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The Prothrombin Gene G20210A Mutation and the Platelet Glycoprotein IIIa Polymorphism PlA2 in Patients with Central Retinal Vein Occlusion
Thrombosis Research 96 (1999) 323–327
BRIEF COMMUNICATION
The Prothrombin Gene G20210A Mutation and the Platelet Glycoprotein IIIa Polymorphism PlA2 in Patients with Central Retinal Vein Occlusion Jo¨rgen Larsson1 and Andreas Hillarp2 Department of Ophthalmology, Lund University Hospital, Lund; 2 Department of Clinical Chemistry, Malmo¨ University Hospital, Malmo¨, Sweden.
1
(Received 1 February 1999 by Editor B.N. Bouma; revised/accepted 9 June 1999)
Abstract The prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 have been shown to be associated with thromboembolic disease. We wondered if mutations were overrepresented in patients with central retinal vein occlusion. We studied 129 consecutive patients with a history of central retinal vein occlusion. We analysed for the prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 and compared the results to controls with no history of thrombosis. For the platelet glycoprotein IIIa polymorphism PlA2, 69% were normal, 26% were heterozygous, and 5% were homozygous. For the G20210A prothrombin mutation, 97% were normal and 3% were heterozygous. Neither the prothrombin gene G20210A mutation nor the platelet glycoprotein IIIa polymorphism PlA2 seem to be associated with central retinal vein occlusion. 1999 Elsevier Science Ltd. All rights reserved. Key Words: Prothrombin gene G20210A mutation; Glycoprotein IIIa polymorphism; Central retinal vein occlusion
T
he three most important factors to the aetiology of central retinal vein occlusion are glaucoma, hypertension, and atherosclero-
Abbreviations: GPIIIA, glycoprotein IIIa; PCR, polymerase chain reaction. Corresponding author: J. Larsson, Department of Ophthalmology, Lund University Hospital, S-221 85 Lund, Sweden. Tel: 146 (46) 17 20 74; Fax: 146 (46) 211 50 74; E-mail: ,Jorgen.Larsson@ oft.lu.se..
sis [1–7]. Hereditary deficiencies in natural anticoagulant proteins (i.e., antithrombin, protein S, and protein C) and resistance to activated protein C are known hereditary risk factors for thromboembolic disease. However, only sporadic case reports of patients with central retinal vein occlusion have shown an association between reduced levels of antithrombin, protein C, and protein S and thrombotic complications of the eye [8–10]. Activated protein C resistance, which is the most common genetic cause of venous thrombosis, has also been associated with central retinal vein occlusion [11,12]. In the majority of vein thromboses of the eye, a genetic association with known risk factors remains elusive. New genetic variants are constantly being found that add to the list of known inherited prothrombotic disorders. Recently, a mutation in the prothrombin gene was associated with an increased risk of deep-vein thrombosis [13]. The mutation involves a single base substitution (G to A) at position 20210 of the 39-untranslated region of the prothrombin gene. Due to the location of the mutation, the primary structure and thus the function of prothrombin is not altered. Instead, it was found that the G20210A allele was associated with increased prothrombin levels in the plasma [13], which suggests that the hypercoagulability conferred by the 20210 A allele is due to hyperactivity of the common coagulation pathway. Other candidate genes for thrombosis encode proteins expressed on the surface of platelets. One of these proteins is the
0049-3848/99 $–see front matter 1999 Elsevier Science Ltd. All rights reserved. PII S0049-3848(99)00111-5
324
J. Larsson et al./Thrombosis Research 96 (1999) 323–327
Table 1. Distribution of observed prothrombin and GPIIIa genotypes and allele frequencies among patients ,50 years of age with central retinal vein occlusion and controls Patients ,50 years n Genotype 20210A/A 20210G/A 20210A/A Total Allele frequency 20210A 20210G Genotype PlA1/A1 PlA1/A2 PlA2/A2 Total Allele frequency PlA1 PlA2
35 2 0 37
% 94.6 5.4 0 100
0.97 0.03 28 8 1 37
Controls n 277 5 0 282
%
p value*
98.2 1.8 0 100
n.s. n.s. n.s.
