Dr Fiona Green

Biography

• University Research Lecturer (from Feb 03, previously Senior Research Fellow)
• Wellcome Trust Centre for Human Genetics, University of Oxford 1999-2003
• Senior Research Fellow, Nuffield Dept Surgery, University of Oxford, 1995-1999
• Lecturer, Dept Medicine, UCL 1990-1995
• Post Doc, Charing Cross Sunley Research Institute, Uof London, 1987-1990

Research Interests

Genetics of Athero-Thrombotic Disease

Function of common polymorphisms (SNPs and VNTRs) in genes involved in the inflammation/ thrombosis axis of athero-thrombotic disease, in particular interleukin 6 and fibrinogen.

PROCARDIS : a genome-wide strategy to identify susceptibility loci in precocious coronary artery disease.

Genetics, genomics and epigenetics of complex disease: cardiovascular disease; prostate and colon cancer (with Prof Margaret Rayman, Division of Nutritional Sciences, FHMS).

More Detail

Function of common polymorphisms in genes involved in the inflammation/thrombosis axis of athero-thrombotic disease, in particular fibrinogen and interleukin 6
Elevated circulating fibrinogen level is a well-established prospective risk factor for athero-thrombotic disease but it remains a possibility that this elevation reflects the presence of pre-existing vascular disease. The inflammatory nature of the atherosclerotic plaque is likely to provoke a low-grade, persistent acute-phase response, mediated through pro-inflammatory cytokines in particular interleukin-6 (IL-6), leading to the observed elevations in plasma fibrinogen and in C-reactive protein (CRP) levels. The known physiological functions of fibrinogen make it very likely that it is itself involved in the disease process. Elevated fibrinogen, CRP and IL6 are likely to be part of a vicious circle of events exacerbating the athero-thrombotic process.
There are 6 polymorphisms in the promoter of the beta-fibrinogen gene that occur in 4 common combinations or "haplotypes". We have recently shown that at least one of these sites shows allele-specific binding to a liver-enriched transcription factor and differential, allele-specific transactivation [Wragg, 2000; Wragg, 2001]. This may explain the associations, reported by us and many other groups, of the particular haplotype with elevated plasma fibrinogen level and, in some studies, with increased tendency to or severity of athero-thrombotic disease [Behague, 1996; Green, 1989; Green, 1993; Green, 1994; Green, 1995; Green, 2001; Green, 2001; Thomas, 1991; Thomas, 1994; Thomas, 1995; Thomas, 1996].
There are 4 polymorphisms in the promoter of the IL6 gene that occur in several common haplotypes. We have shown that one of these IL6 promoter haplotypes is induced approximately twice as much as the others by interleukin-1 treatment [Terry, 2000]. Comparison of reporter constructs of different haplotype that differ at only one of the polymorphic sites has enabled us to conclude that it is not the individual polymorphisms that are functional but the particular haplotype combination. This has implications for genetic studies since, for any given culprit gene, there may be not one but several functional polymorphisms.
Techniques currently used in these studies include the usual mol biol ones together with PCR, rtPCR, EMSAs, transient expression and surface plasmon resonance assays.

Role of cytokine and MMP polymorphisms in determining expression levels in situ in the atherosclerotic plaque
It is becoming increasingly clear that the progression of atherosclerosis to acute endpoints is mediated by factors that govern overall plaque dynamics. The matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), with their crucial roles in connective tissue remodelling, are considered to play pivotal roles in atherosclerotic plaque rupture and abdominal aortic aneurysm (AAA) expansion. These MMPs and TIMPs are regulated by pro- and anti-inflammatory cytokines.
We have recently found that MMPs 2, 9 and 12 are expressed at a significantly higher level in ruptured atherosclerotic plaques, and in rapidly expanding AAA [Senaratne, 1998; Senaratne, 2000; Senaratne, 2001]. Interestingly, analysis of the impact of genotype on MMP expression in the arterial wall revealed that for MMP9 and MMP12, the effect was small. This is in contrast with the major impact of cytokine gene polymorphisms on cytokine expression in the same series of patients. This indicates that factors in addition to the two genetic polymorphisms studied are involved in determining MMP expression levels in end stage arterial disease and we are currently investigating this further.
Techniques currently used in these studies include immunohistochemistry, PCR, rtPCR.

