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Abstracts of Past and Current Research [Dorak et al]
Hemochromatosis Gene in
Childhood Leukemia (Review)
A Female-Specific
Susceptibility Marker for Childhood ALL in the TNF Subregion of the HLA Complex
A Male-Specific
Increase in the HLA-DRB4 (DR53) Frequency in High-Risk and Relapsed Childhood
ALL
Increased
heterozygosity for MHC class II lineages in newborn males
Overall
Homozygosity for HLA Class II Supertypes is Increased in Malignancies
Molecular Analysis of
the MHC in Hodgkin's Disease
HLA-B, -DRB1/3/4/5 and
-DQB1 Gene Polymorphisms in Human Immunodeficiency Virus-related Kaposi's
Sarcoma
***
Hemochromatosis
Gene in Childhood Leukemia [HuGE Review]
M Tevfik Dorak, Alan K Burnett, Mark
Worwood
The hereditary
hemochromatosis (HHC) gene, HFE on chromosome 6p21.3, encodes a protein
involved in iron homeostasis. HFE mutations have low penetrance with a mild
effect on serum iron levels. Animal, twin, and population studies have shown
that carrier state for C282Y can increase iron levels. A proportion of
heterozygotes show slightly elevated serum iron levels. Increased serum iron
has been suggested to increase the risk for oxidative damage to DNA.
Epidemiologic studies established a correlation between iron levels and cancer
risk. Case-control studies have reported associations between HFE mutations
C282Y/H63D and several cancers, some of which in interaction with the
transferrin receptor gene TFRC or dietary iron intake. Increased cancer risk in
C282Y carriers is likely due to higher iron levels in a multifactorial setting.
In childhood acute lymphoblastic leukemia (ALL), there is an association of
C282Y with a gender effect in two British populations. No association has been
found in acute myeloblastic leukemia and Hodgkin disease in adults. The
childhood leukemia association possibly results from elevated intracellular
iron in lymphoid cells increasing the vulnerability to DNA damage at a critical
time window during lymphoid cell development. Interactions of HFE with
environmental and genetic factors, most of which are recognized, may play a
role in modification of susceptibility to leukemia conferred by C282Y. Given
the population frequency of C282Y and the connection between iron and cancer,
clarification of the mechanism of HFE associations in leukemia and cancer will
have strong implications in public health.
See the Summary of a Research
Project funded by Children with
Leukaemia
***
A
Female-Specific Susceptibility Marker for Childhood ALL in the TNF Subregion of
the HLA Complex
M Tevfik Dorak, Helmut KG
Machulla, Tom Lawson, Ken I Mills, Alan K Burnett.
ASH 2001,
Orlando, FL
Our previous studies
have identified two MHC genotypes associated with childhood ALL in males only:
homozygosity for HLA-DRB4 (-DR53) haplotypes and the C282Y mutation of HFE. We
have now completed the TNF subregion analysis in the same patients and
controls. The NcoI polymorphism
within the first intron of LTA and the most polymorphic of the TNF region
microsatellites, TNFa, were analyzed by PCR-RFLP and PCR with fluorescent
labelled primers followed by GeneScan analysis, respectively, in 117 patients
and 207 newborn controls. The patient group consisted of 64 males and 53
females, and represented all patients with childhood ALL diagnosed in a single
centre in Cardiff, Wales, UK over 10 years. The controls were locally collected
anonymous umbilical cord blood samples (100 males, 107 females). There was no
statistically significant allelic association. The female-specific homozygosity
rate for the uncut LTA allele LTA*2 (50.9%) was non-significantly increased
compared to the male patients (35.9%) and controls (40.6%). Likewise, TNFa
microsatellite allele 2 homozygosity was higher in female patients (18.9%) than
in male patients (10.9%, NS) and controls (8.2%, P = 0.02). Despite the lack of significant linkage disequilibrium
between the two alleles in this sample, the 3.5kb TNF subregion haplotype
LTA*2-TNFa2 was over-represented in homozygous form in female patients compared
to controls (11.3% vs 1.0%; P =
0.0006, relative risk = 11.25, 95% confidence interval = 2.8 to 45.1). The
female-specific rate was also higher than the male-specific one (11.3% vs 1.6%;
P = 0.03). There was no sex-specific
difference in homozygosity for this haplotype in controls (one homozygote in
each sex group). These results revealed the first female-specific
susceptibility marker in childhood ALL in the same group of patients who
provided evidence for two other male-specific markers. There was no correlation
with ALL subtype, age at diagnosis or relapse. The female-specific risk marker
is part of the HLA-B*1501-DRB1*0401 haplotype that is relatively frequent in
the Welsh population but this association was independent of the HLA-DRB1
genotypes. Data to rule out an HLA class I association are not available yet.