0.99 0.01 75.7 21.6 2.7 100
0.86 0.14
100 38 2 140
n.s. n.s. 71.4 27.2 1.4 100
0.85 0.15
n.s. n.s. n.s.
n.s. n.s.
* p values were calculated by a standard chi-squared test. n.s. denotes not significant (p.0.05).
glycoprotein IIIa (GPIIIA), a subunit of the fibrinogen receptor glycoprotein IIb/IIIa expressed on platelets. A common polymorphism, called PlA1/A2, which involves a single base substitution in exon 2 of the glycoprotein IIIa gene, has been reported to be associated with coronary thrombosis [14,15]. After its discovery, several contradictory reports were published and it remains unclear if it is or is not an independent risk factor for arterial thrombosis [14–18]. We studied the prevalence of the prothrombin G20210A gene mutation and the PlA1/A2 polymorphism in a group of consecutive patients with central retinal vein occlusion.
tein IIIa polymorphism was determined as described by Jin et al. [19].
1.2. Patients The patient sample was recruited from the records of the eye clinic of the Lund University Hospital and comprised all cases with central retinal vein occlusion diagnosed in a given time period. Of the patients (n5129), 55 were females and 74 were male; 37 were <50 years of age with a mean age of 40.4 years (range 21–49 years); 92 were .50 years of age with a mean age of 69.2 years (range 52–91 years).
1. Subjects and Methods
1.3. Controls
1.1. Methods
The control group for the G20210A prothrombin mutation was comprised of 282 volunteers (102 women and 180 men), with a mean age 59 years (range 34–86) and no history of thrombosis. The control group for the platelet glycoprotein IIIa polymorphism PlA2 was comprised of 140 volunteers (blood donors; 30 females and 110 males), with a mean age of 51 years (range 34–64) and no history of thrombosis. The control groups differ
Genomic DNA was prepared from whole blood using standard procedures. The presence or absence of the 20210 G to A transition of the prothrombin gene was determined by Hind III cleavage of a 345-bp fragment amplified by polymerase chain reaction (PCR), using a mutagenic primer as described previously [13]. The platelet glycopro-
J. Larsson et al./Thrombosis Research 96 (1999) 323–327
325
Table 2. Distribution of observed prothrombin and GPIIIa genotypes and allele frequencies among patients .50 years of age with central retinal vein occlusion and controls Patients .50 years n Genotype 20210A/A 20210G/A 20210A/A Total Allele frequency 20210A 20210G Genotype PlA1/A1 PlA1/A2 PlA2/A2 Total Allele frequency PlA1 PlA2
90 2 0 92
% 97.8 2.2 0 100
0.98 0.02 61 26 5 92
Controls n 277 5 0 282
%
p value*
98.2 1.8 0 100
n.s. n.s. n.s.
0.99 0.01 66.3 28.3 5.4 100
0.80 0.20
100 38 2 140 0.85 0.15
n.s. n.s. 71.4 27.2 1.4 100
n.s. n.s. n.s.
n.s. n.s.
* p values were calculated by a standard chi-squared test. n.s. denotes not significant (p.0.05).
in size because the control group for the 20210 prothrombin mutation was not specifically created for this study. The controls were from the same geographical area as the patients.
2. Results We divided our patients into one group that was <50 years of age and one group that was .50 years of age. The observed genotype distribution and allele frequencies at the two dimorphic sites are shown in Tables 1 and 2. Similar distribution patterns were seen in the groups of patients and controls. The distribution of heterozygotes and homozygotes was also similar for both patients and controls. No homozygotes for the prothrombin 20210 A allele were found. There was no statistical difference between the controls and the two patient groups.
