Other molecular HLA association studies in childhood ALL
The following abstract appeared in the European Journal of Immunogenetics (Febr 1997, Vol.24, No.1, p.52):
SUSCEPTIBILITY TO CHILDHOOD COMMON ALL IN BOYS IS INFLUENCED BY A FREQUENT HLA-DQA1-DQB1 HAPLOTYPE
GM Taylor, SP Dearden, N Payne, M Ayres, DA Gokhale, JM Birch, V Blair, RF Stevens, AS Will, OB Eden. Immunogenetics Laboratory, St Mary's Hospital, Manchester, UK.
There are indications that childhood common ALL (c-ALL) may arise as a rare consequence of a common infection. In an effort to determine whether this is genetically influenced, we have compared the frequency of alleles at the HLA-DQA1 locus in an unselected population-based series of 60 children with c-ALL (38 males, 22 females)., and a random panel of 78 newborn infant controls (38 males, 40 females), using PCR-based molecular typing. The results showed a higher frequency of DQA1*0101 in c-ALL compared with infant controls (relative risk [RR]=1.96; p=0.054). However, analysis of allele frequency by gender showed that the increased frequency of DQA1*0101 is largely confined to males with c-ALL (RR=2.55; p=0.049). A comparison of patients and infant controls typing for DQA1*0101 with those previously typed for DQB1*0501 haplotype showed a high level of concordance, consistent with linkage disequilibrium. Moreover, the DQA1*0101-DQB1*0501 haplotype was significantly more frequent in males with c-ALL than male controls (RR=9.48; p<0.001). Analysis of the data in relation to polymorphic amino-acid coding motifs showed a significantly increased frequency of the DQA1Ser52 - DQB1Val57 haplotype, coded by DQA1*0101-DQB1*0501, in males but not females with c-ALL. Preliminary analysis of the families of 24 c-ALL patients supports evidence of DQA1Ser52 - DQB1Val57 haplotype-associated susceptibility in males with c-ALL.
Seemingly the same study was also presented at a different meeting and the abstract was published in the British Journal of Haematology (April 1998, Vol.101, Suppl.1, p.31):
EVIDENCE THAT AN HLA-DQA1/DQB1 HAPLOTYPE INFLUENCES SUSCEPTIBILITY TO CHILDHOOD COMMON ALL PROVIDES FURTHER SUPPORT FOR AN INFECTION-RELATED AETIOLOGY
GM Taylor, S Dearden, M Ayres, JM Birch, V Blair, OB Eden. Immunogenetics Laboratory, St Mary's Hospital, Manchester, UK.
It has been suggested that childhood common acute lymphoblastic leukaemia (c-ALL) may arise as a rare outcome of a common infection. Since interactions between infections and the immune system are determined by HLA alleles, we have compared the frequency [of] HLA-DQA1 alleles in 60 children with c-ALL (38 males, 22 females). The results revealed a higher frequency of DQA1*01 in c-ALL compared with infant controls (odds ratio (OR)= 1.60; 95% confidence interval (CI)= 0.97 - 2.62), which was attributable to DQA1*0101/*0104 (OR= 2.27; 95% CI= 1.12 - 4.52). This association was entirely confined to males with c-ALL (OR= 4.06; 95% CI= 1.42 - 10.17). When the frequency of subjects typing for both DQA1*0101/*0104 and DQB1*0501 was determined, this was higher in patients than controls (OR= 2.04; 95% CI= 0.91 - 4.45) and was confined to male patients (OR= 3.73; 95% CI= 1.19 - 10.3). DQA1*0101/*0104 and DQB1*0501 code DQa1/DQb1 heterodimers with Serine at position 52 and Valine at position 57, respectively. Analysis of the co-occurrence of these amino acids in patients and controls showed that they both contributed to the risk of c-ALL (OR= 2.34; 95% CI= 1.07 - 4.97) but only in males (OR= 4.18; 95% CI= 1.41 - 11.03). The results suggest that DQa1Serine52/DQb1Valine57 heterodimers jointly contribute to the risk of c-ALL in males. These molecules, and other factors, may influence the binding of infection-derived peptides which play a part in the aetiology of childhood c-ALL.
