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PhD Dissertation

A Search for a Leukaemia Susceptibility Gene in the HLA Complex

M.Tevfik Dorak


Department of Haematology, University of Wales College of Medicine, Cardiff, U.K., 2000

(Supervisor: Professor Alan K Burnett)

Genetic and environmental factors play an interactive role in the development of childhood acute lymphoblastic leukemia (ALL). This is supported by an increased incidence of spontaneous abortions in the maternal history of leukaemics, HLA associations with ALL, and epidemiological evidence for a common virus in the etiology. The HLA system shows some influence on the outcome of human pregnancies, the development of leukaemias, as well as being the major determinant of anti-viral immune responses. In this study, we examined the immunogenetic susceptibility to childhood ALL in 117 patients and 415 newborn controls by PCR analysis of the HLA-DRB loci. As in our previous study, homozygosity for HLA-DRB4*01, encoding for the HLA-DR53 antigen, was increased in boys (P = 0.00001; OR=6.1). To eliminate the effect of disease heterogeneity, when the analyses were restricted to the commonest subtype of ALL (common ALL) both associations were still evident. The homozygous associations in common ALL with the haplotypes HLA-Bw4 - DRB4*01 (P = 0.0007; OR = 13.8) and HSP70-2*183 - HLA-DRB4*01 (P = 0.0000003; OR = 11.9) suggested that the primary association was with the ancestral HLA-DR53 haplotypes. Furthermore, the HSP70-2*183 - HLA-DRB4*01 haplotype had a decreased frequency in newborn boys compared with newborn girls; male blood donors; or the expected homozygosity assuming Hardy-Weinberg equilibrium (all P < 0.05). This would suggest a male-specific reproductive failure associated with this homozygous genotype which also increases susceptibility to develop ALL only in the same gender. The strong association of HLA-DRB4*01 with childhood ALL lends support the postulated interaction between adenovirus and HLA-DR53 in the development of ALL.

Earlier versions of this work were published in BLOOD 1999;94(2):694-700 (full-text) and also in BLOOD 1999;94(11):3957-8 (full-text).


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The following is the analysis of the newborn control group of the PhD work (Dorak et al, Genes & Immunity, 2002 (abstract):


Increased heterozygosity for MHC class II lineages in newborn males


In plants, fungi and marine invertebrates, there are genetic compatibility systems to ensure diversity in the offspring. The importance of genetic compatibility in gametic union and selective abortion in vertebrate animals has also been appreciated recently. There have been suggestions that the major histocompatibility complex (HLA in humans) may be a compatibility system in vertebrates. There is almost always a second expressed DRB locus in an HLA class II haplotype which can be DRB3, DRB4 or DRB5. These encode the supertypical specificities and mark the main ancestral lineages. The members of each lineage have related DNA sequences at the main class II locus HLA-DRB1. We analysed 415 newborns at the HLA-DRB1/3/4/5 loci by PCR analysis to seek evidence for sex-specific prenatal selection events. While there was no significant change in heterozygosity rates between males and females at DRB1, the proportion of males carrying two DRB1 specificities from different ancestral lineages was significantly increased (53.7% in males vs 39.3% in females, P = 0.003). The genotypes consisting of phylogenetically most distinct ones, namely the DRB3 and DRB4 haplotypes, showed the most striking difference between sexes (P = 0.007). These results suggested a more favorable outcome for male concepti heterozygous for supertypical haplotypes. Heterozygosity for most divergent haplotypical families ensures the highest degree of functional heterozygosity at the main HLA class II locus DRB1 while increasing the likelihood of heterozygosity also at other MHC loci. Our observations agree with the previously reported heterozygote excess in male newborn rats and mice. Correlations between MHC class II heterozygosity and advertised male quality in deer and pheasant as well as increased reproductive success in MHC class II heterozygous male macaques are examples of postnatal benefits of heterozygosity in males that may be behind the development of prenatal selection mechanisms. The MHC-mediated prenatal selection of males may also be one of the selective events suggested by the very high primary (male-to-female) sex ratio at fertilization reaching close to unity at birth in humans. These results provide an appealing working hypothesis for further studies in humans and other vertebrates.


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The statistics subsection of the Methods section resulted in the following page:


Statistics in HLA Association Studies


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Few preliminary findings remain unpublished (see Conference Presentations here) awaiting replication in a second study


M.Tevfik Dorak, MD PhD

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