This Article Abstract Full Text (PDF) All Versions of this Article: 25/8/1756    most recent 01.ATV.0000173308.13054.4fv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ajzenberg, N. Articles by Benessiano, J. Search for Related Content PubMed PubMed Citation Articles by Ajzenberg, N. Articles by Benessiano, J. Related Collections Genetics of cardiovascular disease Platelets

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1756.)
© 2005 American Heart Association, Inc.

Thrombosis

Association of the –92C/G and 807C/T Polymorphisms of the ₂ Subunit Gene With Human Platelets ₂ß₁ Receptor Density

Nadine Ajzenberg; Clarisse Berroeta; Ivan Philip; Bernard Grandchamp; Pierre Ducellier; Virginie Huart; Patrice Verpillat; Marie-Claude Guillin; Joelle Benessiano

From the Departments of Hematology (N.A., P.D., M.-C.G.), Anesthesiology (C.B., I.P.), and Biochemistry (B.G.), the Clinical Investigation Center (V.H.), Biostatistics (P.V.), Hopital Bichat, Assistance Publique-Hopitaux de Paris, and INSERM U698 (N.A., C.B., M.-C.G., J.B.), Hopital Bichat, University Paris, France.

Correspondence to Dr N. Ajzenberg, Service d’Hématologie et Immunologie, Hôpital Bichat, 46 rue Henri Huchard, 75018, Paris, France. E-mail nadine.ajzenberg{at}bch.ap-hop-paris.fr

	Abstract

Top Abstract Introduction Patients, Materials, and Methods Results Discussion References

 
Objective— Platelet adhesion to the subendothelial tissue via the collagen receptor ₂ß₁ is a crucial event in vascular biology. Although evidence has been provided that the number of platelets ₂ß₁ copies is genetically determined, the molecular change primary responsible has not been yet elucidated. The aim of our present study was to investigate the effect of combined polymorphisms within both regulatory (–52C/T and –92C/G) and coding regions (807C/T and 1648A/G) of the ₂ subunit gene on human platelets ₂ß₁ receptor density and/or susceptibility to coronary artery disease (CAD).

Methods and Results— Among 254 cardiac surgery patients, no evidence was found for an association between the ₂ subunit gene polymorphisms and CAD. In contrast, in a subgroup of 113 patients, we observed a significant association between all polymorphisms except –52C/T and ₂ß₁ receptor level. Furthermore, when 3 groups of patients were defined according to the tertiles of platelets ₂ß₁ copies, the –92C/807T haplotype was more frequent in the group of patients with high ₂ß₁ receptor level.

Conclusion— These results suggest that an individual effect of each polymorphism located either in the coding or promoter sequence of the ₂ gene may act in combination to modulate variations in platelets ₂ß₁ receptor density.

An important combined effect of the –92C and 807T polymorphisms of the ₂ gene in increasing the expression of human platelet ₂ß₁ receptors has been observed, suggesting that this haplotype could modulate variations in ₂ß₁ receptor density.

Key Words: –92C/G • 807C/T polymorphism • ₂ß₁ density

	Introduction

Top Abstract Introduction Patients, Materials, and Methods Results Discussion References

 
Vessel wall injury triggers platelet activation and platelet plug formation, followed by the formation of fibrin-containing thrombi that occlude the site of injury. The interaction of platelet receptors with subendothelial components such as collagen is central to these events, which both limit blood loss at sites of tissue trauma but may also obstruct diseased vessels, leading to ischemia and infarction of vital organs. The direct platelet–collagen interaction is mediated by 2 receptors, the integrin ₂ß₁ and the nonintegrin receptor glycoprotein VI (GPVI), although there are likely to be others.¹ It is now considered that GPVI provides the primary collagen signal that activates and recruits the integrin receptor ₂ß₁ to further amplify collagen signals and fully activate platelets through a common intracellular signaling pathway.²