Publications

Senaratne JWB, Hands LJ, Handa A, Collin J, Morris PJ, Green FR. Increased elastinolytic MMP expression in the arterial wall is associated with carotid plaque instability and abdominal aortic aneurysm expansion. (in prep)

Senaratne JWB, Hands LJ, Handa A, Collin J, Morris PJ, Green FR.. Pro- and anti-Inflammatory cytokine expression in the diseased artery wall is determined by genotype. (in prep)

Tornvall P, Kovacs A, Hansson L-O, Lundman P, Samnegård A, Boquist S, Ericsson C-G, Watkins HC, Hamsten A, Green FR. A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with plasma concentrations of C-reactive protein. (in prep)

Bennermo M, Held C, Green FR, Strandberg L-E, Ericsson C-G, Hansson L-O, Watkins HC, Hamsten A, Tornvall P. Prognostic value of the Plasma Interleukin-6 concentrations and Promoter Polymorphisms 174 G>C and 572 G>C of the Interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis. (in prep)

Wragg S, Ellis S, Davidson A, Green FR. Allele specific transactivation by HNF3 explains inter-individual differences in plasma fibrinogen level. Blood 2003 (in revision).

Best D, Senis YA, Jarvis GE, Eagleton HJ, Roberts DJ, Saito T, Jung SM, Moroi M, Harrison P, Green FR, Watson SP. GPVI levels in platelets: relationship to platelet function at high shear. Blood 2003 (in press).

Acalovschi D, Wiest T, Hartmann M, Farahmi M, Mansmann U, Auffarth GU, Grau AJ, Green FR, Grond-Ginsbach C, Schwaninger M. Multiple Levels of Regulation of the Interleukin-6 System in Stroke. Stroke 2003 (in press)

Vickers MA, Green FR, Terry CF, Mayosi BM, Julier C, Lathrop M, Ratcliffe PJ, Watkins HC, Keavney B. Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein. Cardiovascular Research 2002; 53(4): 1029-34.

Mayosi BM, Vickers MA, Green FR, Ratcliffe PJ, Julier C, Lathrop GM, Watkins H, Keavney B. Evidence for a quantitative trait locus for plasma fibrinogen from a family-based association study. GeneScreen 2001; 1: 151-155.

Green FR.. Taking the hype out of hyperfibrinogenaemia? Thromb Haemost 2001; 86(2): 509-10.

Green FR.. Fibrinogen polymorphisms & atherothrombotic disease. Ann N Y Acad Sci. 2001; 936: 549-59.

Green FR. Fibrinogen, Fibrin. The Encyclopaedia of Molecular Medicine. John Wiley & Sons. 2001.

Greaves DR, Hakkinen T, Lucas AD, Liddiard K, Jones E, Quinn CM, Senaratne J, Green FR, Tyson K, Boyle J, Shanahan C, Weissberg PL, Gordon S, Yla-Hertualla S. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus- and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2001; 21(6): 923-9.

Curran J, Fatah K, Blomback M, Hamsten A, Humphries S, Green FR. A hypothesis to explain the reported association of the a-fibrinogen A312 allele with thromboembolic disease. Thromb Haemost 2001; 85(6): 1122-3.

Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin-6 (IL6) transcriptional regulation. J Biol Chem 2000; 275: 18138-44.

Senaratne JWB, Green FR. Pathobiology of Atherosclerosis. Oxford Textbook of Surgery 2000 Edition, Eds Prof Sir Peter J Morris, Prof William C Wood.

Green FR. Genetic predisposition to thrombosis in renal transplant recipients: the factor V Q506 (Leiden) allele. Transplantation 2000; 69: 1547-8.

Green FR, Watkins HC. Genetic association studies in coronary disease: the case of GPIIb-IIIa polymorphisms. Eur Ht J 99; 20: 706-8.

Curran JM, Evans A, Luc G, Arveiler D, Cambou JP, Humphries SE, Green FR. The a-fibrinogen T/A312 polymorphism in the ECTIM study. Thromb Haemost 1998; 79: 1057-1058.

Irish AB, Green FR. Factor VII coagulant activity (VIIc) and hypercoagulability in chronic renal disease and dialysis: relationship with dyslipidaemia, inflammation and factor VII genotype. Nephrol Dial Transpl; 1998; 13: 679-684.

de Maat MPM, Green FR, de Knijff P, Jespersen J, Kluft C. Factor VII polymorphisms in populations with different risk of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997; 17: 1918-1923.

Irish AB, Green FR, Gray DWR, Morris PJ. The factor V Leiden (R506Q) mutation and risk of thrombosis in renal transplant recipients. Transplantation 1997; 64: 604-607.

Humphries SE, Panahloo A, Montgomery HE, Green FR, Yudkin J. Gene-environment interaction in the determination of thrombosis and fibrinolysis. Thromb Haemost 1997; 78 (1): 457-461.

