HLA-A, -B, -DRB1 alleles and haplotypes frequencies in Moroccan patients with leukemia
Fréquences des allèles et des haplotypes HLA-A, -B et -DRB1 chez des patients marocains atteints de leucémie
Maria Kabbaj
1,2Mounia Oudghiri
2Abdellah Naya
2Hamid Naamane
1Joumana El Turk
3Siham Bennani
1Mohamed Hassar
11Laboratoire d’immuno-
histocompatibilité, Institut Pasteur, Casablanca, Maroc
<mariakabbaj@gmail.com>
2Laboratoire de physiologie et de génétique moléculaire, Département de biologie, Faculté des Sciences Ain Chock, Université Hassan II, Casablanca, Maroc
3Laboratoire de microbiologie et de biologie moléculaire, Centre national pour la recherche scientifique et technique, Rabat, Maroc
Article reçu le 7 novembre 2009, accepté le 22 janvier 2010
Abstract. Previous studies have demonstrated some significant differences in HLA allele frequencies in leukemic patients and normal subjects. In Moroccan leukemic patients, the frequency of HLA alleles has not already been determi- ned. We have analyzed HLA class I and class II alleles and haplotypes in 62 Moroccan leukemic patients and 98 unrelated normal subjects using PCR- SSO method. Significant positive association with the disease, in patients compared to controls, was found for three alleles: HLA-B*44 (12.7% vs 6.6%; p = 0.02), HLA-DRB1*13 (11.8% vs 9.79%; p = 0.04) and HLA-DRB
*01 (4.5% vs 10.7%; p = 0.05). Regarding haplotypes analysis, no significant association was found between patients and control groups. It is suggested that HLA-B*44 and HLA-DRB1*13 alleles may play a presumptive predispo- sing factor while the HLA-DRB*01 allele could be a protective genetic factor against leukemia.
Key words: HLA, leukaemia, Morocco
Résumé. L ’ implication du système HLA dans le développement des leucé- mies ainsi que la susceptibilité et/ou la résistance à la maladie ont été large- ment étudiées dans diverses ethnies. Dans notre étude, les fréquences alléliques du système HLA de classe I et de classe II ont été analysées chez un groupe de patients leucémiques marocains. Tous ces cas ont été colligés au laboratoire d ’ immuno-histocompatibilité de l ’ Institut Pasteur du Maroc, et comparés à un groupe d ’ individus contrôle de donneurs sains de même ethnie.
Le typage des antigènes HLA classe I (A et B), et classe II (DRB1) pour l ’ ensemble des patients a été réalisé par biologie moléculaire (PCR-SSO).
L ’ analyse statistique des résultats obtenus (patients versus groupe contrôle sain), a montré d ’ une part, la forte expression de certains allèles, citons : HLA-B*44 (12,7 % vs 6,6 % ; p = 0,02) et HLA-DRB1*13 (11,8 % vs 9,79 % ; p = 0,04) et, d ’ autre part, la diminution de la fréquence aléllique du HLA-DRB1*01 (4,5 % vs 10,7 % ; p = 0,05). Ceci semble être en faveur d ’ une association statistiquement significative entre les différents types de leu- cémie et le système HLA. Par ailleurs, l ’ analyse des haplotypes HLA entre la population des malades et les contrôles n ’ a montré aucune association signifi- cative. Ces résultats suggèrent que les allèles HLA-B*44, HLA-DRB1*01 et HLA-DRB1*13 seraient associés aux différents types de leucémies chez les patients marocains, ce qui peut être en faveur soit d ’ une prédisposition soit d ’ une résistance à la leucémie. De plus larges études sont nécessaires pour décrire et confirmer le rôle de ces associations avec cette pathologie.
Mots clés : HLA, leucémie, Maroc
doi:10.1684/abc.2010.0430
Tirés à part :Maria Kabbaj
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The major histocompatibility complex (MHC) is a poly- morphic and polygenic system that contains the loci for genes encoding class I and class II HLA alloantigens.
