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Frequently Asked Questions About Our Research

M.Tevfik Dorak

Possible reasons for failure to detect a strong association in previous studies

Can HLA-DRB4 be a susceptibility locus?

The number of patients and controls

Multiple comparisons

How can the same genotype be a susceptibility marker for more than one leukaemia?

Why males?

References

Possible reasons for failure to detect this association in previous studies

The association found for childhood acute lymphoblastic leukaemia (ALL) in our study of 114 patients and 325 controls is very strong (RR = 11.7; P = 3x10^-8) (Ref.1). Currently, with 117 patients and 415 controls analyzed (RR = 6.1; P = 0.000003), this association remains one of the strongest HLA - cancer associations ever reported. Furthermore, it is a reflection of a haplotypical association. The haplotypes HLA-Bw4 - DR53 and HSP70-183bp - DR53 are increased in homozygous form in male patients (RR = 13.8 and 11.9, respectively, P < 0.001). Both the homozygous association and its male specificity have also been confirmed in a second population (Dorak MT et al, unpublished data). Why, then, in a disease which has attracted much attention for an HLA association since Lilly's original paper on mouse leukaemia in 1964 (Ref.2), and the first HLA association paper in childhood leukaemia ³, no other strong HLA association has been reported?

We believe that the reasons are the general negligence of HLA supertypes, homozygosity and the gender effect. At the time of serological typing, detection of supertypes was cumbersome and assignment of homozygosity was unreliable. We published the first molecular HLA association study in childhood ALL and showed a convincing association for a homozygous genotype of the DQA1 locus by RFLP analysis ⁴. This genotype more or less corresponds to homozygosity for HLA-DR53 and the current research specifically examined this genotype by PCR analysis against a newborn control group (as opposed to an adult control group in the previous RFLP study).

A conventional analysis would have compared the allele frequencies between all patients and all controls leaving out the supertypes (one of which is DRB4*01). In that case, the allele frequencies (or more appropriately marker frequencies) of DRB4*01 would not have been found significantly different between patients and controls in our current series of patients and controls (65.6% vs 54.2%). As a test of our original hypothesis that the HLA-associated susceptibility to childhood leukaemia is a recessive trait and not a simple allelic association ^5;6, we examined the homozygosity rates. The data show an association with homozygosity for DRB4*01 even between all patients and controls (20.5% vs 9.4%; P = 0.0015). The consideration of supertypes, homozygosity and, gender resulted in a very strong association in childhood ALL.

In fact, if one looks carefully, there are both data and hints on a possible DR53/DRB4 association in childhood leukaemia and other leukaemias in previously published papers. The very first paper which studied HLA-A, and -B frequencies in childhood leukaemia found a significant increase in HLA-A2B12 (Ref.3). The cumulative results of the following studies indeed confirmed this original finding. In a meta-analysis of published reports, HLA-A2 and -B12 are separately associated with childhood ALL ⁷. Since the haplotype HLA-A2B12 is the commonest class I part of the DR53 haplotypes, it can be concluded that our finding does not disagree with the HLA class I studies.

The first childhood leukaemia studies examined HLA class-II antigen frequencies found an increased allele frequency of DR7 in Switzerland where DR7 is the most common DR53 group antigen ^8;9. It was also pointed out that this finding was most probably due to an excess of homozygotes for that antigen. HLA-DR7 was also found increased in childhood ALL in another study ¹⁰. Two British studies examined HLA-DR antigens in adult leukaemias and reported the involvement of HLA-DR53 or its members in adult ALL ¹¹ and chronic lymphoid leukaemia (CLL) ¹². None of these studies looked at homozygosity in gender groups. The increased HLA-DR53 allele frequency in adult ALL (66.7% vs 52.3%) could have been significant if homozygosity had been considered ¹¹. The same study found a significantly increased DR4 frequency (52.3% vs 29.4%; RR = 2.61) with no information on homozygosity or gender-specific frequencies.

The most convincing association study in leukaemia is the one which used a monoclonal antibody recognising HVR3 epitope of the DR53 antigen ¹³. That study found a RR risk of 7.88 (P < 0.000005) associated with the presence of this epitope for adult acute myeloid leukaemia (AML). Together with the results of our studies in chronic myeloid leukaemia (CML) ¹⁴ and CLL ¹⁵, it can be concluded that whichever leukaemia has been investigated with the consideration of DR53/DRB4 as a possible risk factor, either an association or a hint of an association have been found depending on the way the data are analysed.

