SEARCH:   Advanced

Blood, 1 February 2004, Vol. 103, No. 3, pp. 963-965. Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2003-05-1502. This Article Abstract Full Text (PDF) Supplemental Table All Versions of this Article: 2003-05-1502v1 103/3/963    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Afshar-Kharghan, V. Articles by López, J. A. Search for Related Content PubMed PubMed Citation Articles by Afshar-Kharghan, V. Articles by López, J. A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Brief report The variable number of tandem repeat polymorphism of platelet glycoprotein Ib and risk of coronary heart disease Vahid Afshar-Kharghan, Nevenka Matijevic-Aleksic, Chul Ahn, Eric Boerwinkle, Kenneth K. Wu, and José A. López From the Department of Medicine, Thrombosis Research Section, Baylor College of Medicine, Houston, TX; and University of Texas at Houston Health Science Center, Houston.    Abstract Top Abstract Introduction Study design Results and discussion References   Glycoprotein (GP) Ib-IX-V complex plays an important role in formation of platelet-fibrin clot at the area of damaged vessel wall. One polymorphism of GP Ib, the main component of GP Ib-IX-V complex, is due to variable numbers of tandem repeats (VNTRs) in the macroglycopeptide region of this molecule. We studied the association between the presence of different VNTR alleles of GP Ib and the frequency of coronary heart disease (CHD) among individuals recruited to a large community-based case-cohort study (Atherosclerosis Risk in Communities [ARIC] study). We found that the distribution of VNTR alleles of GP Ib is different among whites and African Americans. The B allele (with 3 repeats) of GP Ib is relatively more common among African Americans compared with whites. In African Americans, the CC genotype (homozygous with 2 repeats) is associated with a lower risk of CHD events than all other genotypes. (Blood. 2004;103:963-965)    Introduction Top Abstract Introduction Study design Results and discussion References   The glycoprotein (GP) Ib-IX-V complex contains 4 polypeptides, GP Ib, GP Ib, GP IX, and GP V.1 The largest is GP Ib, which contains the binding site for von Willebrand factor (VWF) and for several other proteins important in the genesis of vascular disease: thrombin, factor XI, P-selectin, and leukocyte Mac-1.2-5 GP Ib is highly polymorphic, one polymorphism being due to variable numbers of tandem repeats (VNTRs) in a region encoding the macroglycopeptide, a mucin-like stalk separating the ligand-binding region from the plasma membrane. This region may have from one to four tandem 39-base repeats, each encoding a 13-amino acid sequence. The 4 variants are named A, B, C, and D, with 4, 3, 2, and 1 repeat, respectively. It has been hypothesized that because added repeats increase the length of the macroglycopeptide region of GP Ib, they might also increase the sensitivity of the longer molecule to shear stress, a known modulator of the GP Ib-VWF interaction.1 Here, we analyzed the association of the GP Ib VNTR alleles with risk of incident coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) case-cohort study.    Study design Top Abstract Introduction Study design Results and discussion References   Study population We analyzed the ARIC study population, consisting of a population-based cohort totaling 15 792 men and women between 45 and 64 years of age from 4 US communities.6 We defined CHD incidence as (1) a definite or probable myocardial infarction (MI), (2) a silent MI detected by new electrocardiographic (ECG) changes between examinations, (3) a definite CHD death, or (4) a coronary revascularization procedure. This was a case-cohort study, with frequencies of GP Ib alleles determined for CHD cases and a stratified random sample of the ARIC cohort. We identified 349 individuals as cases with CHD. For the reference cohort, we oversampled participants with low average carotid intima-media thickness measurements at baseline (< 30th percentile) and also stratified the sampling by age and sex. We included 383 individuals as a reference cohort (of whom 22 were also CHD cases). Before selecting the case-cohort sample, we excluded participants identified as having prevalent CHD, stroke, or transient ischemic neurologic attack (TIA). The study included participants from 2 ethnic groups: whites and African Americans. Genotyping We genotyped each individual for the GP Ib VNTR polymorphism by polymerase chain reaction as described previously.7 Data analysis We used analysis of covariance to compute age-, race-, and sex-adjusted frequencies of different genotypes, and means or percentage values of study variables (including lipid profile, plasma VWF and fibrinogen concentrations, history of hypertension, diabetes mellitus, tobacco or alcohol abuse) for CHD cases versus noncases after appropriate weighting for the stratified case-cohort sampling design. We computed the risk ratios and 95% confidence intervals for the time