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Rheumatology 2001; 40: 31-36
© 2001 British Society for Rheumatology

HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients

R. Caliz, T. Atsumi, E. Kondeatis1, O. Amengual, M. A. Khamashta, R. W. Vaughan1, J. S. Lanchbury2 and G. R. V. Hughes

Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London,
1 Tissue Typing Department, Guy's Hospital, London,
2 Molecular Immunogenetics Division of Medicine, UMDS, London, UK


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS).

Methods. HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls.

Results. DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-ß2-glycoprotein I antibodies (anti-ß2GPI) [odds ratio 6.2, 95% confidence interval (2.2–17.6), P=0.0014, corrected P=0.042].

Conclusions. These alleles and haplotypes might affect anti-ß2GPI production and APS development in different and heterogeneous fashion.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Antiphospholipid antibodies (aPL) are recognized as a group of antibodies whose specificity is directed not only towards phospholipids but also towards phospholipid binding proteins or phospholipid protein complexes [1, 2]. The presence of aPL is associated with arterial/venous thrombosis, recurrent fetal loss, neurological disorders, pulmonary hypertension and thrombocytopenia. The term ‘antiphospholipid syndrome’ (APS) was coined to link these clinical manifestations with the persistence of aPL, which is now recognized as one of the most common causes of acquired thrombophilia [3, 4].

A genetic basis for APS has been suggested by previous studies. The genes involved in APS have not been identified with certainty, but some reports have implicated genes within the human leukocyte antigen (HLA) class II region [5]. However, clinical heterogeneity [4] complicates the genetic analysis of APS. For instance, some APS patients also manifest systemic lupus erythematosus (SLE), and constitute a heterogeneous population, making it difficult to analyse the role of a single factor. Therefore, patients with primary APS only may provide a better study group for the effects of genetic factors. The clinical manifestations of APS vary, with thrombosis affecting both veins and arteries, and some patients have recurrent pregnancy loss without any history of thrombosis. In addition, APS patients have heterogeneous profiles of aPL, including permutations of lupus anticoagulant (LA), anticardiolipin antibodies (aCL), anti-ß2-glycoprotein I antibodies (anti-ß2GPI) and antiprothrombin antibodies [1]. This heterogeneity should be taken into account when investigating the genetic background of APS, and subgroup analysis is essential.

Among the aPL family, anti-ß2GPI is one of the most specific markers of APS. In 1990, three groups reported that APS-associated aCL bound to cardiolipin in the presence of an ‘aCL cofactor’, ß2GPI [6–8]. ß2GPI is a 50-kDa phospholipid-binding protein, formed by five short consensus repeat domains (‘Sushi’ domains) [9, 10]. The phospholipid binding site is present within the fifth domain of ß2GPI [11], whereas the possible epitope for aCL binding seems to be located in the fourth domain [12]. Matsuura et al. [13] and Roubey et al. [14] showed that aCL recognized this epitope in the absence of cardiolipin if ß2GPI was coated onto polystyrene plates and oxygen was introduced by radiation, implying that aCL can bind not only the cardiolipin–ß2GPI complex but also to ß2GPI alone. Furthermore, it has been shown that anti-ß2GPI antibodies detected by this irradiated plate system are strongly associated with the clinical features of APS [15, 16].

In this study, to clarify the genetic background of APS, we investigated the association of HLA class II gene polymorphisms with APS in a number of subgroups from a UK Caucasoid population.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients
The study population comprised 83 British Caucasoid patients with APS [53 with primary APS (PAPS) and 30 with APS secondary to SLE (SAPS)] who fulfilled the proposed criteria for the APS [3, 17] [median age, 41 yr (range 16–67); female:male, 73:10]. As a control group, 177 healthy British individuals were employed.

HLA DQB1, DQA1 and DRB1 typing
Genomic DNA was extracted from peripheral white blood cells using a standard phenol–chloroform extraction procedure and dissolved in sterile water. Using sequence-specific primers and polymerase chain reaction (PCR) amplification, each DNA was typed for DQB1, DQA1 and DRB1. In each PCR reaction a primer pair was included that amplified human growth hormone (HGH I and II) and thus functioned as an internal positive amplification control. The primers, amplification protocol and visualization of the amplified products have been fully described [18, 19].