3. Discussion Our findings suggest that neither the G20210A allele of the prothrombin gene nor the platelet glyco-
protein IIIa polymorphism PlA2 are overrepresented in patients with central retinal vein occlusion. Previous reports showed a correlation between the presence of the 20210 A allele of the prothrombin gene and thromboembolic disease [13,20–25]. These investigations were performed mainly on patients with deep venous thrombosis, pulmonary embolism, and myocardial infarction (i.e., disease in vessels that are much bigger than the retinal veins). The retinal veins are very small compared to the vessels in the leg, heart, and lung. It is possible that the aetiology for venous thromboembolic disease is not exactly the same in very small veins (like the retinal veins) and bigger veins (like the ones that are involved in deep venous thrombosis); this could explain why the 20210 A allele of the prothrombin gene is not overrepresented in our group of patients with central retinal vein occlusion. Two recent studies have not found any correlation between the G 20210 A allele of the prothrombin gene and patients with retinal vein occlusion [26,27]. Whether the platelet glycoprotein IIIa polymorphism PlA2 is correlated to thromboembolic disease is still not clear. Some reports show a correlation between thromboembolic disease and the plate-
326
J. Larsson et al./Thrombosis Research 96 (1999) 323–327
let glycoprotein IIIa polymorphism PlA2 [14,15], whereas others do not [16–18]. In our patients with central retinal vein occlusion there was no overrepresentation of the glycoprotein IIIa polymorphism PlA2 compared to the controls. In conclusion, neither the 20210 A allele of the prothrombin gene nor the platelet glycoprotein IIIa polymorphism PlA2 seems to be an important factor in the aetiology of central retinal vein occlusion. This study was supported by Synfra¨mjandets Forskningsfond Sweden, Carmen och Bertil Regne´rs Stiftelse fo¨r Forskning inom Omra˚¨ gonsjukdomar Sweden, Elsa och Ola Ohlssons Fond fo¨r det O ¨ gonforskning Sweden, the faculty of Medicine at the University O of Lund, Malmo¨hus La¨ns Landsting Sweden, Svenska Sa¨llskapet fo¨r Medicinsk Forskning Sweden, the Swedish Medical Research Council (project 14x-2321), Swedish Medical Research Council (grant no. 11195), and research funds from University Hospital, Malmo¨. We would also like to thank Ewa Nilsson and Kerstin Fridh for excellent technical assistance.
References 1. McGrath MA, Wechsler F, Hunyor ABL, Penny R. Systemic factors contributory to retinal vein occlusion. Arch Intern Med 1978;138: 216–20. 2. The Eye Disease Case-Control Study Group. Risk factors for central retinal vein occlusion. The Eye Disease Case-Control Study Group. Arch Ophthalmol 1996;114:545–54. 3. Hirota A, Mishima HK, Kiuchi Y. Incidence of retinal vein occlusion at the Glaucoma Clinic of Hiroshima University. Ophthalmologica 1997;211:288–91. 4. Rath EZ, Frank RN, Shin DH, Kim C. Risk factors for retinal vein occlusions. A case-control study. Ophthalmology 1992;99:509–14. 5. Appiah AP, Greenidge KC. Factors associated with retinal-vein occlusion in Hispanics. Ann Ophthalmol 1987;19:307–12. 6. Elman MJ, Bhatt AK, Quinlan PM, Enger C. The risk for systemic vascular diseases and mortality in patients with central retinal vein occlusion. Ophthalmology 1990;97:1543–8. 7. Laatikainen L, Kohner EM, Khoury D, Blach RK. Panretinal photocoagulation in central retinal vein occlusion: A randomised controlled clinical study. Br J Ophthalmol 1977;61:741–53.