Humphries SE, Thomas A, Montgomery HE, Green FR, Winder A, Miller G. Gene-environment interaction in the determination of plasma levels of fibrinogen. Fibrinolysis & Proteolysis 1997; 11 Suppl 1; 3-7.

Irish AB, Green FR. Environmental and genetic determinants of the hypercoagulable state and cardiovascular disease in renal transplant recipients. Nephrol Dial Transpl 1996; 12: 167-173.

Thomas AE, Green FR, Humphries SE. Association of genetic variation at the b-fibrinogen locus and plasma fibrinogen levels; interaction between allele frequency of the G/A-455 polymorphism, age and smoking. Clin Genet 1996; 50:184-190.

Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G, Cambou JP, Scarabin PY, Bara L, Green FR, Cambien F. Fibrinogen gene polymorphisms contribute to the degree of coronary arteriosclerosis. Circulation 1996; 93: 440-449.

Humphries S, Temple A, Lane A, Green FR, Cooper J, Miller G. Low plasma levels of factor VIIc and antigen are more strongly associated with the 10 base pair promoter (-323) insertion than the glutamine 353 variant. Thromb Haemost. 1996; 75: 567-572.

Lane A, Green FR, Scarabin PY, Nicaud V, Bara L, Humphries S, Evans A, Luc G, Cambou JP, Arveiler D, Cambien F.The factor VII Arg/Gln353 polymorphism determines factor VII coagulant activity in patients with myocardial infarction (MI) and control subjects in Belfast and in France but is not a strong indicator of MI risk in the ECTIM study. Atherosclerosis 1996; 119: 119-127.

Green FR. Genetic and environmental determinants of factor VII, fibrinogen and PAI-1. Fibrinolysis 1996; 10 (S2): 7-8.

Humphries SE, Day INM, Green FR. Common genetic determinants of coagulation and fibrinolysis. In Emery and Rimoin's Principles and Practices of Medical Genetics. 3rd Edition. Eds Rimoin DL, Conner JM, Pyeritz RE. 1996; ch 24: pp 829-842.

Ye S, Green FR, Henney AM, Dawson SJ, Humphries SE, Scarabin PY, Nicaud V, Bara L, Evans A, Luc G, Cambou JP, Arveiler D, Cambien F. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. ThrombHaemostas 1995; 74: 837-41.

de Maat M, Green FR, Johansen L, de Knijff P, Thomas A, Jespersen J, Kluft C. Gender-related association between beta-fibrinogen genotype and plasma fibrinogen levels and linkage disequilibrium at the fibrinogen locus in Greenland Inuit. Arterioscler Thromb Vasc Biol 1995; 15: 856-60.

Thomas AE, Green FR, Lamlum H, Humphries S. The association of combined alpha and beta fibrinogen genotype on plasma fibrinogen levels in smokers and non-smokers. J Med Genet 1995; 32: 585-9.

Meilahn E, Humphries S, Ferrell R, Kiss J, Green FR, Temple A, Kuller L. Genetic determination of coagulation factor VIIc levels among healthy middle-aged women. Thromb Haemostas 1995; 73: 623-625

Lane A, Green FR, Humphries S, Ruddock V, Meade T. Effect of factor VII genotype on response to warfarin treatment. Thromb Haemostas 1995; 73: 325

Panahloo A, Mohamed-Ali V, Lane A, Green FR, Humphries SE, Yudkin JS. Determinants of plasminogen activator inhibitor-1 activity in treated type 2 diabetes and its relation to a polymorphism in the plasminogen acitvator inhibitor-1 gene. Diabetes 1995; 44: 37-42

Green FR, Lane A, Thomas AE, Dawson S, Miller G, Hamsten A, Humphries SE. Gene-environment interactions determining the risk of thrombosis. Proceedings of the 10th International Symposium on Atherosclerosis. Atherosclerosis 1995; X : 805-807.

Humphries SE, Lane A, Thomas A, Green FR, Dawson S, Miller G, Hamsten A. Interaction between genotype and environmental factors in the development of atherosclerotic-thrombotic disease. Proceedings of the 10th International Symposium on Atherosclerosis. Atherosclerosis 1995; X : 628-633.

