Platelet glycoprotein Ibalpha Kozak polymorphism is associated with an increased risk of ischemic stroke.

Platelets are pivotal to the process of arterial thrombosis resulting in ischemic stroke. Occlusive thrombosis is initiated by the interaction of von Willebrand factor (vWf) and platelet glycoprotein (GP) Ibalpha. Three polymorphisms have been described in GP Ibalpha (Kozak T/C polymorphism, variable number of tandem repeats [VNTR], and the human platelet antigen 2a [HPA-2a] [Thr] or HPA-2b [Met] at position 145), each of which may enhance the vWf and GP Ibalpha interaction. This study investigated whether these polymorphisms are candidate genes for first-ever ischemic stroke. A hospital-based case-control study was conducted of 219 cases of first-ever ischemic stroke and 205 community controls randomly selected from the electoral roll and stratified by age, sex, and postal code. The subtypes of stroke were classified, the prevalence of conventional risk factors was recorded, and blood was collected to perform genotyping analysis for Kozak C or T alleles, VNTR, and HPA-2a/b. It was found that the Kozak T/C genotype was over-represented in the stroke group (32.2%) compared with controls (22.8%) (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.03-2.54; P <.03), and the association was still present even after adjusting for conventional risk factors. There was a trend in the increased prevalence of HPA-2a/b in stroke patients (15%) compared with controls (9.9%) (adjusted OR, 1.8; 95% CI, 0.94-3.4; P =.07). No associations were seen with the VNTR polymorphism or with any of the polymorphisms with stroke subtype. It was concluded that the Kozak T/C polymorphism, which is associated with an increase in platelet GP Ibalpha surface expression, is an independent risk factor for first-ever ischemic stroke.     

Polymorphisms of platelet membrane glycoprotein Ib alpha and plasma von Willebrand factor antigen in coronary artery disease.

To examine the relationships of two polymorphisms of platelet glycoprotein (GP) Ib alpha and coronary artery diseases (CAD) in Japanese patients, we conducted a case-control study with 158 Japanese patients and 169 control subjects. The frequencies of HPA-2 polymorphism and the variable number of tandem repeat (VNTR) polymorphisms in the macroglycopeptide region did not significantly differ between CAD patients and control subjects. The polymorphisms of GPIb alpha were not associated with the number of affected vessels in CAD patients. When patients with acute coronary syndrome only were analyzed, the frequencies of the two polymorphisms of GPIb alpha showed no significant difference. Although plasma von Willebrand antigen (vWF:Ag) levels in patients were significantly higher than in controls, no association between vWF concentration and GPIb genotypes was observed. In patient groups with higher or lower vWF:Ag concentrations, no increase in the frequencies of Met145 or larger VNTR polymorphisms was seen in either group. Our findings indicate that no association exists between the frequencies of the two polymorphisms of GPIb alpha and CAD.     

Allelic and genotypic frequencies of platelet glycoprotein polymorphisms in a Portuguese population

Introduction and objectivesWe studied genotypic and allelic frequencies of polymorphisms that can affect platelet function, namely the Kozak, VNTR and HPA-2 polymorphisms of glycoprotein Ibα, the Pl^A polymorphism of glycoprotein IIIa and the C807T polymorphism of glycoprotein Ia, in a Portuguese population composed of 227 donors.MethodsPCR-RFLP was used to assess the Kozak, HPA-2, Pl^A and C807T polymorphisms. The VNTR polymorphism was discriminated by different weight bands on electrophoresis.ResultsAll genotypic frequencies were in Hardy-Weinberg equilibrium and do not differ from other Caucasian populations. Genotypic frequencies were 68.3%, 26.9% and 4.8% for Pl^A1/A1, Pl^A1/A2 and Pl^A2/A2 genotypes of the Pl^A polymorphism, 79.3%, 20.3% and 0.4% for TT, TC and CC genotypes of the Kozak polymorphism, 81.1%, 18.9% and 0.0% for aa, ab and bb genotypes of the HPA-2 polymorphism, 15.4%, 0.9%, 70.5%, 11.5%, 1.3% and 0.4% for BC, BD, CC, CD, DD and CE genotypes of the VNTR polymorphism, and 39.7%, 50.2% and 10.1% for CC, CT and TT genotypes of the C807T polymorphism.ConclusionsThe Portuguese population has now been characterized in terms of major platelet glycoprotein polymorphisms, which will be an important tool for further studies to assess the role of platelet glycoproteins in individual predisposition to prothrombotic conditions and response to antithrombotic therapy.     

