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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).
* * * * *
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.
* * * * *
The statistics subsection of the Methods section resulted in the
following page:
Statistics in HLA Association Studies
* * * * *
Few preliminary findings remain
unpublished (see Conference Presentations here) awaiting replication
in a second study
M.Tevfik Dorak, MD PhD
MHC HLA Biostatistics
Genetics Genetic Epidemiology Population Genetics Evolution
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