These genes are closely linked to each other on the short arm of human chromosome 6. HLA complex encompas- ses some four million base pairs of DNA. It encodes for the HLA-A, B, C (class I), and HLA-DR, DQ, and DP (class II) antigens. The function of the MHC in immune responsiveness is also reflected in its genetic polymor- phism. In addition to the control of transplant acceptance and immune responsiveness, it has been recognized for many years that the MHC in the human plays an impor- tant role in the etiology of a number of diseases [1].
Numerous studies have been performed to date to study the HLA polymorphism in different populations and ethnic groups [2-12]. Practical applications of HLA antigens include the probability of finding donors for stem cell transplantation [13] and the investigation of HLA and disease associations like leukemia [14], which is a mali- gnancy of the hematopoietic system characterized by dif- fuse replacement of the bone marrow by neoplastic cells.
In acute leukemia lymphoblastic (ALL) and myeloblastic (AML) the immature hematopoietic cells are increased in the blood, and chronic leukemia lymphoblastic (CLL) and myeloblastic (CML) are characterized by an excess of well-differentiated blood cells. The first HLA study on human leukemia found an increased frequency of HLA- A2 in ALL in 1967 [15]. A second study in ALL extended the first HLA-A*02 association to HLA-A2B12 haplotypi- cal association in 1970 [16]. Others studies have investi- gated HLA associations in childhood and adult leukemia, some of which included the analysis of HLA-DR/DQ anti- gens [17-37]. The largest HLA association study in leuke- mia was carried out on the International Bone Marrow Transplant Registry data [24, 25]. These studies analyzed a total of 1834 patients with ALL, AML, and CML treated between 1969 and 1985. These studies showed that HLA- Cw3 and -Cw4 are both susceptibility markers for all the three major leukemia. HLA-DR studies in childhood ALL showed an increase for HLA-DR7 [17-19]. In one study, adult ALL showed a weak association with HLA-DRB1
*04 [27] and in another CLL was associated with HLA- DRB4*01 [28]. The strongest association in leukemia reported to date has been presented by Seremetis et al.
[29]. They used a monoclonal antibody specific for the HVR3 epitope of HLA-DR53 in AML. Also, in the only molecular studies examined the HLA-DRB loci, directly or indirectly, in ALL, CML and CLL, the homozygous geno- type for HLA-DRB4*01 had an increased frequency in patients [32-34, 38]. In childhood ALL, this effect was observed only in male patients [33, 38]. It thus appears that in the HLA-DR region, the HLA-DRB1*04 locus is
the susceptibility marker for all major leukemia (AML, ALL, CML, CLL) examined so far.
The frequency of HLA alleles has not been already deter- mined in Moroccan leukemic patients. The aim of this work was to investigate the frequency of HLA class I (HLA-A and HLA-B) and class II (HLA-DRB1) alleles in a group of Moroccan leukemic individuals. We were searching to study the specificity of the association of the HLA system and all major leukemia in the Moroccan patients, and also to define susceptible alleles for leuke- mia. Our study is serving as begin for further studies on the associations between HLA and leukemia that we are working on with a large number of patients with each type of leukemia.
Material and methods
Population samples
The studied samples consisted of individual and unrelated patients who are BMT candidates, referred from the labo- ratory of immuno-histocompatibility of Institut Pasteur, Maroc, Casablanca. All individuals were ascertained to be of Moroccan origin. The sample set studied was com- posed of 98 normal individuals and 62 patients with leu- kemia.
HLA typing
HLA typing was performed using peripheral blood lym- phocytes by molecular technique. DNA was extracted and purified from whole blood collected in 5% EDTA using the salting out procedure proposes by Miller [39]. HLA- A, -B and -DRB1 typing was carried out with polymerase chain reaction and using sequence-specific oligonucleoti- des (PCR-SSO) of HLA-A, -B and -DRB1 alleles (Line Probe Assay, Innogenetics INNO-LiPA HLA Update).
Statistical analysis
Statistical significance of differences in HLA allele fre- quencies between patients and controls was determined using χ
2and Mann-Whitney tests. A p value of 0.05 or less was considered to be significant using InStat version 3.06 (GraphPad Software Inc, CA, 2003). The haplotypes frequencies for the three-loci were calculated using the maximum likelihood method.