8. Ririe DG, Cosgriff TM, Martin B. Central retinal vein occlusion in a patient with familial antithrombin III deficiency: Case report. Ann Ophthalmol 1979;11:1841–5. 9. Zwierzina WD, Kunz F, Miller K. Retinaler Gefassverschluss bei Antithrombin III-Mangel [Retinal vascular occlusion in antithrombin III deficiency]. Klin Monatsbl Augenheilkd 1985; 187:534–6. 10. Vine AK, Samama MM. The role of abnormalities in the anticoagulant and fibrinolytic systems in retinal vascular occlusions. Surv Ophthalmol 1993;37:283–92. 11. Larsson J, Olafsdottir E, Bauer B. Activated protein C resistance in young adults with central retinal vein occlusion. Br J Ophthalmol 1996;80:200–2. 12. Williamson TH, Rumley A, Lowe GD. Blood viscosity, coagulation, and activated protein C resistance in central retinal vein occlusion: A population controlled study. Br J Ophthalmol 1996;80:203–8. 13. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 39untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698–703. 14. Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996;334:1090–4. 15. Carter AM, Ossei Gerning N, Wilson IJ, Grant PJ. Association of the platelet Pl(A) polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bbeta 448 polymorphism with myocardial infarction and extent of coronary artery disease. Circulation 1997;96:1424–31. 16. Herrmann SM, Poirier O, Marques Vidal P, Evans A, Arveiler D, Luc G, Emmerich J, Cambien F. The Leu33/Pro polymorphism (PlA1/PlA2) of the glycoprotein IIIa (GPIIIa) receptor is not related to myocardial infarction in the ECTIM Study. Etude Cas-Temoins de l’Infarctus du Myocarde. Thromb Haemost 1997;77:1179–81. 17. Wagner KR, Giles WH, Johnson CJ, Ou CY, Bray PF, Goldschmidt Clermont PJ, Croft JB,
J. Larsson et al./Thrombosis Research 96 (1999) 323–327
18.
19.
20.
21.
22.
Brown VK, Stern BJ, Feeser BR, Buchholz DW, Early CY, Macko RF, McCarete RJ, Sloan MA, Stolley PD, Wityk RJ, Wozniak MA, Price TR, Kittner SJ. Platelet glycoprotein receptor IIIa polymorphism P1A2 and ischemic stroke risk: The Stroke Prevention in Young Women Study. Stroke 1998;29:581–5. Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpaintner K. PIA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997;349:385–8. Jin Y, Dietz HC, Nurden A, Bray PF. Singlestrand conformation polymorphism analysis is a rapid and effective method for the identification of mutations and polymorphisms in the gene for glycoprotein IIIa. Blood 1993;82: 2281–8. Hillarp A, Zo¨ller B, Svensson PJ, Dahlba¨ck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997;78:990–2. Kapur RK, Mills LA, Spitzer SG, Hultin MB. A prothrombin gene mutation is significantly associated with venous thrombosis. Arterioscler Thromb Vasc Biol 1997;17:2875–9. Ferraresi P, Marchetti G, Legnani C, Cavallari E, Castoldi E, Mascoli F, Ardissino D, Palareti G, Bernardi F. The heterozygous 20210 G/A prothrombin genotype is associated with early
23.
24.
25.
26.
27.
327
venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease. Arterioscler Thromb Vasc Biol 1997;17: 2418–22. Arruda VR, Annichino Bizzacchi JM, Goncalves MS, Costa FF. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost 1997;78:1430–3. Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood 1997;90:1747–50. Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 39-untranslated region of the prothrombin gene. Br J Haematol 1997;98:907–9. Salomon O, Moisseiev J, Rosenberg N, Vidne O, Yassur I, Zivelin A, Treister G, Steinberg DM, Seligsohn U. Analysis of genetic polymorphisms related to thrombosis and other risk factors in patients with retinal vein occlusion. Blood Coagulation & Fibrinolysis 1998;9: 617–22. Delahousse B, Arsene S, Piquemal R, Iochmann S, Le Lez ML, Pouplard C, Gruel Y. The 20210A allele of the prothrombin gene is not a risk factor for retinal vein occlusion [letter]. Blood Coagulation & Fibrinolysis 1998; 9:447–8.
BRIEF COMMUNICATION
The Prothrombin Gene G20210A Mutation and the Platelet Glycoprotein IIIa Polymorphism PlA2 in Patients with Central Retinal Vein Occlusion Jo¨rgen Larsson1 and Andreas Hillarp2 Department of Ophthalmology, Lund University Hospital, Lund; 2 Department of Clinical Chemistry, Malmo¨ University Hospital, Malmo¨, Sweden.