Also in reproductive failure, a great number of studies have investigated parental sharing of HLA alleles but none of them included the supertypes. One study explicitly stated that the supertypes were left out ¹⁶. The most authoritative of this group of studies did not examine the HLA class-II supertypes -DRB3/4/5 loci- either ¹⁷. It has been, however, stated that "because deficiency of offspring who were homozygous for HLA was not noted, it is unlikely that fetal losses were due to the effects of deleterious recessive genes in the HLA region" (p.37 in Ref.17). When we examined the supertypical haplotypes, however, there was deficit for the most common homozygous ones and an excess for heterozygosity in boys (Dorak MT et al, manuscript submitted).

In summary, given the design of the studies, it appears that this association could not have been detected in the previous studies, anyway. The absence of firm evidence in the literature does not seem to mean evidence of absence for an HLA-DRB4 association in leukaemia. There is no longer a legitimate reason or excuse to leave supertypes and genotypes out of the study design.

Can HLA-DRB4 be a susceptibility locus?

Since our first report on a HLA-DR53 association in leukaemia ¹⁴, we have been frequently asked why the susceptibility genotype is that of a class-II supertype but not a classical class-II genotype. There seems to be some scepticism about the association of DR53/DRB4 with leukaemia. The HLA-DRB4 locus is one of the MHC class-II loci. As a structurally separate gene and similar to three other HLA-DRB genes, it is expressed, except when it is on some DR7 haplotypes, albeit at a lower level than classical DRB1 alleles. Although it is a difficult antigen to be picked up by standard serology, there are monoclonal antibodies that recognize the HLA-DR53 antigen. One of them, 109d6, is specific for the HVR3-encoded epitope, and positivity for this epitope is associated with a very high risk (RR = 7.88; P < 0.000005) for adult AML ¹³. Interestingly, this epitope is mimicked by a number of carcinogenic / leukaemogenic viruses in its entirety, i.e., up to seven out of seven consecutive amino acids ¹⁸. This extra-ordinary level of mimicry may account for an immunological mechanism through a defect in anti-viral immunity as discussed elsewhere ¹⁹. There are several other diseases associated with HLA-DR53, the most important one in the present context being primary anti-phospholipid antibody syndrome ²⁰ (a full list is available at HLA-DR53 fact file).

It is a common practice to start presenting an HLA association study by quoting the mouse studies, usually the very first one which happens to be a leukaemia study ². Indeed, Lilly et al. found a strong influence of a homozygous MHC genotype on the development of virus-induced and importantly also 'spontaneous' leukaemia in congenic mice ². Since then, the influence of homozygosity for the H-2^k haplotype has been confirmed in many other studies ^21-23 and one of the several leukaemia susceptibility loci has been mapped to the MHC class II region ^23-25. This homozygous association was not a by-product of using inbred mice but a specific observation. Similar to the lack of any increase in the allele frequency of HLA-DRB4*01 in human childhood leukaemia, heterozygosity for the H-2^k haplotype has no effect on mouse leukaemogenesis. Most important similarity between the homozygous HLA-DRB4*01 association in humans and H-2^k homozygous association in mice is that a monoclonal antibody specific for the class II supertype of the H-2^k haplotype (H-2E^k) is cross-reactive with the human HLA-DR53 specificity ^26;27. Thus, having found an association in human leukaemia we do not propose a putative similarity with the established mouse models but seem to have found its human analogue.

An important feature of HLA-DRB4*01 haplotypes is their increased DNA content compared to other HLA class II haplotypes ^28-32. It has been repeatedly shown that the DR/DQ region of DRB4 haplotypes contain 110-160kb extra DNA which may include yet unknown genes. The human MHC has been extensively searched for all the genes, and one haplotype has been completely sequenced ³³. The haplotype sequenced is, however, the shortest HLA-DR52 haplotype ³³. Thus, an unknown gene linked to HLA-DRB4 may still be responsible for the deleterious effects of the susceptibility genotype as this possibility has not been ruled out by sequencing an HLA-DR52 haplotype. It is understood that the Sanger Centre is now sequencing an HLA-DR53 haplotype ^33;34. Only this effort, when completed, will clarify the nature of the extra DNA in the HLA-DR53 haplotypes and whether or not an unknown gene exists in it.

