Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

被引：50

作者：

Huffman, Jennifer E. ^{[1
,2
,3
,4
]}

de Vries, Paul S. ^{[5
]}

Morrison, Alanna C. ^{[6
]}

Sabater-Lleal, Maria ^{[7
]}

Kacprowski, Tim

Auer, Paul L.

Brody, Jennifer A. ^{[8
]}

Chasman, Daniel I. ^{[9
,10
]}

Chen, Ming-Huei ^{[11
]}

Guo, Xiuqing ^{[12
,13
]}

Lin, Li-An ^{[6
,14
]}

Marioni, Riccardo E. ^{[15
,16
,17
]}

Mueller-Nurasyid, Martina ^{[18
,19
,20
]}

Yanek, Lisa R. ^{[21
]}

Pankratz, Nathan ^{[22
]}

Grove, Megan L. ^{[6
]}

de Maat, Moniek P. M. ^{[23
]}

Cushman, Mary ^{[24
,25
]}

Wiggins, Kerri L. ^{[8
]}

Qi, Lihong ^{[26
]}

Sennblad, Bengt ^{[7
,27
]}

Harris, Sarah E. ^{[15
,16
]}

Polasek, Ozren ^{[28
]}

Riess, Helene

Rivadeneira, Fernando ^{[5
,29
]}

Rose, Lynda M. ^{[9
]}

Goel, Anuj ^{[30
]}

Taylor, Kent D. ^{[12
,13
]}

Teumer, Alexander ^{[31
]}

Uitterlinden, Andre G. ^{[5
,29
]}

Vaidya, Dhananjay ^{[21
,32
]}

Yao, Jie ^{[12
]}

Tang, Weihong ^{[33
]}

Levy, Daniel ^{[3
,4
]}

Waldenberger, Melanie ^{[20
,34
]}

Becker, Diane M. ^{[21
,35
]}

Folsom, Aaron R. ^{[33
]}

Giulianini, Franco ^{[9
]}

Greinacher, Andreas ^{[36
]}

Hofman, Albert ^{[5
]}

Huang, Chiang-Ching

Kooperberg, Charles ^{[37
]}

Silveira, Angela ^{[7
]}

Starr, John M. ^{[15
,38
]}

Strauch, Konstantin ^{[18
,39
]}

Strawbridge, Rona J. ^{[7
]}

Wright, Alan F. ^{[1
]}

McKnight, Barbara ^{[40
]}

Franco, Oscar H. ^{[5
]}

Zakai, Neil ^{[24
,25
]}

机构：

[1] Univ Edinburgh, Inst Genet & Mol Med, Med Res Council, Human Genet Unit, Edinburgh, Midlothian, Scotland

[2] NHLBI, Framingham Heart Study, Cardiovasc Epidemiol & Human Genom Branch, Framingham, MA USA

[3] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[4] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA

[5] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[6] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA

[7] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden

[8] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[9] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Boston, MA USA

[11] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[12] Harbor Univ Los Calif Angeles UCLA, Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA USA

[13] Harbor Univ Los Calif Angeles UCLA, Med Ctr, Dept Pediat, Torrance, CA USA

[14] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA

[15] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[16] Univ Edinburgh, MRC Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland

[17] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

[18] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Genet Epidemiol, Neuherberg, Germany

[19] Univ Munich, Dept Med 1, Munich, Germany

[20] German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany

[21] Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Program,Div Gen Internal Med, Baltimore, MD 21205 USA

[22] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[23] Erasmus MC, Dept Hematol, Rotterdam, Netherlands

[24] Univ Vermont, Dept Med, Colchester, VT USA

[25] Univ Vermont, Dept Pathol, Colchester, VT USA

[26] Univ Calif Davis, Davis, CA 95616 USA

[27] Karolinska Inst, Sci Life Lab, Stockholm, Sweden

[28] Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia

[29] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[30] Univ Oxford, John Radcliffe Hosp, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England

[31] Univ Med Greifswald, Inst Community Med, Clin & Epidemiol Res Dept, Study Hlth Pomerania, Greifswald, Germany

[32] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[33] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[34] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Res Unit Mol Epidemiol, Neuherberg, Germany

[35] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA

[36] Univ Med Greifswald, Dept Transfus Med, Inst Immunol & Transfus Med, Greifswald, Germany

[37] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[38] Univ Edinburgh, Dept Psychol, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland

[39] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[40] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[41] Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA

[42] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[43] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[44] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA

[45] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland

[46] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[47] Tech Univ Munich, German Heart Ctr Munich, D-80290 Munich, Germany

[48] Seattle Epidemiol Res & Informat Ctr, Vet Affairs Off Res & Dev, Seattle, WA USA

来源：

BLOOD | 2015年 / 126卷 / 11期

基金：

英国生物技术与生命科学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; VON-WILLEBRAND-FACTOR; CORONARY-HEART-DISEASE; FACTOR-VIII; VONWILLEBRAND-FACTOR; AFRICAN-AMERICANS; SEQUENCE VARIANTS; COMPOUND HETEROZYGOSITY; CIRCULATING FIBRINOGEN; EUROPEAN AMERICANS;

D O I：

10.1182/blood-2015-02-624551

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] >= 0.01 and < 0.05) and rare (MAF < 0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76 000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n=2) andrare (n=10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

引用

页码：E19 / E29

页数：11

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