And finally, a full paper has been published in the British Journal of Cancer (Sept 1998, Vol.78, No.5. pp.561-5):
EVIDENCE THAT AN HLA-DQA1 - DQB1 HAPLOTYPE INFLUENCES SUSCEPTIBILITY TO CHILDHOOD COMMON ACUTE LYMPHOBLASTIC LEUKAEMIA PROVIDES FURTHER SUPPORT FOR AN INFECTION-RELATED AETIOLOGY
GM Taylor, S Dearden, N Payne, M Ayres, DA Gokhale, JM Birch, V Blair, RF Stevens, AM Will, OB Eden. Immunogenetics Laboratory, St Mary's Hospital, Manchester M13 0JH, UK.
Comparison of DQA1 and DQB1 alleles in 60 children with common acute lymphoblastic leukaemia (c-ALL) and 78 newborn infant control subjects revealed that male but not female patients had a higher frequency of DQA1*0101/*0104 and DQB1*0501 than appropriate control subjects. The results suggest a male-associated susceptibility haplotype in c-ALL and supports an infectious aetiology.
Comment: There seem to be two problems with this study: (1) Intra-study inconsistency: As the number of the patients and control stayed the same over the years, it can be assumed that the study examined the same group of patients and controls. The concerned genotype, however, yielded a RR of 9.48 (p<0.001) in 1997, and an OR of 3.73 in 1998 for the same association; (2) Inter-study inconsistency: No sign of such an association was found in any other study including the only HLA-DRB1 study in cALL published to date.
The same group had previously published their results of HLA-DQB1 analysis in childhood ALL. There is no statistically significant (at the level of even uncorrected 1%) association between any allele or genotype and childhood common ALL:
MOLECULAR ANALYSIS OF HLA-DQB1 ALLELES IN CHILDHOOD COMMON ACUTE LYMPHOBLASTIC LEUKAEMIA
Dearden, S.P., Taylor, G.M., Gokhale, D.A., Robinson, M.D., Thompson, W., Ollier, W., Binchy, A., Birch, J.M., Stevens, R.F., Carr, T., and Bardsley, W.G. British Journal of Cancer 1996;73(5):603-9.
Epidemiological studies suggest that childhood common acute lymphoblastic leukaemia (c-ALL) may be the rare outcome of early post-natal infection with a common infectious agent. One of the factors that may determine whether a child succumbs to c-ALL is how it responds to the candidate infection. Since immune responses to infection are under the partial control of HLA genes, an association between an HLA allele and c-ALL could provide support for an infectious aetiology. To define the limit of c-ALL susceptibility within the HLA region, we have compared HLA-DQB1 allele frequencies in a cohort of 62 children with 76 newborn controls, using group-specific PCR amplification, and SSCP analysis. We find that a significant excess of children with c-ALL type for DQB1*05 [relative risk (RR):2.54; uncorrected p=0.038], and a marginal excess with DQB1*0501 (RR=2.18; p=0.095). Only 3 of the 62 children with c-ALL have the other susceptibility allele, DPB1*0201 as well as DQB1*0501, whereas 15 had one or the other allele. This suggests that HLA-associated susceptibility may be determined independently by at least two loci, and is not due to linkage disequilibrium. The combined RR of the two groups of children with DPB1*0201 and/or DQB1*0501 is 2.76 (p=0.0076). Analysis of amino acids encoded by exon 2 of DQB1 reveal additional complexity , with significant (p<0.05) or borderline-significant increases in Gly26, His30, Val57, Glu66-Val67 encoding motifs in c-ALL compared with controls. Since these amino acids are not restricted to DQB1*0501, our results suggest that, as with DPB1, the increased risk of c-ALL associated with DQB1 is determined by specific amino acid encoding motifs rather than by an individual allele. These results also suggest that HLA-associated susceptibility to c-ALL may not be restricted to the region bounded by DPB1 and DQB1.
Comment: To date, there has been no HLA-DQB1 association in c-ALL therefore these findings would have been the first association if they had been statistically validated. None of these P values would stand the compulsory correction for the number of comparisons, or even the number of alleles/haplotypes of the relevant locus/loci (the number of alleles detected only at the DQB1 locus in this study is 14!). Therefore, there is no significant association in this study (or in its continuation presented above) and the conclusions drawn can hardly be justified.
Further contributions to this field were presented in the ASHI 1999 meeting in New Orleans as a local preliminary study and a large nation-wide study in ASHI 2000 meeting in San Francisco by Klitz's group:
THE INFLUENCE OF HLA GENETIC DETERMINANTS ON THE RISK OF DEVELOPING PEDIATRIC ACUTE LYMPHOCYTIC LEUKEMIA
E Trachtenberg, C Hoppe, H Erlich, P Buffler, W
Klitz. Childrens Hospital Oakland
Research Institute, Oakland, CA.