Integrin ₂ß₁ is a heterodimer composed of 2 noncovalently associated subunits (₂ and ß₁) that are encoded by separate genes. By virtue of its expression on platelets and vascular cells,^3–5 the integrin ₂ß₁ may play a significant role in vascular pathobiology. Among healthy individuals, platelet ₂ß₁ density is highly variable and correlates with the rate and extent of platelet adhesion to collagen type I or type III under static conditions.^4,6 The differences in platelet ₂ß₁ density also correlate with the inheritance of certain allelic combinations, defined by linked polymorphisms within the coding sequence of the ₂ gene.^7–10 In addition, 2 single-base substitutions at positions –52 and –92 have been identified¹¹ within the "core" region defined by Zutter et al¹² in the proximal 5'-regulatory region of the gene. In vitro, the –52C/T and –92C/G dimorphisms have been shown to influence the rate of the ₂ gene transcription in transfected human megakaryocytic cell lines.¹¹ It has also been suggested that 1 of the 2 promoter dimorphisms (–52C/T) could correlate with platelet ₂ß₁ density in healthy individuals.¹³

A potentially important role for the ₂ß₁ integrin is suggested by recent epidemiologic data.^7,14,15 Several studies suggest a direct correlation between the genetically determined number of copies of ₂ß₁ at the platelet surface and the risk of thrombotic events. The T allele of 807C/T polymorphism, which is associated with high-level expression of ₂ß₁ on platelets, has been reported as an independent risk factor for myocardial infarction in selected groups of patients^16–18 for the development of diabetic retinopathy in patients with type 2 diabetes mellitus¹⁹ and for stroke in the young,²⁰ although other studies failed to find such a correlation.^21–24 However, no data are yet available for the clinical impact of the dimorphisms present in the core region of the promoter that may modulate the expression of ₂ß₁ at the cell surfaces.

The aim of the present study was to examine the distribution of the –92C/G, –52C/T, 807C/T, and 1648A/G dimorphisms in a population of patients undergoing cardiac surgery and to analyze the influence of particular haplotypes on platelets ₂ß₁ receptor density. We hypothesized that the profile of an individual with combined polymorphisms in coding and regulatory regions of the ₂ subunit gene may constitute a hereditary background for the susceptibility to the development of coronary artery disease (CAD).

	Patients, Materials, and Methods

Top Abstract Introduction Patients, Materials, and Methods Results Discussion References

 
Patient Selection
The protocol was approved by the local ethics committee, and all patients gave their written informed consent to participate in the study. The total study population comprised 254 consecutive white patients (179 men and 75 women; 59±14 years of age) scheduled for either coronary artery bypass grafting or valve surgery. By means of coronary angiography, the study population was divided into patients with CAD (n=171) for subjects referred to the hospital for coronary artery bypass grafting in whom coronary artery stenosis was >70% (50% for left main artery) and non-CAD patients (n=83) for subjects referred to the hospital for valve surgery and without any angiographic signs of CAD (no atherosclerotic coronary plaque). We excluded patients with acute coronary syndrome who required emergency coronary artery bypass.

Blood Sampling
Blood sample was collected before coronary artery bypass or valve surgery. Blood was drawn in evacuated container tubes (Vacutainer; Becton Dickinson) containing EDTA for DNA analysis or 0.129 mol/L trisodium citrate for platelet ₂ß₁ density determination.

DNA Genotyping
We obtained genomic DNA from blood samples after extraction from blood leukocytes by a standard procedure with the QIAmp DNA blood Midi kit (Qiagen GmbH) according to manufacturer instructions.

We studied 2 nucleotide polymorphisms located at 807C/T bp and 1648A/G bp within the coding region of the ₂ gene^25,26 and single-base substitutions at 2 positions, –92C/G and –52C/T, within the proximal 5'-regulatory region of the ₂ gene.¹³ Genotyping of these 4 polymorphisms was conducted using an adapted method of DNA amplification by polymerase chain reaction (PCR) procedure with specific primers. PCR products were digested by specific restriction enzymes and separated by appropriate electrophoresis.

Quantitation of Platelet ₂ß₁
We quantified the platelet ₂ß₁ level in a subgroup of 113 patients (CAD n=49; non-CAD n=64). Determination of platelet ₂ß₁ density was performed on citrated whole blood by flow cytometry using a kit "platelet Gp Screen test" (Biocytex). Briefly, whole blood was incubated with mouse monoclonal antibody against ₂ß₁ integrin (CD 69b) and followed by an incubation with a polyclonal antibody anti-mouse IgG coupled to fluorescein isothiocyanate.²⁷ Cytometric analysis was performed on a FACScalibur (Becton Dickinson). The number of platelet receptors was determined by converting the fluorescence intensity into corresponding number of sites per platelet on the basis of a calibrated bead standard curve using beads varying from 260 to 80 000 sites per platelet.