A novel isoform of platelet glycoprotein Ibα is prevalent in African Americans

The heavy chain of platelet glycoprotein Ib (GPIb) contains two prevalent sequence polymorphisms. The first, Thr/Met¹⁴⁵ is responsible for the human platelet alloantigen system, human platelet antigen (HPA)-2. The second is a tandem repeat polymorphism that consists of four variants, A, B, C, and D. Previous linkage studies in Caucasian and Eastern Asian populations have demonstrated that HPA-2a (Thr¹⁴⁵) is associated with variants C and D, while HPA-2b (Met¹⁴⁵) is associated with variants A and B. We have determined HPA-2 and variable number of tandem repeats (VNTR) genotypes in three different North American ethnic groups. The gene frequency of HPA-2b in the North American Indians was intermediate between African Americans and Caucasians, and similar to the frequency previously reported in Japanese. Furthermore, the VNTR-A allele, which previously has been reported only in Eastern Asian populations, was present in two of 101 North American Indian individuals. These data are consistent with the hypothesis that the first Native Americans migrated to North America from Eastern Asia. Analysis of HPA-2 and VNTR haplotypes demonstrated an unexpected linkage pattern in the African American population. A rare GPIbα isoform, HPA-2b/VNTR-C, was present in 2.2% of African American haplotypes. Furthermore, a novel GPIbα isoform, HPA-2a/VNTR-B, was present in 6.5% of African American haplotypes. These data suggest a more complex evolutionary pattern of GPIbα isoforms than previously proposed. Am. J. Hematol. 60:77–79, 1999. © 1999 Wiley-Liss, Inc.     

Genetic variability of platelet glycoprotein Ibalpha gene

Platelet membrane glycoprotein (GP) Ibalpha is a critical component of platelet adhesion complex to subendothelium structures following tissue injury or pathological surfaces, such as atherosclerotic plaques. Polymorphisms of the GPIbalpha gene have been associated with a high risk for occlusive vascular disease, and its distribution varies considerably among distinct populations. These polymorphisms comprise the human platelet antigen (HPA)-2 system, the -5C/T dimorphism of the Kozak sequence, and the variable number of tandem 39-bp repeats (VNTR). Here we report the prevalence of the GPIbalpha gene polymorphisms among Brazilians, a highly ethnically diverse population. We analyzed 492 subjects of European, African, or Indigenous origin. It was possible to determine ten distinct haplotypes. The most common ( reverse similar 40%) haplotype was the Kozak-TT/HPA-2aa/VNTR-CC for both Caucasian and African descent. However, among Indigenous, Kozak-TT/HPA-2aa/VNTR-CC and Kozak-TC/HPA-2aa/VNTR-CC were equally present. Although a strong linkage disequilibrium between VNTR and HPA-2 polymorphism had also been observed, here we determined incomplete linkage disequilibrium in 10% of subjects from all ethnic groups. VNTR-E, a rare variant lacking the 39-bp repeat, was identified in two unrelated subjects, and functional platelet studies revealed no abnormalities. The VNTR-A allele, the largest variant containing four copies of the repeats, was not identified in this population. However, homozygosity for the VNTR-A allele (Kozak-TT/HPA-2aa/VNTR-AA) was determined in two distinct species of nonhuman primates. These results suggest a greater complex evolutionary mechanism in the macroglycoprotein region of the GPIbalpha gene and may be useful in the design of gene-disease association studies for vascular disease.     

Role of five platelet membrane glycoprotein polymorphisms in branch retinal vein occlusion.