Silveira A, Green FR, Karpe F, Blombäck M, Humphries S, Hamsten A. Plasma factor VII antigen and activity levels are determined by factor VII genotype and postprandial triglyceride-rich lipoprotein levels. Arterioscler Thromb 1994; 72(5): 734-739

de Knijff P, Green FR, Johansen LG, Grootendorst D, Temple A, Cruickshank JK, Humphries SE, Jespersen J, Kluft C. New alleles in F7 VNTR. Hum Mol Genet 1994: 3(2): 384

Thomas A, Lamlum H, Humphries S, Green FR. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A-455 (HaeIII), C/T-148 (HindIII/AluI), T/G-1689 (AvaII), and BclI (b-fibrinogen) and TaqI (a-fibrinogen), and their detection by PCR. Human Mutation 1994; 3(1): 79-81

Humphries SE, Lane A, Green FR, Cooper J, Miller GJ. Factor VII coagulant activity and antigen levels in healthy men are determined by interaction between factor VII genotype and plasma triglyceride concentration. Arterioscler Thromb 1994; 14: 193-8

Green FR, Humphries S. Genetic Determinants of Arterial Thrombosis. In "Thrombophilia". Ed; Meade TW, Baillière's Clinical Haematology 1994; 7: 675-692.

Green FR, Hamsten A, Blombäck M, Humphries S. The role of b-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden. Thromb Haemostas 1993; 70: 915-20

Dawson SJ, Wiman B, Hamsten A, Green FR, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the PAI-1 gene respond differently to IL-1 in HepG2 cells. J Biol Chem 1993; 268 (15): 10739-45

Humphries SE, Seed M, Mailly F, Gudnason V, Lane A, Green FR, Talmud PJ. Molecular genetics in the diagnosis of hyperlipidaemia and other risk factors for cardiovascular disease. Eur J Clin Chem Clin Biochem 1993; 31(9): A13-A14.

Ye S, Green FR, Humphries S. Allele specific amplification by tetra-primer PCR. Nucl Acids Res 1992; 20 (5): 1152

Lane A, Cruickshank JK, Stewart J, Henderson A, Humphries S, Green FR. Genetic and environmental determinants of factor VII coagulant activity in different ethnic groups at differing risk of coronary heart disease. Atherosclerosis 1992; 94: 43-50

Humphries SE, Lane A, Dawson SJ, Green FR. The study of gene-environment interactions that influence thrombosis and fibrinolysis. Genetic variation at the loci for factor VII and PAI-1. Arch Pathol Lab Med 1992: 116 (12); 1322-9.

Thomas A, Green FR, Dawson S, Lane A, Henney A, Kelleher C, Wilkes H, Brennan P, Cruickshank J, Hamsten A, Wiman B, Meade T, Humphries S. Possibilities of DNA analysis for the detection of predisposition to thrombotic disease. Annals New York Acad Sciences 1992; 667: 332-42.

Humphries SE, Green FR, Temple A, Dawson S, Henney A, Kelleher C, Wilkes H, Meade T, Wiman B, Hamsten A. Genetic factors determining thrombosis and fibrinlysis. Ann Epidemiol 1992; 2: 371-85.

Humphries SE, Green FR, Henney AM, Talmud PJ. DNA polymorphisms: the variability gene concept and the risk of coronary heart disease. In "Genetics of Coronary Heart Disease". Ed; Bearn AG. Pubs; Institute of Medical Genetics, University of Oslo, Norway. 1992: 123-42.

Lane A, Graham L, Cook M, Chantry D, Green FR, Nigon F, Humphries S. Cytokine production by cholesterol-loaded human peripheral monocyte-macrophages: the effect on fibrinogen mRNA levels in HepG2 cells. Biochem Biophys Acta 1991; 1097: 161-165

Green FR, Kelleher C, Wilkes H, Temple A, Meade T, Humphries S. A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Arteriosclerosis Thromb 1991; 11: 540-6

Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promotor region of the b-fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemostas 1991; 65: 487-90

Humphries SE, Green FR, Thomas A, Kelleher C, Meade T. Genetic control of plasma fibrinogen levels: an example of gene-environment interaction in the etiology of a multifactorial disorder. In "Etiology of Human Disease at the DNA Level". Eds J Lindsten and U Petterson. Pubs; Raven Press Ltd. 1991: 115-28.

Houlston RS, Snowden C, Green FR, Alberti G, Humphries SE. Apolipoprotein (apo) E genotypes by polymerase chain reaction and allele-specific oligonucleotide probes: no detectable linkage disequilibrium between apo E and apo CII. Hum Genet 1989; 83: 364-8

Green FR and Humphries SE. Control of plasma fibrinogen levels. In "Molecular Biology of Coagulation". Ed; Tuddenham EGD, Baillière's Clinical Haematology. 1989; 2(4): 945-959

Departmental Duties

Head of the Department of Biochemistry and Physiology

Affiliations

• British Atherosclerosis Society
• British Society for Thrombosis & Haemostasis
• Biochemical Society Genes Theme Panel
• Genetics Society 
• American Heart Association Basic Sciences Council