It appears that HLA-DRB4/DR53 has unique features to be the risk factor for the development of leukaemia. For this association, both immunological and genetic mechanisms may be considered for which strong circumstantial evidence is already available. Therefore, there is no need to suggest putative molecular mimicry with a putative leukaemogenic virus or any yet unknown similarity to the experimental mouse leukaemia models which are the starting points of these studies.

The number of patients and controls

Random, anonymous umbilical cord blood samples were obtained from babies born in the University Hospital of Wales and Llandough Hospital in Cardiff over a period of 12 months. In practice, it was not possible to collect samples from all births but no newborn baby was excluded on the basis of any selection criteria. The samples were collected until the number in each sex group exceeded 100. As there were only four boys bearing the concerned genotype in the first 101 new-born boys (and in 13/103 girls), sample collection was not ended at this point as planned originally but continued until the numbers in both sex groups exceeded 200. In the final group of 415 newborns, there were 201 boys and 415 girls (with 14 and 25 homozygotes for DRB4*01, respectively). This larger group also helped to analyse haplotypical associations and indeed showed the 'ancestral' haplotypical nature of both the HLA-DR53 association and the deficit of the haplotypical susceptibility genotype in newborn boys.

The patient group consisted of 117 patients with childhood ALL consecutively diagnosed in Cardiff since 1988. Cross-checking with the Wales Leukaemia Registry revealed that five samples (one boy with cALL) were missing in the study group. Non-Caucasoid patients were not excluded (n = 4). The unintentional omissions were not thought to have had any influence on the results obtained.

Multiple comparisons

It is true that multiple comparisons have been made in the analysis of the data. The main hypothesis of the study was to investigate the homozygosity rate for HLA-DRB4*01 which was previously shown to have an association with a smaller group of patients in comparison to adult controls, and by RFLP analysis of the HLA-DQA1 locus. The present study investigated this association in a larger group of consecutively diagnosed patients (over the last 10 years) against a large local newborn control group, and by PCR analysis of the DRB4 locus. All other typings and comparisons were made to test the specificity of this association but not to find additional associations.

Therefore, although the statistical analysis included multiple and subgroup comparisons, the conventional statistical safeguards were not applied because of the magnitude of the P value for comparisons between two groups (P = 3x10^-8) and the fact that this study was performed with a specific hypothesis. Furthermore, when the patients were divided into two groups, i.e., those diagnosed before 1995 (n = 63) and reported previously ⁴ and those diagnosed since then (n = 54), the same association was noted in also in the latter group (P = 0.00002) therefore ruling out a chance finding. In fact, in the first 63 patients, there were 10 boys homozygous out of 36 (27.8%); in the latter group, there were 10 homozygous boys out of 28 (35.7%). The conclusive evidence for the presence of a homozygous DR53 association in childhood ALL came from the second study we carried out on 135 patients and 238 newborns from the West of Scotland using the same methodology. The association was confirmed in this study together with its male-specificity and homozygous nature (Dorak MT et al, unpublished data). For a discussion of the statistical analysis of HLA associations, see HLA and Statistics).

How can the same genotype be a susceptibility marker for more than one leukaemia?

Our molecular studies to date have shown that homozygosity for HLA-DR53 is a susceptibility genotype for childhood ALL ^1;4, chronic myeloid leukaemia ¹⁴, and chronic lymphoid leukaemia ¹⁵. It may be associated with other malignancies too. Does that mean that there is something wrong with these studies?

Leukaemias are not the only group of diseases sharing the same HLA-related susceptibility marker. A brief look at the list of HLA-DR53 associated diseases will reveal many more [see HLA-DR53 fact file]. Since correlation (association) does not mean causation, it is perfectly possible that many seemingly unrelated diseases with multifactorial etiologies may share the same susceptibility factor. Although they act totally differently from the HLA system, a single proto-oncogen or tumour suppressor gene can play a role in the development of several malignancies.

The opposite is also possible that the same disease may show different associations. Hereditary hemochromatosis, which is now known to be due to the C282Y mutation in the HFE, is associated with different HLA class I alleles in Celts and Italians; primary anti-phospholipid antibody syndrome shows different associations at the HLA-DRB1 locus in Latins and North Americans / Europeans; and rheumatoid arthritis does not show the classical HLA-DR4 association in Greece, Chile or Japan.