to development of CHD using a weighted proportional hazard regression, accounting for the stratified random sampling and the case-cohort design by the Barlow method.8 Because the prevalence of different GP Ib genotypes was significantly different between whites and African Americans, we performed separate weighted proportional hazard regression analyses for whites and African Americans. In the weighted proportional hazard regression model, we adjusted for sex, age, and the other factors related to CHD. The number of subjects with BB (5 cases and 5 noncases) and DD (1 case and 3 noncases) genotypes were very small and were combined with BC and CD, respectively, in analysis. Only 4 individuals with the A allele were identified, and these were omitted from the analysis.    Results and discussion Top Abstract Introduction Study design Results and discussion References   Ethnicity and GP Ib genotype The association of 3 genotype groups (BC+BB, CC, and CD+DD) with age, sex, ethnicity, and conventional risk factors is shown in Table 1. The CC and CD+DD groups were smaller by percentage in African Americans than whites, with a corresponding increase in the BC+BB group. Aramaki and Reiner have previously shown the higher frequency of the B allele in African Americans compared with whites.9 View this table: [in this window] [in a new window]   Table 1.. Age-, race-, and sex-adjusted means and proportions of CHD risk factors in the cohort random sample in relation to the GP lb genotypes   CHD incidence and GP Ib genotype In the entire population, we found no significant differences in genotypes between incident CHD cases and noncases (Table 2). However, when we examined the 2 ethnic groups separately, we found an association in African Americans between the non-CC genotypes and incident CHD (Table 2). Put another way, African Americans with the CC genotype had a significantly lower incidence of CHD than those with either the BC+BB or CD+DD genotypes. The weighted proportional hazard regression analysis showed that GP Ib genotypes correlate with the development of CHD in African Americans (Table 2) In contrast, whites in either the BC+BB or CD+DD groups did not have a significantly higher risk of CHD (risk ratios, 1.1 and 1.4, respectively). View this table: [in this window] [in a new window]   Table 2.. GP lb genotypes and CHD   We also analyzed the association according to the presence of the C allele (on the Blood website; see the Supplemental Table link at the top of the online article). The C allele was associated with lower incident CHD in African Americans (P = .003), whereas no such association was noted in the whole group or in whites (P = .091 and .521, respectively). African Americans homozygous for the C allele had significantly lower incident CHD compared to those with one C allele. We have found a protective effect of the CC genotype in African Americans participating in the ARIC study, but not in the group overall or in whites. This may indicate a interaction between GP Ib genotype and another environmental or genetic variable that is more prevalent in African Americans than whites. Alternatively, it is possible that the increased prevalence of the B allele in African Americans unmasks an increased risk for cardiovascular disease associated with this variant. Of interest, 2 GP Ib haplotypes for GP Ib have been reported with much higher frequency in African Americans than in whites, the C/Met145 variant and the B/Thr145 variant, present in this population with frequencies of 2.2% and 6.5%, respectively.9 Because Met145 has been associated with an increased prevalence and severity of coronary artery disease,10 the protective effect of the CC genotype in the African-American population is even more striking. The hypothesis that the length of GP Ib affects its function, and as a result the propensity to develop CHD, is not a new one.11 Other groups have also studied the role of the GP Ib VNTR polymorphism in case-control studies, with contradictory results.10,12-14 All of these studies were cross-sectional case-control studies. The design of these studies makes it less likely that an ideal control group will be chosen, with the case and control subjects being fully matched for all other risk factors. In the current study, 15 792 individuals were followed prospectively over a period of 10 years. Another mechanism by which the VNTR polymorphism may influence CHD susceptibility is suggested by the results of our study. Most of the individuals in the non-CC group were heterozygous for 2 length variants, either carrying the BC or the CD genotypes. Thus, it is possible that it is the disparity in length between the 2 allele products in a heterozygous individual that influences the interaction of GP Ib with the receptor (it has been postulated that GP Ib may be able to associate into dimers or tetramers to form the functional VWF-binding unit1). Nevertheless, because of the relative shortage of BB homozygotes, a larger study is needed to determine whether it is the length of the macroglycopeptide stalk or a length disparity in heterozygotes that determines the increased risk in the non-CC African-American individuals.    