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Results
HLA-A, -B, -DRB1 allele frequencies in a normal population
The polymorphism of HLA-A, -B and -DRB1 genes was investigated in 98 normal individuals. As indicated in tables 1 to 3, HLA-A*02, HLA-B*51, HLA-DRB1*04 and DRB1*07 had the highest frequency in normal popu- lation (19.39, 8.16, 15.82 and 14.29% respectively) and other frequent alleles included HLA-A*01 (12.76%), HLA-B*44 (6.63%), HLA-DRB1*01 (10.71%) and DRB1*13 (9.69%).
HLA-A, -B, -DRB1 allele frequencies in leukemic patients
As demonstrated in table 1, frequencies of HLA-A*02 (20%), -A*03 (11.82%) and -A*26 (4.55%) alleles are higher in patients compared to the control (19.39, 10.2, 1.02% respectively). Table 2 shows that HLA-B*44 (12.73%) was more expressed in patients than the normal individuals (6.63%). For HLA-DRB1 locus (table 3), the most frequent alleles are HLA-DRB1*03 (17.27%), HLA- DRB1*04 (16.55%), -DRB1*13 (11.82%) and -DRB1*15 (10%) observed in patients with leukemia compared to the control (13.78, 15.82%, 9.69 and 7.65% respectively).
Whereas some frequencies of HLA-A, -B and – DRB1 alleles were increasing, others are decreasing. The fre-
Table 1.HLA-A allele frequencies in Moroccan leukemic patients and controls.
HLA-A alleles Frequencies (%) in leukemic patients (n= 55)
Frequencies (%) in normal subject (n= 98)
P value
A*01 10 12.76 0.54
A*02 20 19.39 0.97
A*03 11.82 10.2 0.61
A*10 1.82 1.02 0.7
A*11 2.73 3.06 0.59
A*23 2.73 4.08 0.15
A*24 8.18 8.16 0.82
A*25 0.91 1.02 0.36
A*26 4.55 1.02 0.23
A*28 1.82 1.53 0.74
A*29 1.82 1.53 0.65
A*30 6.36 6.12 0.86
A*31 0.91 1.02 0.51
A*32 4.55 3.06 0.46
A*33 4.55 5.10 0.68
A*34 3.64 2.04 0.6
A*36 0.91 0.51 0.48
A*66 1.82 1.53 0.72
A*68 8.18 9.18 0.69
Allele frequencies less than 0.91% are not shown.
Table 3.HLA-DRB1 allele frequencies in Moroccan leukemic patients and controls.
HLA-DRB1 allele Frequencies (%) in leukemic patients (n= 55)
Frequencies (%) in normal subject (n= 98)
P value
DRB1*01 4.55 10.71 0.05
DRB1*02 0.91 0.51 0.65
DRB1*03 17.27 13.78 0.1
DRB1*04 18.55 15.82 0.08
DRB1*07 14.55 14.29 0.92
DRB1*08 1.82 3.57 0.27
DRB1*09 0.91 0.51 0.48
DRB1*11 6.36 6.12 0.87
DRB1*12 0.91 0.51 0.52
DRB1*13 11.82 9.69 0.04
DRB1*14 1.82 1.53 0.74
DRB1*15 10 7.65 0.09
DRB1*17 0.91 0.51 0.73
Allele frequencies less than 0.91% are not shown.
Table 2.HLA-B allele frequencies in Moroccan leukemic patients and controls.
HLA-B allele Frequencies (%) in leukemic patients (n= 55)
Frequencies (%) in normal subject (n= 98)
P value
B*07 6.36 6.12 0.92
B*08 9.09 5.1 0.2
B*12 0.91 1.02 0.58
B*14 4.55 5.61 0.76
B*15 4.55 6.12 0.33
B*16 2.73 2.04 0.84
B*18 5.45 4.08 0.61
B*21 0.91 2.04 0.59
B*27 2.73 0.51 0.36
B*35 4.55 6.12 0.53
B*38 3.64 4.59 0.81
B*39 0.91 0.51 0.44
B*40 0.91 0.51 0.56
B*41 1.82 2.04 0.49
B*42 0.91 0.51 0.5
B*44 12.73 6.63 0.02
B*45 1.82 3.06 0.22
B*47 0.91 0.51 0.58
B*49 4.55 5.61 0.74
B*50 2.73 6.12 0.09
B*51 7.27 8.16 0.72
B*52 4.55 3.06 0.68
B*53 0.91 4.59 0.37
B*57 0.91 1.02 0.53
B*58 3.64 3.06 0.91
B*72 0.91 0.51 0.38
B*78 1.82 0.51 0.43
Allele frequencies less than 0.91% are not shown.