To determine whether polymorphisms of platelet surface glycoprotein associated with arterial thrombosis are risk factors for branch retinal vein occlusion. A case-control study in which 69 patients with branch retinal vein occlusion and 147 controls who attended the eye clinic for nonvascular complications participated. DNA was extracted from whole blood and analyzed for genotyping of platelet glycoprotein polymorphisms by polymerase chain reactions and specific restricted enzymes. No relationship was found between the four platelet glycoprotein polymorphisms i.e. GPIa C807T, VNTR and Kozak of glycoprotein Ibalpha, the HPA-1 of glycoprotein IIIa and the occurrence of branch retinal vein occlusion. The HPA-2 polymorphism was found in 18 out 60 (30%) patients with branch retinal vein occlusion in comparison with 27 out 142 (19%) of controls, with an estimated odds ratio of 1.8 (95% confidence interval, 0.91-3.65). The four platelet glycoprotein polymorphisms are not risk factors for branch retinal vein occlusion and therefore it seems unnecessary to screen those patients for it. A larger study is required, however, to determine whether HPA-2 is a novel risk factor for branch retinal vein occlusion.     

The largest variant of platelet glycoprotein Ib alpha has four tandem repeats of 13 amino acids in the macroglycopeptide region and a genetic linkage with methionine145

Platelet membrane glycoprotein Ib alpha (GPIb alpha) bears the human platelet alloantigen (HPA)-2 and molecular weight (MW) polymorphisms on sodium dodecyl sulfate-polyacrylamide gels. HPA-2 arises from a threonine/methionine dimorphism at residue 145 of the GPIb alpha sequence, whereas different numbers of tandem repeats of a 39-bp sequence encoding 13-amino acids corresponding to a region between serine399 and threonine411 of the GPIb alpha account for the latter. To identify the genetic basis of the MW polymorphism among Japanese, we counted the tandem repeats in 103 individuals. In addition to the reported three variants with one, two, or three tandem repeats, we identified a new variant with four perfect tandem repeats of the 39-bp sequence that corresponded to the largest phenotype. Phenotypic analysis of the MW polymorphism on 12 individuals including all four phenotypes completely accorded in the genotype. We also determined the genotype of HPA-2 and found that methionine145 was in complete linkage disequilibrium, with the larger variants containing three or four tandem repeats. These results imply a model of evolutionary steps in the gene encoding GPIb alpha.     

Role of 4 platelet membrane glycoprotein polymorphisms on experimental arterial thrombus formation in men.

This study investigates whether the polymorphisms of 3 important platelet receptors affected experimental thrombus formation in men. Forty healthy male volunteers randomly recruited were genotyped for the variable number of tandem repeat (VNTR) of GPIbalpha, the -5T/C polymorphism in the Kozak sequence of GPIbalpha, the 807C/T polymorphism of GPIa, and the PI(A1)/PI(A2) polymorphism of GPIIb/IIIa. Platelet thrombus formation was induced ex vivo by exposing a collagen-coated coverslip in a parallel plate perfusion chamber to native blood for 4 minutes. The shear rates at the collagen surface were 650 and 2600 x s(-1). At 2600 x s(-1) platelet thrombus formation was significantly related only to the 807C/T polymorphism. In contrast, at 650 x s(-1) thrombus formation was significantly altered only by the Kozak sequence polymorphism. The VNTR and the PI(A1)/PI(A2) polymorphisms did not influence thrombus formation. Thus, platelet thrombus formation is significantly influenced by genetic variations of the GPIbalpha and GPIa receptors. The effect of these polymorphisms was dependent on the blood flow rate.     

Polymorphism of the human platelet antigen-5 system is a risk factor for occlusive vascular complications in patients with sickle cell anemia

BACKGROUND: Polymorphisms of platelet membrane glycoproteins such as human platelet antigen (HPA)-1b, HPA-2b, the -5T/C Kozak sequence and C807T have been described as risk factors for vascular disease. Vaso-occlusion episodes are a common feature of sickle cell anaemia (SCA), leading to complications such as stroke, acute chest syndrome, avascular head femur necrosis and priapism. Complex interactions are involved in vaso-occlusion, and activated platelets may play an important role. These data raised the question of whether platelet polymorphisms could be implicated in occlusive vascular complications (OVC) of SCA. MATERIALS AND METHODS: In this study, 97 patients with SCA were analysed in two groups: 34 patients presenting with OVC (SCA-VC) and 63 without these complications (SCA-N). The distribution of the HPA-1, -2 and -5 systems, as well as C807T dimorphism and -5T/C Kozak sequence alleles, was evaluated using DNA-based methods. RESULTS: Patients of the SCA-VC group showed a higher frequency of the HPA-5b allele (0.324) compared with those of the SCA-N group (0.111) (chi2 = 13.19, P = 0.0002). None of the other polymorphisms, isolated or associated as haplotypes, demonstrated any correlation with the development of OVC in these patients. CONCLUSIONS: The findings of this study suggest that the HPA-5b allele is a genetic risk factor for the development of OVC in patients with SCA. This allele could be explored as a target for the development of new therapeutic approaches.     