Anti-ß2GPI antibody ELISA
Serum samples were collected at the same time as DNA samples and kept at -70°C until use. Anti-ß2GPI was detected by ELISA using irradiated ELISA plates as described previously [16]. Briefly, irradiated microtitre plates (Sumilon type C; Sumitomo Bakelite, Tokyo, Japan) were coated with purified human ß2GPI in phosphate-buffered saline at 4°C overnight. Wells were blocked with 3% gelatin for 1 h at 37°C. After three washes with PBS–Tween, 50 µl of serum diluted in PBS containing 1% BSA in 1:50 were added in duplicate. Plates were incubated for 1 h at room temperature, followed by alkaline phosphatase-conjugated goat anti-human IgG and substrate. The anti-ß2GPI titre of each sample was derived from the standard curve according to the dilutions of the positive control.

aCL and LA
aCL was measured according to the standard aCL ELISA [20].

Because many patients were on warfarin at the time of the study, data regarding LA were those historically present in the patients' clinical records before the start of anticoagulant therapy. A prolonged activated tissue thromboplastin time or dilute Russell's viper venom time and their neutralization were taken as evidence of LA.

Statistical analysis
Comparisons were expressed as odds ratio (OR) and P values were determined by Fisher's exact test. P values were further corrected for all HLA haplotype associations by multiplying by the number of HLA haplotypes investigated (corrected P).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Twenty-eight haplotypes were investigated. The allele frequencies are shown in Tables 1Go and 2Go.


View this table:
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  		TABLE 1. Distribution of the DQB1-DQA1-DRB1 haplotypes in patients with antiphospholipid syndrome: numbers of alleles (%)

 

View this table:
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  		TABLE 2. Distribution of the DQB1-DQA1-DRB1 haplotypes in patients with primary antiphospholipid syndrome: numbers of alleles (%)

 
The frequencies of each haplotype in the APS patients are shown in Table 1Go. The haplotypes DQB1*0604/ 5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 showed significantly positive correlations with APS [frequency in APS vs controls, 7.8 vs 2.5%, OR 3.3, 95% confidence interval (CI) (1.4–7.8), P=0.0087 and 7.2 vs 2.3%, OR 3.4, 95% CI (1.4–8.4), P=0.0120 for the two haplotypes respectively]. Both correlations remained significant in the subgroups of APS patients, as shown in Table 1Go. In subgroup analysis, the frequency of the DQB1*0301/4-DQA1*0301/ 2-DRB1*04 haplotype was slightly higher in patients with pregnancy loss compared with controls (P=0.0293). DQB1*0302-DQA1*0301/2-DRB1*04 was less frequent in patients with venous thrombosis than in controls (P=0.0111).

Table 2Go shows the frequencies of these haplotypes in patients with primary APS only. DQB1*0301/4-DQA1* 0301/2-DRB1*04 and DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 were more frequent in primary APS than in controls [13.2 vs 6.3%, OR 2.3, 95% CI (1.1–4.7), P=0.0238, and 9.4 vs 2.5%, OR 4.0, 95% CI (1.6–10.1), P=0.0040, respectively]. The frequencies of the haplotypes in each subgroup of primary APS patients are shown in Table 2Go. The most striking association was found between DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and anti-ß2GPI in primary APS [14 vs 2.5%, OR 6.2, 95% CI (2.2–17.6), P=0.0014].

Although the associations between each DQB1, DQA1 and DRB1 allele of the haplotypes and APS have been reported previously [21], a complete haplotype analysis in HLA class II has not been done. Therefore, all the above P values were corrected according to the number of haplotypes investigated in this study. After correction for all haplotypes analysed, only the correlation between DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and anti-ß2GPI in primary APS remained significant (corrected P=0.042).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
This is a study of genetic association between APS and HLA class II gene polymorphisms by precise genomic typing in a large cohort of patients with APS.