1
(Received 1 February 1999 by Editor B.N. Bouma; revised/accepted 9 June 1999)
Abstract The prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 have been shown to be associated with thromboembolic disease. We wondered if mutations were overrepresented in patients with central retinal vein occlusion. We studied 129 consecutive patients with a history of central retinal vein occlusion. We analysed for the prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 and compared the results to controls with no history of thrombosis. For the platelet glycoprotein IIIa polymorphism PlA2, 69% were normal, 26% were heterozygous, and 5% were homozygous. For the G20210A prothrombin mutation, 97% were normal and 3% were heterozygous. Neither the prothrombin gene G20210A mutation nor the platelet glycoprotein IIIa polymorphism PlA2 seem to be associated with central retinal vein occlusion. 1999 Elsevier Science Ltd. All rights reserved. Key Words: Prothrombin gene G20210A mutation; Glycoprotein IIIa polymorphism; Central retinal vein occlusion
T
he three most important factors to the aetiology of central retinal vein occlusion are glaucoma, hypertension, and atherosclero-
Abbreviations: GPIIIA, glycoprotein IIIa; PCR, polymerase chain reaction. Corresponding author: J. Larsson, Department of Ophthalmology, Lund University Hospital, S-221 85 Lund, Sweden. Tel: 146 (46) 17 20 74; Fax: 146 (46) 211 50 74; E-mail: ,Jorgen.Larsson@ oft.lu.se..
sis [1–7]. Hereditary deficiencies in natural anticoagulant proteins (i.e., antithrombin, protein S, and protein C) and resistance to activated protein C are known hereditary risk factors for thromboembolic disease. However, only sporadic case reports of patients with central retinal vein occlusion have shown an association between reduced levels of antithrombin, protein C, and protein S and thrombotic complications of the eye [8–10]. Activated protein C resistance, which is the most common genetic cause of venous thrombosis, has also been associated with central retinal vein occlusion [11,12]. In the majority of vein thromboses of the eye, a genetic association with known risk factors remains elusive. New genetic variants are constantly being found that add to the list of known inherited prothrombotic disorders. Recently, a mutation in the prothrombin gene was associated with an increased risk of deep-vein thrombosis [13]. The mutation involves a single base substitution (G to A) at position 20210 of the 39-untranslated region of the prothrombin gene. Due to the location of the mutation, the primary structure and thus the function of prothrombin is not altered. Instead, it was found that the G20210A allele was associated with increased prothrombin levels in the plasma [13], which suggests that the hypercoagulability conferred by the 20210 A allele is due to hyperactivity of the common coagulation pathway. Other candidate genes for thrombosis encode proteins expressed on the surface of platelets. One of these proteins is the
0049-3848/99 $–see front matter 1999 Elsevier Science Ltd. All rights reserved. PII S0049-3848(99)00111-5
324
J. Larsson et al./Thrombosis Research 96 (1999) 323–327
Table 1. Distribution of observed prothrombin and GPIIIa genotypes and allele frequencies among patients ,50 years of age with central retinal vein occlusion and controls Patients ,50 years n Genotype 20210A/A 20210G/A 20210A/A Total Allele frequency 20210A 20210G Genotype PlA1/A1 PlA1/A2 PlA2/A2 Total Allele frequency PlA1 PlA2
35 2 0 37
% 94.6 5.4 0 100
0.97 0.03 28 8 1 37
Controls n 277 5 0 282
%
p value*
98.2 1.8 0 100
n.s. n.s. n.s.
0.99 0.01 75.7 21.6 2.7 100
0.86 0.14
100 38 2 140
n.s. n.s. 71.4 27.2 1.4 100
0.85 0.15
n.s. n.s. n.s.
n.s. n.s.
* p values were calculated by a standard chi-squared test. n.s. denotes not significant (p.0.05).
glycoprotein IIIa (GPIIIA), a subunit of the fibrinogen receptor glycoprotein IIb/IIIa expressed on platelets. A common polymorphism, called PlA1/A2, which involves a single base substitution in exon 2 of the glycoprotein IIIa gene, has been reported to be associated with coronary thrombosis [14,15]. After its discovery, several contradictory reports were published and it remains unclear if it is or is not an independent risk factor for arterial thrombosis [14–18]. We studied the prevalence of the prothrombin G20210A gene mutation and the PlA1/A2 polymorphism in a group of consecutive patients with central retinal vein occlusion.
tein IIIa polymorphism was determined as described by Jin et al. [19].