Platelet functional implications of glycoprotein Ibalpha polymorphisms in African Americans

The platelet glycoprotein Ibalpha is crucial in the binding of platelets to Von Willebrand Factor within areas of high stress. A single nucleotide polymorphism of GP Ibalpha gives rise to the Ko(a) (HPA-2b) and the -5C Kozak polymorphism. The presence of these polymorphisms has been associated with an increased risk for atherothrombotic disease. The Ko(a) polymorphism has been shown to have a higher prevalence in African Americans compared to American Caucasians. However, very little is known regarding any functional consequences of these platelet polymorphisms in African Americans. We assessed the prevalence of the Ko and -5C Kozak polymorphisms in a population of both African American and American Caucasian patients with and without CAD and determined whether there were platelet functional consequences in both groups. We studied 99 patients of which 22 were African American and 77 were American Caucasian. Aggregations were performed and shear induced platelet plug formation was tested using a platelet function analyzer. The HPA-2b allele was significantly higher in African Americans when compared to Caucasians (P = 0.001). Genotype frequencies of the -5C Kozak polymorphism were not significantly different between the two groups. We found no differences in platelet aggregation in African Americans who were either heterozygous or homozygous for the HPA-2b allele or the -5C Kozak allele when compared to American Caucasians of the same category. We found no significant differences in PFA-100 testing. We conclude from our study that these polymorphisms do not lead to altered platelet function in African Americans.     

Platelet receptor HPA-1 polymorphism of alphaIIbbeta3 and 807 C/T polymorphism of alpha2beta1 and Buerger's disease

Thromboangiitis obliterans or Buerger's disease is an episodic and segmental inflammatory and thrombotic process of the medium and small arteries of the lower extremities. Even though the disease was described 90 years ago, the etiopathogenesis is still under consideration. Afflicted patients are mostly young male cigarette smokers without signs of atherosclerosis or other risk factors for peripheral arterial occlusive disease. This indicates that hereditary thrombophilic factors could play a role in the etiopathogenesis. Recently, increasing evidence shows that platelet receptor polymorphisms (HPA-1 polymorphism of beta3 subunit of alphaIIbbeta3 and 807 C/T polymorphism alpha2beta1) are associated with early onset of arterial thrombosis (myocardial infarction, stroke). This case-control study was designed to assess whether the 807 C/T polymorphism or the HPA-1 polymorphism is involved in the pathogenesis of Buerger's disease or has any influence on the clinical course of Buerger's disease. Eighteen patients with Buerger's disease and 81 (sex and age matched) healthy control subjects (mean age 44 +/- 10 vs 45 +/- 8 years, respectively) were genotyped for platelet receptor HPA-1 and GPIa 807 C/T polymorphism. The gene frequency of HPA-1 and GPIa 807 C/T polymorphisms was identical in both groups. Prevalence of hetero- and homozygous carriers of the HPA-1b allel (1a1b and 1b1b genotype) as well as the prevalence of the 807 C/T and 807 T/T carriers did not differ significantly between the two groups, p >0.05. The grade of clinical disease manifestation as well as disease progression did not reveal any significant relationship with HPA-1 and 807 C/T polymorphisms. A relationship between the age at onset of the disease and HPA-1 polymorphism was not found. Otherwise analysis of the GPIa 807 C/T platelet receptor polymorphism showed that the average age of patients who are carriers of the T allele at early onset of disease was 32 +/- 6 years (range 27-48 years) compared to 42 +/- 6 years (range 34-53 years) of the C/C carriers (p <0.05). This indicates that the GPIa 807 C/T polymorphism does not represent a risk factor for Buerger's disease itself, but could be associated with premature onset of this disorder in predisposed individuals.     