Statistical Analysis
Genotype distributions in different groups were compared by testing the hypothesis of homogeneity using ² test and SAS software (SAS Institute; V8.0). Estimation of haplotype frequencies and linkage disequilibrium (D and D') were computed using the Arlequin software V2.000. Data were expressed as mean±SD and analyzed within genotype groups using ANOVA and Tukey–Kramer test for post hoc comparisons. For categorical variables and tertile comparisons, ² test was performed. Differences were considered to be significant when P<0.05.

	Results

Top Abstract Introduction Patients, Materials, and Methods Results Discussion References

 
Distribution of the ₂ Gene Polymorphisms
Table 1 summarizes the genotype distribution of the 807C/T, 1648 A/G, –92 C/G, and –52 C/T polymorphisms of the ₂ gene in the CAD and non-CAD groups. We reported similar genotype distribution in both groups. The genotype distribution is in agreement with the frequencies predicted by Hardy–Weinberg equilibrium (P=0.76, P=0.48, P=0.54, and P=0.38, respectively.)

View this table: [in this window] [in a new window]   TABLE 1. Genotype Distribution in CAD and Non-CAD Patients

Measure of Linkage Disequilibrium Between ₂ Gene Polymorphic Sites
In the total population of 254 patients, we investigated the linkage disequilibrium between the 4 polymorphic sites of ₂ gene (Table 2). A significant linkage disequilibrium was observed between the 807C/T and 1648A/G polymorphisms and between the –52C/T and –92C/G polymorphisms within the proximal 5' regulatory region of the ₂ gene: all patients carrying the –92C allele were found to carry the –52T allele.

View this table: [in this window] [in a new window]   TABLE 2. Measure of Linkage Disequilibrium (D and D') Between 2 Polymorphic Sites in the Total Population

In contrast, we observed a moderate linkage disequilibrium between the 807C/T and the promoter sequence –92C/G and –52C/T (Table 2).

Relationship Between ₂ Genotypes and Differences in Platelet ₂ß₁ Levels
A subgroup of 113 patients (CAD n=49; non-CAD n=64) was available for the measurement of platelet ₂ß₁ levels in whole blood by flow cytometry. No difference in ₂ß₁ density was observed between CAD and non-CAD patients (3960±1098 and 3881±1084 receptors per platelet, respectively). In consequence, the 2 groups were pooled to examine the relationship between genotypes and ₂ß₁ platelet density. In Figure 1, the number of platelet ₂ß₁ copies per platelet is plotted according to the ₂ genotypes within the coding sequence of each individual. As originally reported by Kunicki et al²⁸ and confirmed by others,^21,29 in healthy subjects, we observed (Figure 1A) an association between ₂ß₁ densities and 807 polymorphism (ANOVA P<0.0001). Lowest ₂ß₁ densities (3200±906 receptors per platelet) were observed in 807CC patients; and conversely, highest receptor density in 807TT patients (4782±1216 receptors per platelet; P<0.05). In the same way, the platelet ₂ß₁ levels measured in 1648GG patients were lower than in heterozygous 1648AG patients (ANOVA P=0.0082), reaching 3774±1090 and 4435±958 receptors per platelet, respectively (P<0.05). Unfortunately, no homozygous 1648AA patient was available for quantification of platelet ₂ß₁ copies.

View larger version (13K): [in this window] [in a new window]   Figure 1. Relationship between platelet 2ß1 density and polymorphisms within the 2 coding region: 807C/T (A) and 1648 G/A (B) in a population of 113 patients. Box and whisker plots show median value (horizontal lines), 25th and 75th percentiles (boxes), and 10th and 90th percentiles (error bars). *P<0.05.