Homozygosity for the TNF subregion haplotype did not extend to the flanking
loci (BF and HSP70-2) or to HLA-DRB1 in any of the patients. Rather than
reflecting linkage disequilibrium with another marker, this haplotype may be
directly relevant in susceptibility as another study showed its association
with higher production of TNFa.
Although the reason for the female-specificity of this association is unknown,
gender-specific differences in LTA or TNF microsatellite associations have also
been reported in atopic asthma and rheumatoid arthritis. The association of
TNFa2 with colorectal cancer in another Celtic population further suggests the
possible involvement of the TNF/LTA loci in cancer susceptibility.
***
A Male-Specific
Increase in the HLA-DRB4 (DR53) Frequency in High-Risk and Relapsed Childhood
ALL
M Tevfik Dorak, Fatma S Oguz, Nevin
Yalman, A Sarper Diler,
Sevgi Kalayoglu, Sema Anak, Deniz
Sargin, Mahmut Carin
Previous
studies reported significant HLA-DR associations with various leukemias one of
which is with HLA-DRB4 (DR53) family in male patients with childhood ALL. We
have HLA-DR-typed 212 high-risk or relapsed patients with childhood (n=114) and
adult (n=98) ALL and a total of 250 healthy controls (118 children, 132 adult)
by PCR-SSP analysis. The members of the HLA-DRB3 (DR52) family were
underrepresented in patients most significantly for HLA-DRB1*12 (P=0.0007)
and ‑DRB1*13 (P=0.0001). In
childhood ALL, the protective effect of DRB3 was evident in homozygous form (P=0.001).
The DRB4 marker frequency was increased in males with childhood ALL (67.4%)
compared to age- and sex-matched controls (42.1%, P=0.003) and female
patients (35.7%, P=0.004). Besides being a general marker for increased
susceptibility to childhood ALL in males, HLA-DRB4 is over-represented in
high-risk patients. These results further suggest that the HLA system is one of
the components of genetic susceptibility to leukemia but mainly in childhood
and in boys only.
***
Increased
Heterozygosity for MHC class II Lineages in Newborn Males
M Tevfik Dorak, Tom Lawson, Helmut KG
Machulla, Ken I Mills, Alan K Burnett.
(Department of Haematology, University
of Wales College of Medicine, Cardiff, UK)
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
either 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 favourable 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.
***
Overall
Homozygosity for HLA Class II Supertypes is Increased in Malignancies
M Tevfik Dorak, Helmut KG Machulla, Chris
Darke, Chris H Poynton, Peter Barrett-Lee, Alan K Burnett.
(Department of Haematology, University
of Wales College of Medicine, Cardiff, U.K.)
The immune
surveillance theory predicts a deleterious effect of homozygosity for HLA
alleles in the development of cancer. Having shown associations between
specific homozygous genotypes for HLA class II supertypes in leukemias and
Hodgkin's disease, we analysed overall homozygosity for HLA class II supertypes
as well as classical HLA-DRB1 alleles at the DNA level. Patients with childhood
leukemia [ALL] (n=117), Hodgkin's disease [HD] (n=113) and breast cancer [BC]
(n=236); and healthy controls (415 newborns and 400 blood donors) were typed at
the HLA-DRB1/3/4/5 loci by the Biotest DRB-ELPHA kit. In the DRB1 locus, there
was no significant change in overall homozygosity: 16.2% in ALL, 19.5% in HD,
13.1% in BC, 12.8% in newborns and 14.3% in adult controls (13.2% in females).
The HLA class II supertypical (DRB3/4/5) homozygosity rates corresponding to
HLA-DR52/53/51 homozygosity were increased in HD (39.8%, p<0.003); BC
(31.4%; p<0.01) and males with ALL (p<0.03) compared to corresponding
control frequencies: 25.5% in adults, 20.9% in adult females, 28.0% in newborns
and 22.9% in newborn boys. The increase was mainly due to homozygosity for
HLA-DR53 in males with ALL (p=0.000001; Dorak et al, Blood 1999); and for HLA-DR52
in HD (p=0.002; Dorak et al, ASHI99) but not attributable to any specific genotype
in BC. The results suggested that HLA class II supertypes may be more
functional in the immune surveillance of transformed cells than HLA-DRB1
alleles and should be included in HLA and cancer association studies.
***
Molecular
Analysis of the MHC in Hodgkin's Disease: Association with a Supertypical
Homozygous Genotype
M Tevfik Dorak, Chris Darke, Chris H
Poynton.