Vienna Stroke Registry. Impact of the platelet glycoprotein Ib alpha Kozak polymorphism on the risk of ischemic cerebrovascular events: a case-control study.

We performed a multicenter case-control study to evaluate the impact of the glycoprotein 1b alpha (-5)T/C Kozak polymorphism on the risk of ischemic cerebrovascular events. The genetic analysis in 1399 patients (745 men; median age, 70 years; interquartile ratio, 58-78) and 1066 control subjects (549 men; median age, 47 years; interquartile ratio, 39-59) was carried out with mutagenically separated polymerase chain reaction. Homozygous C/C genotype carriers had a 3.5-fold increased risk for ischemic cerebrovascular events (95% confidence interval, 1.5-7.9, P = 0.003) over T/T or T/C genotype carriers together. The effect was independent of well-established atherosclerotic risk factors. Our findings could be explained by the reported gene dose effect of the Kozak polymorphism on the density of the glycoprotein 1b alpha/IX/V receptors on platelets. According to our data, the (-5)C Kozak allele may represent a candidate genetic susceptibility factor for ischemic cerebrovascular events.     

血小板膜糖蛋白Ⅰb Kozak序列-5T/C及纤维蛋白原β-148C/T基因多态性与脑梗死

目的研究雷州半岛地区汉族人群血小板膜糖蛋白(GP)ⅠbKozak序列-5T/C和纤维蛋白原(Fib)β-148C/T基因多态性位点与脑梗死的关系。方法选择雷州半岛地区汉族人群健康体检者130例(对照组)和经头颅CT和(或)MRI证实的脑梗死患者148例(脑梗死组),用PCR-RFLP检测GPⅠbKozak序列-5T/C和Fibβ-148C/T基因多态性,分析两组频率分布特点及与脑梗死的关系。结果脑梗死组β-148C/T位点T等位基因频率为30.1%,对照组为21.9%,(P<0.05),脑梗死组GPⅠbKozak序列C等位基因频率为48.7%,对照组为39.6%,(P<0.05),两个多态性位点连锁不平衡系数D为-0.018(P>0.05)。结论Fibβ-148C/T位点T等位基因和GPⅠbKozak序列C等位基因是雷州半岛地区汉族人群脑梗死的遗传易感因素,但二者不存在连锁不平衡关系。     

血小板膜糖蛋白Ⅰa和Ⅰbα基因多态性与脑梗死的相关性研究

目的探讨血小板膜糖蛋白(GP)Ⅰa基因和Ⅰbα基因多态性与脑梗死发生的关系,为缺血性脑卒中的预防及治疗提供理论基础。方法选择经CT或MRI证实的脑梗死患者302例(脑梗死组)和健康体检者196例(对照组);采用PCR-RFLP方法检测GPⅠa C807T基因与Ⅰbα基因HPA-2、Kozak序列多态性在2组中的分布频率。结果脑梗死组GPⅠa C807T等位基因频率明显高于对照组,差异有统计学意义(P0.05);脑梗死组GPⅠbα基因Kozak序列C等位基因频率明显高于对照组差异有统计学意义(25.33% vs 10.20%,P0.05);脑梗死组GPⅠbα基因HPA-2序列等位基因频率、基因型与对照组比较,差异无统计学意义(P0.05)。结论 GⅠbα基因HPA-2序列多态性与脑梗死无相关性;GPⅠa C807T等位基因和Ⅰbα基因Kozak序列多态性可能是脑梗死的遗传危险因素。     

New alleles of the platelet glycoprotein Ibα gene

Platelet membrane glycoprotein Ibα (GP Ibα) bears two molecular polymorphisms which are in linkage disequilibrium: the C/T dimorphism at codon 145 (HPA-2) and the variable number of tandem repeats (VNTR) polymorphism in the macroglycopeptide region. The frequencies of these two polymorphisms, and of another three recently described silent polymorphisms, were investigated by genotypic identification in 729 Caucasian individuals from the south of Spain. Eight different alleles of this gene, including the longest VNTR A allele of the GP Ibα gene, were found in this population. Moreover, we detected an unexpected linkage between the B and A variants of the VNTR polymorphism and the HPA-2a allele in 5.9% of this population. These results suggest a new evolutionary model of GP Ibα, in which homologous recombination could account for the genetic diversity of the GP Ibα.     

