequence of loss of the translation start codon.Inter?estingly，the commonCYP2C9*2and*3variants associ?ated with reducedCYP2C9function and lower warfarin dose requirement were found at lower frequencies in both AN populations than that seen in Caucasians. Thus，genotyping for only previously knownCYP2C9variants in an population would lead to significant misclassi?fication and inappropriate genotype-guided dose recom?mendations.In the case of antiplatelet therapy，we exam?ined the relationship between putative dietary modulators of platelet activation（ω3 polyunsaturated fatty acids；ω3 PUFAs）and basal platelet activationin the same western AN population，using a novel，nitrogen-isotope based biomarker of dietary ω3 PUFA consumption and mem?brane ω3 PUFA levels（δ15N；8）.A significant fraction of the AN population in western Alaska adheres to a′tra?ditional′diet of marine foods rich in ω3 PUFAs.In that population，the degree of platelet activation，as deter?mined by measurement of plasma sP-selectin concentra?tion，correlated strongly and inversely with ω3 PUFA con?sumption.This finding is consistent with older reports of nutritionally-based blood diathesis in other circumpolar populations.Thus，diet，or more specifically ω3 PUFA consumption，may modify the efficacy and safety of anti?platelet therapies.

This work was supported in part by grants from the US National Institutes of Health-U01GM092676