The causes of leukemia are likely to be a result of both environmental and genetic factors, with the risk of developing leukemia involving multiple genes conferring susceptibility to the development of malignancy. There is evidence that immunologic mechanisms are involved in the etiology of leukemia. We studied the effect of HLA genetic variation on the risk of developing childhood acute lymphocytic leukemia (ALL), with the aim of establishing the role that HLA alleles or haplotypes play in increasing the risk of leukemia through their interaction with environmental agents, such as infectious or toxic agents. We analyzed a 31 Caucasian pediatric ALL cases from California using the PCR and SSOP methods to analyze the HLA class I (A, B, C) and II (DRB, DQB, DPB) alleles. Caucasian control samples (N = 124) came from analysis of CEPH family samples typed with similar methods. The overall heterogeneity between controls and ALL cases for the class II DRB1 genes was significant [G = 41.5, df = 19, p <0.01]. HLA class II DRB1 gene analysis in our study indicates a significant association of DRB1*1104 with ALL cases [OR= 8.4, p <0.01]. The very similar allele DRB1*1101 was nominally protective [OR = 0.2, p = 0.05]. Another protective association was observed with DRB1*0404 [OR=0.1, p <0.01], and DRB1*0404 alleles were completely missing in the ALL cases. The DRB1*1401 allele was also nominally protective [OR = 0.2, p<0.05]. Analysis of class I HLA-A alleles suggested a risk effect with A*2402 [RR=2.5, p <0.10]. No significant association was found with the B locus. This study underscores the need for high resolution typing in disease association analyses. To our knowledge, this is the first study analyzing the contribution of HLA class I and II alleles in the development of pediatric ALL. Moreover, our data suggests significant associations of both class I and II alleles with development of childhood ALL in Caucasians. Disease association analysis using the HLA class I and II data on Caucasian pediatric ALL patients from the NMDP, which may be skewed due to severity of disease, is also underway. Finally, more comprehensive molecular studies, using many more samples, are still needed to identify genetic predispositional effects of HLA on the development of pediatric ALL.
THE ROLE OF HLA IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA
William Klitz and Elizabeth Trachtenberg. Children's Hospital Oakland Research Institute and School of Public Health, University of California, Berkeley.
Childhood acute lymphoblastic leukemia (cALL) is the most common leukemia of childhood, but few etiological factors have been firmly established. In this study we determine the association of HLA polymorphism with cALL. A Case-Control study design utilized cALL patients receiving bone marrow transplants and a like number of unrelated individuals randomly selected from the National Marrow Donor Program (NMDP) database matched for the year of sampling and HLA typing methodology of each patient. Differences in frequencies of HLA alleles and haplotypes between cases and controls in 2xk tests were used to analyze the influence of the HLA complex on disease. Data from low resolution DNA-based and serological HLA typing performed on 2,130 cases and 2,130 controls was obtained from the NMDP. Of the three HLA loci examined, A, B and DR, each had alleles with both positive and negative associations with cALL. Positive unadjusted odds ratios ranged from 1.2 to 2.2 for the alleles A24, A30, B18, B35, B49, B51, B63 and DRB1*11, and from 0.6 to 0.8 for the negative associations, including alleles A1, B7, B8, B44 and DRB1*3. Relative risks for HLA genotypes at each locus ranged from 0.3 (0.19-0.62) to 2.0 (1.49-2.54). The protective effect of the extended haplotype common in Northern Europeans, A1-B8-DRB1*3, was examined in more detail. Neither A1 nor DRB1*3 themselves could be responsible for the effect, while the B8-DRB1*3 segment of the haplotype gave the strongest signal. We also confirm a prediction of the hypothesized influence of genotypes of the supertypic DRB loci, namely that heterozygotes of DRB3/DRB4 are less common in cALL. Although a slight significant difference in age of onset was present between males and females, neither sex nor age interact with HLA to produce cALL predisposition. We conclude that both alleles of HLA class I and class II loci have significant impacts on the likelihood of acquiring cALL. Mechanistically, this can be interpreted as further evidence for an underlying infectious etiology of cALL.
(This page needs updating which is planned for 2007)
Medline search for papers by Dorak MT
M.Tevfik DORAK, MD, PhD
Last edited on 23 January 2007