TY - JOUR
T1 - Meta-analysis of genome-wide association studies for circulating phylloquinone concentrations
AU - Dashti, Hassan S.
AU - Shea, M. Kyla
AU - Smith, Caren E.
AU - Tanaka, Toshiko
AU - Hruby, Adela
AU - Richardson, Kris
AU - Wang, Thomas J.
AU - Nalls, Mike A.
AU - Guo, Xiuqing
AU - Liu, Yongmei
AU - Yao, Jie
AU - Li, Dalin
AU - Johnson, W. Craig
AU - Benjamin, Emelia J.
AU - Kritchevsky, Stephen B.
AU - Siscovick, David S.
AU - Ordovás, José M.
AU - Booth, Sarah L.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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 metaanalyzed with inverse variance weights (n = 2138). Associations with circulating phylloquinone at P , 1 3 1026 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 3 1028. However, from the discovery GWA, there were 11 single-nucleotide polymorphism (SNP) associations with circulating phylloquinone at P , 1 3 1026, 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 otential 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. Trials related to this study were registered at clinicaltrials.gov as NCT00005121 (Framingham Offspring Study) and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
AB - 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 metaanalyzed with inverse variance weights (n = 2138). Associations with circulating phylloquinone at P , 1 3 1026 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 3 1028. However, from the discovery GWA, there were 11 single-nucleotide polymorphism (SNP) associations with circulating phylloquinone at P , 1 3 1026, 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 otential 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. Trials related to this study were registered at clinicaltrials.gov as NCT00005121 (Framingham Offspring Study) and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
KW - CYP4F2
KW - GWAS
KW - Genetics
KW - Phylloquinone
KW - Vitamin K
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UR - http://www.scopus.com/inward/citedby.url?scp=84911413738&partnerID=8YFLogxK
U2 - 10.3945/ajcn.114.093146
DO - 10.3945/ajcn.114.093146
M3 - Article
C2 - 25411281
AN - SCOPUS:84911413738
SN - 0002-9165
VL - 100
SP - 1462
EP - 1469
JO - American Journal of Clinical Nutrition
JF - American Journal of Clinical Nutrition
IS - 6
ER -