Localization of the platelet-specific HPA-2 (Ko) alloantigens on the N-terminal globular fragment of platelet glycoprotein Ib alpha.

The human platelet-specific alloantigens HPA-2a and HPA-2b (= Kob and Koa) together constitute a biallelic antigen system. The HPA-2 antigens have not, to date, been located on a particular platelet membrane molecule. Here, we describe the localization of these antigens on platelet glycoprotein (GP) Ib alpha. Platelets from two patients with the Bernard-Soulier syndrome (BSS) were HPA-2(a-,b-) in the immunofluorescence test with HPA-2 alloantibodies on chloroquine-treated platelets. With monoclonal antibody (MoAb) immobilization of platelet antigen assay (MAIPA), positive reactions were obtained only when MoAbs against the platelet GPIb/IX complex were used in combination with anti-HPA-2a or -2b alloantibodies and normal donor platelets. By immunoprecipitation under nonreducing and reducing conditions a protein of 160 Kd and 145 Kd, respectively, was precipitated by the anti-HPA-2a serum. A protein migrating identically to this was precipitated by anti-GPIb MoAb. Normal donor platelets became HPA-2(a-,b-) after elastase treatment, suggesting that anti-HPA-2 antibodies bind to the N-terminal elastase-sensitive part of GPIb alpha. Anti-HPA-2a antibodies inhibited the ristocetin-induced agglutination of HPA-2a-positive platelets but not of HPA-2a-negative platelets, indicating that the epitopes recognized by these alloantibodies are localized in the proximity of the von Willebrand-factor-binding domain. Together, these data provide evidence that the HPA-2 alloantigens are located on the N-terminal globular elastase-sensitive part of GPIb alpha. Furthermore, we show that the recently described Siba antigen is probably identical to HPA-2a.     

Polymorphisms of IL4, IL13, and ADRB2 genes in COPD

STUDY OBJECTIVES: Interleukin (IL)-4, IL-13, and beta(2)-adrenoceptor (ADRB2) are involved in airway hyperresponsiveness (AHR), and their coding genes are located on chromosome 5q31-q33. AHR is one of the risk factors for COPD. Investigating polymorphisms within these genes may help to pinpoint the genetic susceptibility to COPD. SUBJECTS AND MEASUREMENTS: A case-control association study was conducted on two different ethnic groups: Japanese subjects (88 patients with COPD and 61 control subjects) and Egyptian subjects (106 patients with COPD and 72 control subjects). The following polymorphisms were genotyped: - 589 C/T, - 33 C/T, and variable number of tandem repeat (VNTR) in IL4, - 1111 C/T and + 2044 G/A in IL13, and + 46 A/G and + 79 C/G in ADRB2. Pairwise haplotype frequencies as well as genotype and allele frequencies were analyzed. RESULTS: The distribution of the genotype frequencies of ADRB2 + 79 C/G was significantly different between the COPD and the control groups in the Egyptians (p = 0.002). The distributions of the haplotypes in the Japanese (IL4 - 589 C/T: IL4 VNTR; IL4 - 33 C/T: IL4 VNTR) [corrected p values < 0.001 and 0.022, respectively], and those in the Egyptians (IL4 - 589 C/T: ADRB2 + 79 C/G; IL4 VNTR: ADRB2 + 79 C/G) [corrected p values, 0.033 and 0.001, respectively] showed significant differences between the COPD and the control groups. CONCLUSIONS: The ADRB2 + 79 C/G polymorphism and the haplotypes shown in this study may be involved in the pathogenesis of COPD.     