Acknowledgements   The authors thank the staff and participants in the ARIC study for their important contributions.    Footnotes   Submitted May 12, 2003; accepted September 8, 2003. Prepublished online as Blood First Edition Paper, October 30, 2003; DOI 10.1182/blood-2003-05-1502. Supported by grant R01 HL65205 from the National Institutes of Health and National Heart, Lung, and Blood Institute contracts N01 HC-55015, -55016, -55018, -55019, -55020, -55021, and -55022. V.A.-K. is a recipient of the LLS and MPD Foundation's Translational Research Grant and American Heart Association, Texas Affiliate BGIA. The online version of this article contains a data supplement. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: José A. López, Thrombosis Research Section, Department of Medicine, BCM 286, N1319, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030; e-mail: josel{at}bcm.tmc.edu.    References Top Abstract Introduction Study design Results and discussion References   López JA. The platelet glycoprotein Ib-IX complex. Blood Coagul Fibrinolysis. 1994;5: 97-119.[Medline] [Order article via Infotrieve] Romo GM, Dong JF, Schade AJ, et al. The glycoprotein Ib-IX-V complex is a platelet counter-receptor for P-selectin. J Exp Med. 1999;190: 803-813.[Abstract/Free Full Text] López JA, Dong JF. Structure and function of the glycoprotein Ib-IX-V complex. Curr Opin Hematol. 1997;4: 323-329.[Medline] [Order article via Infotrieve] Simon DI, Chen Z, Xu H, et al. Platelet glycoprotein Ib is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med. 2000;192: 193-204.[Abstract/Free Full Text] Baglia FA, Shrimpton CN, Lopez JA, Walsh PN. The glycoprotein Ib-IX-V complex mediates localization of factor XI to lipid rafts on the platelet membrane. J Biol Chem. 2003;278: 21744-21750.[Abstract/Free Full Text] Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1997;96: 1102-1108.[Abstract/Free Full Text] Afshar-Kharghan V, López JA. Bernard-Soulier syndrome caused by a dinucleotide deletion and reading frameshift in the region encoding the glycoprotein Ib transmembrane domain. Blood. 1997;90: 2634-2643.[Abstract/Free Full Text] Barlow WE. Robust variance estimation for the case-cohort design. Biometrics. 1994;50: 1064-1072.[CrossRef][Medline] [Order article via Infotrieve] Aramaki KM, Reiner AP. A novel isoform of platelet glycoprotein Ib is prevalent in African Americans. Am J Hematol. 1999;60: 77-79.[CrossRef][Medline] [Order article via Infotrieve] Murata M, Matsubara Y, Kawano K, et al. Coronary artery disease and polymorphisms in a receptor mediating shear stress-dependent platelet activation. Circulation. 1997;96: 3281-3286.[Abstract/Free Full Text] López JA, Ludwig EH, McCarthy BJ. Polymorphism of human glycoprotein Ib results from a variable number of tandem repeats of a 13-amino acid sequence in the mucin-like macroglycopeptide region: structure/function implications. J Biol Chem. 1992;267: 10055-10061.[Abstract/Free Full Text] Gonzalez-Conejero R, Lozano ML, Rivera J, et al. Polymorphisms of platelet membrane glycoprotein Ib associated with arterial thrombotic disease. Blood. 1998;92: 2771-2776.[Abstract/Free Full Text] Ito T, Ishida F, Shimodaira S, Kitano K. Polymorphisms of platelet membrane glycoprotein Ib and plasma von Willebrand factor antigen in coronary artery disease. Int J Hematol. 1999;70: 47-51.[Medline] [Order article via Infotrieve] Carter AM, Catto AJ, Bamford JM, Grant PJ. Platelet GP IIIa PlA and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke. Arterioscler Thromb Vasc Biol. 1998;18: 1124-1131.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. E. Breslow, T. Lumley, C. M. Ballantyne, L. E. Chambless, and M. Kulich Using the Whole Cohort in the Analysis of Case-Cohort Data Am. J. Epidemiol., June 1, 2009; 169(11): 1398 - 1405. [Abstract] [Full Text] [PDF] S.-Z. Luo, X. Mo, V. Afshar-Kharghan, S. Srinivasan, J. A. Lopez, and R. Li Glycoprotein Ib{alpha} forms disulfide bonds with 2 glycoprotein Ib{beta} subunits in the resting platelet Blood, January 15, 2007; 109(2): 603 - 609. [Abstract] [Full Text] [PDF] H Douglas, G J Davies, K Michaelides, D A Gorog, H Timlin, N Ahmed, and E G D Tuddenham Detection of functional differences between different platelet membrane glycoprotein Ibalpha variable number tandem repeat and Kozak genotypes as shown by the PFA-100 system. Heart, May 1, 2006; 92(5): 676 - 678. [Full Text] [PDF] This Article Abstract Full Text (PDF) Supplemental Table All Versions of this Article: 2003-05-1502v1 103/3/963    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Afshar-Kharghan, V. Articles by López, J. A. Search for Related Content PubMed PubMed Citation Articles by Afshar-Kharghan, V. Articles by López, J. A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020