(Department of Haematology, University
of Wales College of Medicine, Cardiff, U.K.)
To investigate the association
of MHC genotypes with Hodgkin's disease, we carried out molecular analyses of
the HFE, HLA-B (Bw4/6), TNFB, HSP70-2 and HLA-DRB1/3/4/5 loci in a group of 113
patients with Hodgkin's disease (age=18-76; median=36 yr) and 400 healthy blood
donors (age=18-45). There was no difference between patients and controls in
gene and allele frequencies at any of these loci. Despite the lack of an
allelic association, a significant difference was noted in the frequency of
HLA-DRB3 genotypes corresponding to homozygosity for the class II supertype
HLA-DR52 without a gender effect (23.9% vs 12.3%; p=0.002, OR=2.25, 95%
CI=1.3-3.8). In the nodular sclerosing type of Hodgkin's disease (HD-NS, n=74),
the homozygosity rate for HLA-DR52 was similar to the rest of the patients. All
patients homozygous for DR52 and below the median age had HD-NS. Because of
this, the HD-NS patients within the age range of controls (18-45 yr) were
analysed separately. The frequency of the susceptibility genotype in this group
of HD-NS patients was 31.5% yielding an OR of 3.29 (p<0.0004; 95%
CI=1.7-6.3). The allele frequency of HLA-DR11, which belongs to the DR52 family
and was previously shown as a susceptibility marker, was not significantly
higher in patients (13.0% vs 9.5%). There were, however, two patients with
HD-NS homozygous for HLA-DR11 in the age group of 18-45 yr (p=0.006; OR=12.7,
95% CI=2.1-77.7). Homozygosity for HLA-B supertypes in patients was not
different between controls. Our results may be a reflection of the findings that
the HLA-A1B8DR3 (DR52) haplotype is a marker for low response to antigens of
EBV which is frequently associated with HD. Together with the previously found
associations of homozygosity for HLA-DR53 in leukaemias, these results show the
necessity of including supertypical genotypes in HLA and cancer association
studies.
***
HLA-B,
-DRB1/3/4/5 and -DQB1 Gene Polymorphisms in Human Immunodeficiency
Virus-related Kaposi's Sarcoma
M Tevfik Dorak, Leland J Yee, James
Tang, Wenshuo Shao, Elena S Lobashevsky, Lisa P Jacobson, Richard A Kaslow.
(Department of Epidemiology, University
of Alabama at Birmingham, USA)
Polymorphisms of
genes in the human leukocyte antigen (HLA) complex, particularly those encoding
HLA-DR, have been suggested as markers of susceptibility to Kaposi’s
sarcoma (KS). We conducted a case-control study comparing 147 homosexual men
who developed KS after infection by human immunodeficiency virus-1 (HIV-1) and
human herpes virus 8 (HHV8) with 147 matched dually infected men without
HIV-associated KS (HIV-KS) from the Multicenter AIDS Cohort Study. HLA‑B,
DRB1, DRB3, DRB4, DRB5, and DQB1 polymorphisms were examined by high-resolution
DNA-based methods. Differences in distributions of genetic variants were tested
by conditional logistic regression. Previously reported relationships with HLA‑DRB1
alleles could not be confirmed. Instead, other associations were observed. In univariate analysis, KS was weakly
associated with B*2702/5 (OR = 0.40, 95% CI = 0.18 to 0.91). Similar or stronger associations, positive or
negative, were seen for haplotypes containing class II alleles: DRB1*1302-DQB1*0604 (OR = 3.67, 95% CI = 1.02
to 13.1), DRB4 (DR53) haplotype family members {odds ratio (OR) = 0.52, 95%
confidence interval (CI) = 0.32 to 0.85}, and DRB3 (DR52) haplotype family
members (OR = 1.69, 95% CI = 1.07 to 2.67).
The B*1402-DRB1*0102 haplotype, which invariably contains the V281L mutation
in the 21-hydroxylase gene governing adrenal steroid biosynthesis, occurred in
five cases and one control (OR = 5.0, 95% CI = 0.58 to 42.8). In a final
multivariable analysis, only DRB1*1302-DQB1*0604 (OR = 6.43, 95% CI = 1.28 to
32.3, P = 0.02) remained significantly associated with KS. Associations of
HLA-DRB families with HIV-KS could reflect underlying immune dysregulation. The
HLA B*1402-DRB1*0102 haplotype associated with increased risk of KS might
represent an antigen-presenting pathway unfavourable for immune response to
HHV8. Alternatively, the relationship might hold a clue to the predilection of
KS for men because that haplotype harbours the mutant form of the
21-hydroxylase gene.
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Last
edited on 23 January 2007
(an update is overdue!)
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