Not only the susceptibility genotype but the protective HLA genotype is also shared by leukaemias ^1;12;14;15, and other malignancies ^11;35-41. More convincing evidence about the possibility of sharing the same susceptibility genotype by various malignancies comes from animal studies. In mice, most cancers ^22;42-48 but particularly, spontaneous or virally-induced leukaemias all occur more frequently in H-2^k homozygous animals ^2;21;49. A less well-known example is the virus-induced neoplasms of the chicken. The chicken MHC is called B complex and chickens with the B complex genotypes B5B5 and B15B15 are equally and highly susceptible to Marek's disease (induced by a herpes virus), RSV-induced sarcoma and ALV-induced erythroblastosis ^50;51.

The examples presented above do not cast any suspicion on the biological plausibility of the homozygous H-2^k associations in mouse cancers, B5/B15 associations in chickens or HLA-DR53 associations in human cancers. They just suggest that these genotypes may be markers for general cancer susceptibility.

Why males?

The deficit for homozygous genotypes (i.e., heterozygote advantage) and its male-specificity found in this study is in agreement with predictions and results of experimental studies. The deficit for homozygotes in males suggests prenatal selection against males. This may be due to selective fertilization, implantation, losses during organogenesis and abortions later in pregnancy. It is believed that detectable abortions constitute only a minority of prenatal losses due to MHC effect. The high primary sex ratio at fertilization ^52-54 which gets closer to unity towards birth, the loss of a large proportion conceptions ⁵⁵, and an increased male-to-female ratio at different stages of prenatal development ^56-62 suggest that in general, prenatal selection concerns males. It is clear that more males are being conceived, but relatively fewer males are being born.

There is no human study examined the deficit for MHC homozygosity in newborns, but there are studies in mice ⁶³ and rats ^64;64-67. In one of the earliest studies and its continuation, Palm found that depending on the MHC type, newborn rats may have deficits for homozygosity which appears as increased heterozygosity. He repeatedly showed that this only occurs in newborn males ^64-67. Similarly, it has been noted in mice that when deficit for homozygosity for an MHC type occurs, this concerns males ⁶³. In mice bearing two different recessive lethal t-haplotypes, some embryos may survive till birth whereas all embryos homozygous for the same lethal t-haplotype die. In the group of t6/tw5 heterozygotes bearing two recessive lethal allele, sex affects the lethality and a deficit of males among live births has been noted in two independent experiments ^68;69. Another mouse study found an excess heterozygosity at a different histocompatibility locus, H-3, only in males for certain combinations ⁷⁰. Whatever the reason for this, there is consistency in the observations that MHC homozygosity preferentially affects males in the intrauterine period. Our results, therefore, are simply a replication of these not well-recognized animal studies.

There is yet no explanation for the male-specificity of the leukaemia association but if the long-held view suggesting a link between embryogenesis and leukaemogenesis is correct ^6;71, there is no doubt that male-specificity of prenatal selection would extend to leukaemia susceptibility too. Since abortions and childhood leukaemia tend to occur in the same families ^72-77 and parental HLA sharing is a risk factor for them, it is plausible that the same HLA genotype may be a risk factor for both conditions. This connection is further supported by the reports that survivors of threatened abortions are at a higher risk to develop childhood leukaemia ^75;78. In the largest of these studies, mothers had a history of at least one fetal loss in almost one third of childhood ALL cases ⁷⁷. Another line of support is the well-known association of HLA-DR53 or its members (HLA-DR4 and -DR7) with anti-phospholipid antibody syndrome ^20;79-82. This antibody is present in 15% of women with a recurrent abortion history and causes usually early (first trimester) abortions in 90% of them ⁸³. Also in a group of women experiencing recurrent abortions, an HLA-DR7 association has been reported in those who were positive for this antibody ⁸⁴. The overall interpretation of all these data would be that HLA-DR53 does not only confer increased susceptibility childhood ALL but also influences pregnancy outcome and both effects are male-specific.

References

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HLA-DR53 fact file Research by Dorak et al.

M.Tevfik DORAK, MD, PhD

Last edited on 23 January 2007

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