Interestingly, we also found a significant correlation between the –92 C/G polymorphism and the platelet ₂ß₁ level (ANOVA P=0.0056; Figure 2). The –92CC homozygous patients exhibited higher levels of ₂ß₁ receptors than the heterozygous –92CG patients (4066±1122 and 3384±744 receptors per platelet, respectively; P<0.05). The 4 homozygous patients for the –92 G allele had low density of ₂ß₁ (2810±646 receptors per platelet), but the difference with the –92CC homozygous did not reach significance. In contrast, the platelet ₂ß₁ receptor level was not found to be associated with the –52 C/T polymorphism (ANOVA P=0.565) because density of ₂ß₁ varies between 3792±1115 receptors per platelet for –52CC and 3829±911 receptors per platelet for –52TT.

View larger version (13K): [in this window] [in a new window]   Figure 2. Relationship between platelet 2ß1 density and polymorphisms within the 5' regulatory region: –92 C/G in a population of 113 patients. Box and whisker plots show median value (horizontal lines), 25th and 75th percentiles (boxes), and 10th and 90th percentiles (error bars). *P<0.05.

We looked for a possible influence of combined polymorphisms within regulatory and coding regions of the ₂ subunit gene on human platelet ₂ß₁ receptor density. Because of the strong linkage disequilibrium between the 807C/T and 1648G/A polymorphisms on one hand, and the absence of association between the –52C/T polymorphism and the ₂ß₁ receptor density on the other hand, we determined the frequencies of haplotypes defined by the –92C/G and 807C/T polymorphisms in a panel of 113 patients in which the platelet ₂ß₁ receptor level has been quantified (Table 3). Patients were studied according to tertiles of platelet ₂ß₁ receptor level: low (<3348 copies per platelet), medium (ranging from 3348 to 4191), and high (>4191) platelet ₂ß₁ receptor level. We observed that haplotype distribution was significantly different among the 3 groups of patients (ANOVA P<0.001). The most striking observation was that the –92C/807T haplotype is more frequent in the high-platelet ₂ß₁ receptor level group (0.60 versus 0.12 in the first tertile), whereas the –92G/807C haplotype is more frequent in the low-platelet ₂ß₁ receptor level group (0.16 versus 0.02 in the third tertile). Moreover, to determine whether this haplotype frequency was related to the linkage disequilibrium of polymorphisms or to the effect of each polymorphism, we compared the ₂ß₁ density according to the 807 genotype in the subgroup of 88 patients homozygous for –92C: significant differences in ₂ß₁ receptor level between 807TT, 807CT, and 807CC were observed, suggesting an individual effect of each polymorphism (ANOVA P<0.0001) and reaching 4872±1290, 4251±917, and 3316±912 receptors per platelet, respectively).

View this table: [in this window] [in a new window]   TABLE 3. Haplotype Frequency in the 3 Groups of Patients Defined by Tertiles of Platelet 2ß1 Receptors per Platelet

	Discussion

Top Abstract Introduction Patients, Materials, and Methods Results Discussion References

 
Platelet adhesion to the subendothelial tissue via the collagen receptor ₂ß₁ is a crucial event in vascular biology and interindividual variations in ₂ß₁ expression levels could have a significant impact on vascular pathology and risk of arterial thrombosis. Although evidence has been provided that the number of platelets ₂ß₁ copies is genetically determined,^7–10 the molecular change primarily responsible has not been yet elucidated. The aim of our present study was to investigate the effect of combined polymorphisms within regulatory and coding regions of the ₂ subunit gene on human platelet ₂ß₁ receptor density or susceptibility to CAD.

Among a total population of 254 patients, we report new data about the –92C/G, –52C/T, 807C/T, and 1648G/A polymorphic sites of the ₂ gene. The linkage disequilibrium between the 807C/T and 1648A/G nucleotide polymorphisms on one hand, and between the –92C/G and –52C/T single-base substitutions on the other hand, is confirmed, as reported previously by other groups.^26,28 The platelet ₂ß₁ receptor quantification performed in freshly drawn whole blood also confirms that the level of collagen receptor ₂ß₁ can vary up to 4-fold among individuals.⁶ As originally reported by Kunicki et al²⁸ in healthy subjects and confirmed by others,^10,29 we observed an obvious association between the 807C allele and low ₂ß₁ level. However, homozygous patients for the 1648G allele exhibited the lowest ₂ß₁ density, in agreement with previous data of Corral et al.¹⁰ No association was observed between the –52C/T dimorphism and platelet receptor density. Interestingly, we found that the platelet ₂ß₁ receptor level was significantly associated with the –92 C/G promoter nucleotide dimorphism. This finding is supported by the previous work of Jacquelin et al,¹³ demonstrating that in vitro, in transfected human megakaryocytic cell lines, the –92G promoter sequence has a negative regulatory effect on the ₂ gene transcription. Altogether, these findings emphasize the potential importance of the –92C promoter substitution on human platelet ₂ß₁ receptor expression.

