Meta-analysis of genome-wide association studies for circulating phylloquinone concentrations

Authors: DASHTI, HASSAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SHEA, KYLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TANAKA, TOSHIKO - National Institute On Aging (NIA, NIH); HRUBY, ADELA - Harvard University; RICHARDSON, KRIS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, THOMAS - Vanderbilt University; NALLS, MIKE - National Institute On Aging (NIA, NIH); GUO, XIUQING - Harbor-Ucla Medical Center; LIU, YONGMEI - Wake Forest University; YAO, JIE - Harbor-Ucla Medical Center; LI, DALIN - Cedars-Sinai Medical Center; JOHNSON, W CRAIG - University Of Washington; BENJAMIN, EMELIA - Boston University; KRITCHEVSKY, STEPHEN - Wake Forest University; SISCOVICK, DAVID - University Of Washington; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/5/2014
Publication Date: 10/8/2014
Citation: Dashti, H.S., Shea, K., Smith, C.E., Tanaka, T., Hruby, A., Richardson, K., Wang, T.J., Nalls, M.A., Guo, X., Liu, Y., Yao, J., Li, D., Johnson, W., Benjamin, E.J., Kritchevsky, S.B., Siscovick, D.S., Ordovas, J.M., Booth, S.L. 2014. Meta-analysis of genome-wide association studies for circulating phylloquinone concentrations. American Journal of Clinical Nutrition. 100:1462-1469. https://doi.org/10.3945/ajcn.114.093146.

Interpretive Summary: Low circulating vitamin K concentrations are associated with an increased likelihood of developing certain diseases. Vitamin K concentrations vary with age, sex, and diet, but there are potentially additional factors that have not been explored yet, including genetics. In this genome-wide association study, we assessed which genes across the entire genome could influence concentrations of vitamin K in the blood. We investigated this separately in two populations of European decent. Vitamin K was measured in the blood in all participating individuals. Results from each population analysis were then combined across the two populations. No genome-wide significant associations were observed. However, we identified 11 individual genomic base pairs that show potential significant associations with circulating vitamin K, including one base pair that was previously identified as associated with oral anticoagulant dose and vitamin K metabolism. These base pairs are located within or near the genes that regulate lipid metabolism in humans. In conclusion, multiple candidate genes related to lipid and vitamin K metabolism were identified as potential genetic determinants of circulating concentrations of vitamin K. These data can provide insight into the observed variability among individuals in response to dietary vitamin K intake and potentially variability related to oral anticoagulant therapy.

Technical Abstract: Background: Poor vitamin K status is linked to greater risk of several chronic diseases. Age, sex, and diet are determinants of circulating vitamin K; however, there is still large unexplained interindividual variability in vitamin K status. Although a strong genetic component has been hypothesized, this has yet to be examined by a genome-wide association (GWA) study. Objective: The objective was to identify common genetic variants associated with concentrations of circulating phylloquinone, the primary circulating form of vitamin K. Design: We conducted a 2-stage GWA meta-analysis of circulating phylloquinone in 2 populations of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Nutrition Working Group. Circulating phylloquinone was measured by using reversed-phase high-performance liquid chromatography. Results from adjusted cohort-specific discovery GWA analyses were meta-analyzed with inverse variance weights (n=2138). Associations with circulating phylloquinone at P < 1 x 10^-6 were then evaluated in a second-stage analysis consisting of one independent cohort (n=265). Results: No significant association was observed for circulating phylloquinone at the genome-wide significance level of 5 x 10^-8. However, from the discovery GWA, there were 11 single-nucleotide polymorphism (SNP) associations with circulating phylloquinone at P < 1 x 10^-6, including a functional variant previously associated with warfarin dose and altered phylloquinone metabolism. These SNPs are on 5 independent loci on 11q23.3, 8q24.3, 5q22.3, 2p12, and 19p13.12, and they fall within or near the candidate genes APOA1/C3/A4/A5 cluster (involved in lipoprotein metabolism), COL22A1, CDO1, CTNAA2, and CYP4F2 (a phylloquinone oxidase), respectively. Second-stage analysis in an independent cohort further suggests the association of the 5q22.3 locus with circulating phylloquinone (P <0.05). Conclusions: Multiple candidate genes related to lipoprotein and vitamin K metabolism were identified as potential determinants of circulating phylloquinone. Further investigation with a larger sample is warranted to verify our initial findings and identify other loci contributing to circulating phylloquinone.