1.2. Patients The patient sample was recruited from the records of the eye clinic of the Lund University Hospital and comprised all cases with central retinal vein occlusion diagnosed in a given time period. Of the patients (n5129), 55 were females and 74 were male; 37 were <50 years of age with a mean age of 40.4 years (range 21–49 years); 92 were .50 years of age with a mean age of 69.2 years (range 52–91 years).
1. Subjects and Methods
1.3. Controls
1.1. Methods
The control group for the G20210A prothrombin mutation was comprised of 282 volunteers (102 women and 180 men), with a mean age 59 years (range 34–86) and no history of thrombosis. The control group for the platelet glycoprotein IIIa polymorphism PlA2 was comprised of 140 volunteers (blood donors; 30 females and 110 males), with a mean age of 51 years (range 34–64) and no history of thrombosis. The control groups differ
Genomic DNA was prepared from whole blood using standard procedures. The presence or absence of the 20210 G to A transition of the prothrombin gene was determined by Hind III cleavage of a 345-bp fragment amplified by polymerase chain reaction (PCR), using a mutagenic primer as described previously [13]. The platelet glycopro-
J. Larsson et al./Thrombosis Research 96 (1999) 323–327
325
Table 2. Distribution of observed prothrombin and GPIIIa genotypes and allele frequencies among patients .50 years of age with central retinal vein occlusion and controls Patients .50 years n Genotype 20210A/A 20210G/A 20210A/A Total Allele frequency 20210A 20210G Genotype PlA1/A1 PlA1/A2 PlA2/A2 Total Allele frequency PlA1 PlA2
90 2 0 92
% 97.8 2.2 0 100
0.98 0.02 61 26 5 92
Controls n 277 5 0 282
%
p value*
98.2 1.8 0 100
n.s. n.s. n.s.
0.99 0.01 66.3 28.3 5.4 100
0.80 0.20
100 38 2 140 0.85 0.15
n.s. n.s. 71.4 27.2 1.4 100
n.s. n.s. n.s.
n.s. n.s.
* p values were calculated by a standard chi-squared test. n.s. denotes not significant (p.0.05).
in size because the control group for the 20210 prothrombin mutation was not specifically created for this study. The controls were from the same geographical area as the patients.
2. Results We divided our patients into one group that was <50 years of age and one group that was .50 years of age. The observed genotype distribution and allele frequencies at the two dimorphic sites are shown in Tables 1 and 2. Similar distribution patterns were seen in the groups of patients and controls. The distribution of heterozygotes and homozygotes was also similar for both patients and controls. No homozygotes for the prothrombin 20210 A allele were found. There was no statistical difference between the controls and the two patient groups.
3. Discussion Our findings suggest that neither the G20210A allele of the prothrombin gene nor the platelet glyco-
protein IIIa polymorphism PlA2 are overrepresented in patients with central retinal vein occlusion. Previous reports showed a correlation between the presence of the 20210 A allele of the prothrombin gene and thromboembolic disease [13,20–25]. These investigations were performed mainly on patients with deep venous thrombosis, pulmonary embolism, and myocardial infarction (i.e., disease in vessels that are much bigger than the retinal veins). The retinal veins are very small compared to the vessels in the leg, heart, and lung. It is possible that the aetiology for venous thromboembolic disease is not exactly the same in very small veins (like the retinal veins) and bigger veins (like the ones that are involved in deep venous thrombosis); this could explain why the 20210 A allele of the prothrombin gene is not overrepresented in our group of patients with central retinal vein occlusion. Two recent studies have not found any correlation between the G 20210 A allele of the prothrombin gene and patients with retinal vein occlusion [26,27]. Whether the platelet glycoprotein IIIa polymorphism PlA2 is correlated to thromboembolic disease is still not clear. Some reports show a correlation between thromboembolic disease and the plate-
326
J. Larsson et al./Thrombosis Research 96 (1999) 323–327
let glycoprotein IIIa polymorphism PlA2 [14,15], whereas others do not [16–18]. In our patients with central retinal vein occlusion there was no overrepresentation of the glycoprotein IIIa polymorphism PlA2 compared to the controls. In conclusion, neither the 20210 A allele of the prothrombin gene nor the platelet glycoprotein IIIa polymorphism PlA2 seems to be an important factor in the aetiology of central retinal vein occlusion. This study was supported by Synfra¨mjandets Forskningsfond Sweden, Carmen och Bertil Regne´rs Stiftelse fo¨r Forskning inom Omra˚¨ gonsjukdomar Sweden, Elsa och Ola Ohlssons Fond fo¨r det O ¨ gonforskning Sweden, the faculty of Medicine at the University O of Lund, Malmo¨hus La¨ns Landsting Sweden, Svenska Sa¨llskapet fo¨r Medicinsk Forskning Sweden, the Swedish Medical Research Council (project 14x-2321), Swedish Medical Research Council (grant no. 11195), and research funds from University Hospital, Malmo¨. We would also like to thank Ewa Nilsson and Kerstin Fridh for excellent technical assistance.