Systemic lupus erythematosus and genetic variation in the interleukin 1 gene cluster: a population based study in the southeastern United States

BACKGROUND: Interleukin (IL)1alpha and IL1beta, and their endogenous receptor antagonist (IL1Ra), have been related to the pathology of systemic lupus erythematosus (SLE), but the role of IL1 polymorphisms in the aetiology of SLE is unknown. OBJECTIVE: To examine polymorphisms at IL1alpha -889(C-->T), IL1alpha +4845(C-->T), IL1beta -511(C-->T), IL1beta +3953(G-->T), and IL1Ra (86 bp VNTR) in a population based study of SLE in North Carolina and South Carolina. METHODS: Genotypes from 230 cases who met ACR classification criteria, and from 275 controls matched for age, sex, and state, were analysed separately for African Americans and whites. Odds ratios (ORs) were estimated by logistic regression models for each locus alone and also after adjusting for polymorphisms at adjacent loci. RESULTS: An increased risk of SLE for the IL1alpha -889C/C genotype compared with carriage of the -889T allele was found in both African Americans (OR = 3.1, p = 0.001) and whites (OR = 2.9, p = 0.005). In African Americans, carriage of the IL1beta -511T allele was associated with a higher risk of SLE than carriage of the -511C/C genotype (OR = 2.4, p = 0.017), independent of variation at IL1alpha -889. CONCLUSIONS: The observed associations support the hypothesis that genetic variation in IL1 is involved in the aetiology of SLE and merit further investigation.     

Iron deficiency anaemia in young women

OBJECTIVES: The expression density of GPIaIIa, the primary platelet collagen receptor (integrin alpha2beta1), is linked to two polymorphisms (GPIa-807C/T and HPA-5a/b). During evolution a gene shift from the genotypes GPIa-807CC-HPA-5bb to the genotypes GPIa-807CT-HPA-5aa has taken place. The aim of the study was to assess whether iron deficiency anaemia (e.g. increased blood loss) in young women could be associated with a specific genotype, indicating a role as potential evolutionary selection factor. STUDY DESIGN: Women between 18 and 40 yr of age presenting for their first blood donation were asked about alimentary habits and use of oral contraception. Haemoglobin and serum ferritin were measured and the GPIa-C807T and HPA-5 genotypes were determined. RESULTS: Two hundred women were included and grouped according to the WHO definition for iron deficiency anaemia (haemoglobin <121 g L(-1) and ferritin <15 microg L(-1)). Eight women fulfilled both WHO-criteria for iron deficiency anaemia, 145 women fulfilled none. No differences regarding age, use of oral contraceptives, alimentary habits, and HPA-5 were found between the groups. The GPIa-807CC genotype was strongly over-represented in the WHO-anaemic women as compared to the non-WHO-anaemic women (87.5% vs. 33.1%, P=0.003). CONCLUSION: Iron deficiency anaemia in young women might have been the evolutionary disadvantage causing the gene shift from GPIa-807CC to 807CT.     

The Kozak sequence polymorphism of platelet glycoprotein Ibalpha and risk of nonfatal myocardial infarction and nonfatal stroke in young women

Several platelet membrane glycoprotein polymorphisms have been identified as potential risk factors for cardiovascular disease. Recently a nucleotide -5T/C dimorphism in the translation initiation site (Kozak sequence) of the platelet glycoprotein Ibalpha (GPIbalpha) gene was associated with increased platelet surface levels of the GPIb-IX-V receptor complex. The role of this GPIbalpha Kozak sequence polymorphism in the occurrence of arterial thrombotic disease is unknown. We performed genotype analysis of the Kozak sequence polymorphism of GPIbalpha in a population-based study of 18- to 44-year-old women with nonfatal myocardial infarction (MI) (n = 78), nonfatal stroke (n = 106), and 384 demographically similar female control subjects. Analysis of -5T/C genotypes revealed that at least one copy of the C allele was present in 14.1% of MI cases, 23.6% of stroke cases, and 23.7% of controls. The age-adjusted odds ratio for MI in women carrying at least one copy of the C allele was 0.53 (95% confidence interval [CI] 0.27-1.05). The age-adjusted odds ratio for stroke in women carrying at least one copy of the C allele was 0.99 (95% CI 0.59-1.65). Analyses stratified by stroke type (ischemic, hemorrhagic) yielded similar results. In conclusion, young women carrying the C allele of the Kozak sequence polymorphism of GPIbalpha are not at increased risk of MI or stroke. Paradoxically, the C allele may even be associated with a reduced risk of MI in this population. This finding requires further study.