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quencies of HLA-A*01 and HLA-A*23 in leukemic patients were 10 and 2.73% respectively vs 12.76 and 4.08% respectively in normal individuals. Also, HLA-B
*50 frequency was 1.82 in leukemic patients and 3.06%
in normal individuals. For HLA-DRB1 locus, we found that the frequency of HLA-DRB1*01 was largely decrea- sing in leukemic patients (4.55% vs 10.71% in normal individuals).
Comparison of the results between the normal population and patients revealed that there is an allelic association between certain HLA-B, -DRB1 antigens leukemia disease. Our results showed that in leukemic patients and in normal individuals, the difference between DRB1*13, DRB1*01 and B*44 was significant (p = 0.04, p = 0.05 and p = 0.02 respectively), but there were moderate difference among DRB1*04 (p = 0.08), *03 (p = 0.1), and *15 (p = 0.09). However, we did not observe any significant difference for the others HLA-A, -B and -DRB1 allele frequencies.
Haplotypes analysis
We also analyzed the rate of expression of the haplotypes associating the three alleles in the patients and the case controls. As showed in table 4, these analyses showed no significant differences in frequencies of haplotypes between patients and controls.
Discussion
The rate of expression of certain HLA alleles and haplo- types is considered among the factors of susceptibility to
develop leukemia. Many studies have been carried out in humans investigating the role of HLA antigens in the pathogenesis of hematological malignancies. The associa- tion of HLA with major molecular features of leukemic cells is also lacking.
Our results, supported by the different statistical calcula- tions, showed a statistically significant association (p <
0.05) between leukemia and HLA-B*44, DRB1*01, DRB1*13 in the group of patients studied compared with the control group of normal individuals. For HLA- B locus, we observed a statistically significant association between HLA-B*44 (p = 0.02) and leukemia. Mundhada et al. [43] demonstrated a positive association between the expression of the protein b3a2 and HLA-B alleles B* 49, B*51, B*53, B*56, B*60, B*62.
Our results showed also that HLA-DRB1*01 has decrea- sed in patients. Therefore, this allele may be protective against leukemia, whereas DRB1*03, DRB1*04, DRB1*13 has been moderately increased in patients. It therefore might be considered as susceptible alleles in leu- kemia disease. HLA-DRB1*04 is the marker of suscepti- bility for all the types of leukemia AML, ALL, CML, CLL [27-29, 32-34]. In a European study, it was revealed the protective effect of HLA-DRB1*04 against the acqui- sition of CML [41].
Our results showed no association between HLA-A*02 and A*03 alleles and leukemia (p = 0.97 and p = 0.61 res- pectively). Whereas, the first association study HLA- leukemia showed an association between HLA-A*02 to the ALL [15]. Thereafter, others studies in different popu- lations, such as Turkey, also associated HLA-A*02 to the CLL [40]. It has been demonstrated that HLA-A*03 is playing a protective role against CML through its ability to fix the protein b3a2 [41, 42].
We are working on larger studies in purpose to investigate more extensively the role of HLA class I and class II allele in the development of different types of leukemia (ALL, AML, CML and CLL) in Morocco. We are also interested to study the immunological functions of the alleles of resistance or susceptibility involved in the immune response against the proliferation of malignant cells.
Declaration of interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Table 4.HLA-A, -B, -DRB1 three locus haplotypes frequencies in Moroccan leukemic patients and controls.
Haplotypes Frequencies (%) in leukemic patients (n= 55)
Frequencies (%) in normal subject (n= 98)
Pvalue
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Haplotype frequencies less than 0.9% are not shown.
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