References 1. McGrath MA, Wechsler F, Hunyor ABL, Penny R. Systemic factors contributory to retinal vein occlusion. Arch Intern Med 1978;138: 216–20. 2. The Eye Disease Case-Control Study Group. Risk factors for central retinal vein occlusion. The Eye Disease Case-Control Study Group. Arch Ophthalmol 1996;114:545–54. 3. Hirota A, Mishima HK, Kiuchi Y. Incidence of retinal vein occlusion at the Glaucoma Clinic of Hiroshima University. Ophthalmologica 1997;211:288–91. 4. Rath EZ, Frank RN, Shin DH, Kim C. Risk factors for retinal vein occlusions. A case-control study. Ophthalmology 1992;99:509–14. 5. Appiah AP, Greenidge KC. Factors associated with retinal-vein occlusion in Hispanics. Ann Ophthalmol 1987;19:307–12. 6. Elman MJ, Bhatt AK, Quinlan PM, Enger C. The risk for systemic vascular diseases and mortality in patients with central retinal vein occlusion. Ophthalmology 1990;97:1543–8. 7. Laatikainen L, Kohner EM, Khoury D, Blach RK. Panretinal photocoagulation in central retinal vein occlusion: A randomised controlled clinical study. Br J Ophthalmol 1977;61:741–53.
8. Ririe DG, Cosgriff TM, Martin B. Central retinal vein occlusion in a patient with familial antithrombin III deficiency: Case report. Ann Ophthalmol 1979;11:1841–5. 9. Zwierzina WD, Kunz F, Miller K. Retinaler Gefassverschluss bei Antithrombin III-Mangel [Retinal vascular occlusion in antithrombin III deficiency]. Klin Monatsbl Augenheilkd 1985; 187:534–6. 10. Vine AK, Samama MM. The role of abnormalities in the anticoagulant and fibrinolytic systems in retinal vascular occlusions. Surv Ophthalmol 1993;37:283–92. 11. Larsson J, Olafsdottir E, Bauer B. Activated protein C resistance in young adults with central retinal vein occlusion. Br J Ophthalmol 1996;80:200–2. 12. Williamson TH, Rumley A, Lowe GD. Blood viscosity, coagulation, and activated protein C resistance in central retinal vein occlusion: A population controlled study. Br J Ophthalmol 1996;80:203–8. 13. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 39untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698–703. 14. Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996;334:1090–4. 15. Carter AM, Ossei Gerning N, Wilson IJ, Grant PJ. Association of the platelet Pl(A) polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bbeta 448 polymorphism with myocardial infarction and extent of coronary artery disease. Circulation 1997;96:1424–31. 16. Herrmann SM, Poirier O, Marques Vidal P, Evans A, Arveiler D, Luc G, Emmerich J, Cambien F. The Leu33/Pro polymorphism (PlA1/PlA2) of the glycoprotein IIIa (GPIIIa) receptor is not related to myocardial infarction in the ECTIM Study. Etude Cas-Temoins de l’Infarctus du Myocarde. Thromb Haemost 1997;77:1179–81. 17. Wagner KR, Giles WH, Johnson CJ, Ou CY, Bray PF, Goldschmidt Clermont PJ, Croft JB,
J. Larsson et al./Thrombosis Research 96 (1999) 323–327
18.
19.
20.
21.
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