When 3 groups of patients were defined according to the tertiles of the number of platelets ₂ß₁ copies, it appeared that haplotype distribution was different: the –92G/807C haplotype was more frequent in the group of patients with low ₂ß₁ receptor levels, whereas the –92C/807T haplotype was in a large majority found in the group of patients with high ₂ß₁ receptor levels. Moreover, in the subgroup of patients, –92CC significant differences of ₂ß₁ density were observed according to 807C/T polymorphism. Because of moderate linkage disequilibrium between the –92C/G and 807C/T polymorphisms, the present results confirm evidence for more than a single genetic factor involved in the number of ₂ß₁ molecules per platelet. Our findings indicate that an individual effect of each polymorphism in either the coding or promoter sequence may act in combination to modulate variation in receptor density. Although the –92C/G promoter substitution may have a direct impact on expression levels of ₂ gene, the silent 807C/T polymorphism within the coding sequence that does not modify the deduced amino acid sequence of the translated protein may be linked to other polymorphisms within the ₂ gene, which remain to be determined.

Looking for a clinical relevance of the ₂ alleles, we investigated the relationship between the platelet ₂ß₁ receptor density and nucleotide polymorphisms of the ₂ subunit gene and CAD. No significant difference was observed in the surface expression of platelet ₂ß₁ in CAD versus non-CAD patients. It is likely that the ₂ß₁ receptor number alone is not sufficient to compromise platelet function and an individual’s susceptibility to arterial diseases, which are probably under the dependence of an other major collagen receptor, GPVI,³⁰ or of other platelet receptors such as GPIb or _2bß₃. Abnormalities of the vessel wall (as atherosclerosis) could also modulate platelet adhesion. Genotype distributions and allele frequencies were not significantly different in CAD versus non-CAD patients. With regard to nucleotide polymorphisms located within the coding region of the gene, several previous reports have extensively studied 807C/T and 1648A/G dimorphisms. In agreement with us, some authors failed to show an association between 807C/T polymorphism and CAD,^21,22,24,31 whereas conflicting studies showed a significant correlation between 807T allele and myocardial infarction.^16,17 Furthermore, Kroll et al found in a large population a significant association between the 1648A/G polymorphism and CAD.³² Possible explanations for these apparent discrepancies may be the differences of population size and the fact that numerous other factors are involved in the progression of atherosclerosis. Furthermore, our negative results may be attributable to the choice of an anatomic (angiographic) criteria rather than a more clinically relevant one such as evolutivity of coronary disease (occurrence of acute coronary syndrome).

In summary, we showed evidence for a possible influence of the inheritance of particular haplotypes of ₂ gene on differences in human platelet ₂ß₁ receptor density. Our results suggest an important combined effect of the –92C and 807T nucleotide sequences in increasing the expression of human platelet ₂ß₁ receptors. These results must be confirmed in a larger study to precisely determine the involvement of the ₂ gene allelic combinations in coronary disease through the platelet ₂ß₁ receptor expression. Further studies are also required in a larger population to test whether or not the –92C/G and 807C/T polymorphisms have a functional effect on gene expression, and, if not, to identify the causal single-nucleotide polymorphisms in linkage disequilibrium with –92C/G and 807C/T polymorphisms. A more generalized haplotype strategy on the basis of polymorphisms described in single-nucleotide polymorphism databases would probably be most pertinent.

Received September 7, 2004; accepted May 17, 2005.

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Top Abstract Introduction Patients, Materials, and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) All Versions of this Article: 25/8/1756    most recent 01.ATV.0000173308.13054.4fv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ajzenberg, N. Articles by Benessiano, J. Search for Related Content PubMed PubMed Citation Articles by Ajzenberg, N. Articles by Benessiano, J. Related Collections Genetics of cardiovascular disease Platelets