Associations of HLA with SLE have been investigated extensively in many ethnic groups. Several HLA haplotypes have been shown to predispose to SLE [22]. In our subjects, 30 patients had SLE as well as APS, and in order to minimize the possible effect of the correlation between HLA and SLE, it was therefore necessary to analyse the data in patients with primary APS only. We found a number of possible APS-associated HLA alleles and haplotypes. The major association observed was between the DQB1*0604/5/6/7/9-DQA1* 0102-DRB1*1302 haplotype and APS. The frequency of this haplotype was further increased when we analysed a more clinically homogeneous group; its frequency was increased more in primary APS than in SAPS, the association being even stronger in anti-ß2GPI-positive primary APS. Accordingly, it is suggested that this haplotype predisposes to anti-ß2GPI. Anti-ß2GPI is one of the most specific markers of APS [23–25]. In vitro [26, 27] and animal experiments [28, 29] have shown potential pathogenic roles for these antibodies. The DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 haplotype correlates with anti-ß2GPI production and, ultimately, thrombotic events. HLA-DR and DQ molecules function by binding specific peptides with subsequent presentation by antigen-presenting cells to regulatory or effector T cells [30, 31]. Our data may be viewed in this context and suggest that a molecule encoded by the DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 haplotype may preferentially present peptides derived from ß2GPI or associated molecules. Consequently, individuals bearing this haplotype may be prone to generate anti-ß2GPI, after taking other genetic and environmental variables into account.

The DQB1*0303 allele is a component of the haplotypes DQB1*0303-DQA1*0201-DRB1*0701 and DQB1*0303-DQA1*0301/2-DRB1*0901 [32]. The former haplotype was correlated with APS but the latter was not. Furthermore, neither DRB1 component (DQB1*0701 and DQB1*0901) alone was increased in patients with APS in this study (data not shown). This implies that DQB1*0303 may relate more closely to APS than DQB1* alleles associated with DQB1*0303. Therefore, the relationship between HLA class II alleles or haplotypes and APS is heterogeneous and complex.

Few studies have been published on the relationship of HLA with APS or aPL. Asherson et al. [33] reported an increased frequency of DR4 in 13 patients with PAPS, and this was confirmed by Camps et al. [34]. We did not confirm the association between DR4 and any subgroup of APS in our larger cohort. Several studies have shown an association of aCL with DR7 [35] or DQ7 [34] and aCL in SLE, possibly reflecting the DRB1*0701-DQB1*0303-DQA1*0201 haplotype, in which DQB1*0303 was increased more in APS. Of interest is the fact that we saw no increase of DRB1*0701 in our study. Vargas-Alarcon [36] found that HLA DR5 was increased in 17 Mexican patients with PAPS, and that all haplotypes that contained DR5 also contained DQ7 (DQB1*0301 or *0304). HLA DR4 is in linkage disequilibrium with DQB1*0301 and *0302 in Caucasoids, and *0303 with HLA DR7 [32, 37]. Arnett et al. [38] reported the correlation between HLA DQ7 and LA in 20 patients with a group of connective tissue diseases, and suggested that the risk factor for aPL was an HLA DQB1 sequence comprising seven consecutive amino acid residues (71–77, TRAELDT) in the third hypervariable region in the DQB1 outer domain. This region in the domain is involved in antigen presentation, thus influencing the resulting immune response. The DQB1*0301, *0302, *0303 and *0602 alleles share the same sequence in the 71–77 region.

After the completion of our work, a study in the USA was published which corroborates the DQB1 and DRB1 associations in black and Mexican American populations [21]. The US study did not find any correlations between the investigated genotypes and anti-ß2GPI in the white population, unlike in black and Mexican American populations, a conclusion which is not coincident with ours. Presumably this is due to the following reasons: (i) the US study included only 34 white patients with primary APS (compared with 53 in ours) and the remaining 88 patients were diagnosed as having SLE with or without APS; (ii) all of the patients and controls in our study were British Caucasoids, constituting a more homogeneous racial background than that in the US study. Therefore, our study population had more advantages in detecting associations of HLA with anti-ß2GPI in APS. Consequently the correlations were emphasized and confirmed in this study.

We conclude that several HLA class II gene polymorphisms are associated with APS, and may determine the development of different aspects of the disease, although it is clear that HLA class II should not be considered to be a single genetic factor predisposing to APS. These polymorphisms may be correlated with the immune response against thrombosis-related autoantigens, such as phospholipid binding proteins and phospholipids. It is also possible that some undefined polymorphisms in linkage disequilibrium with the HLA region are responsible for the induction of anti-ß2GPI antibodies.


   Acknowledgments
 
This work was supported by Lupus UK and Fondo de Investigationes Sanitarias, Spain (FIS 95/5490). We thank Dr Ahmed Raphy of the Lupus Research Unit, The Rayne Institute, St Thomas' Hospital for his help in collecting DNA samples.


   Notes
 
Correspondence to: M. A. Khamashta, Lupus Research Unit, the Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK Back


   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 15 December 1999; Accepted 24 July 2000


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