Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3957-3958
CORRESPONDENCE
The C282Y Mutation of HFE Is Another Male-Specific Risk
Factor for Childhood Acute Lymphoblastic Leukemia
 |
LETTER |
To the Editor:
We have recently reported a strong HLA class II association in
childhood acute lymphoblastic leukemia (ALL) that is restricted to male
patients.1 The reason for this gender effect is currently unknown. Here we report another genetic association in childhood ALL
with an HLA-linked polymorphism, which again showed male-specificity. The gender-specific association with the C282Y mutation of the HFE gene was found in 2 independent groups of patients.
More than 90% of patients with hereditary hemochromatosis (HH) are
homozygous for the C282Y missense mutation of the HLA class I-like
gene HFE in Britain.2 This mutation causes the loss of surface expression of the HFE protein and, consequently, the control
mechanism on iron transport via the transferrin receptor may be
affected.3 There is no evidence yet that it has an immune function. Because the same HLA genotype conferred susceptibility to HH
and leukemia, we had postulated that HFE might also be a leukemia susceptibility gene.4 To test this hypothesis, we analyzed 2 independent groups of children with ALL, and corresponding newborn controls from South Wales (group I) and the West of Scotland (group II) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.5 In both groups, male but not female patients had a higher frequency of the C282Y mutation than
controls, although the increase was caused by heterozygosity but not by
homozygosity (Table 1). When the analysis
was restricted to the more homogeneous and the most common subtype
(cALL), the association was still evident. In group I, the frequency of
the mutation was 24.4% in boys with cALL (P = .035; odds
ratio = 2.3; 95% confidence interval = 1.1 to 4.9); and in group
II, it was 45.5% (P < 5 × 10
6; odds
ratio = 4.7; 95% confidence interval = 2.6 to 8.6). In group II,
the other known mutation of the HFE gene, H63D, was also
examined as an internal control. There was no change in the frequency
of this mutation between male or female patients and controls (data not
shown).
Besides providing evidence for our earlier hypothesis, the results
confirmed the previous epidemiological finding that `male' carriers
of the HH gene have an increased risk for hematopoietic malignancies.6 This finding lends support to the unexpected gender effect we noted. The mechanisms of neither the HLA-DRB4*01 nor
the C282Y association are known. It is likely that the class II
association has an immune mechanism. Because increased iron content in
lymphoid cells interferes with their immune function,7 and
the C282Y mutation may cause abnormalities of iron transport inside the
cell, immune deterioration resulting from this mutation may be the
reason for the HFE association. The male-specific C282Y association, shown in 2 independent groups, warrants further studies on
the function of the HFE gene and its relevance in
susceptibility to childhood ALL.
| |
ACKNOWLEDGMENT |
This study was supported by research grants from the Leukaemia Research
Appeal for Wales, and in part by EU contract BMH4-CT96-0994. We thank
Ceri Edwards for her contribution to the genotype analysis.
M. Tevfik Dorak
Alan K. Burnett
Mark Worwood
Department of Hematology
University of Wales College of
Medicine
Cardiff, UK
Anne M. Sproul
Brenda E.S. Gibson
Royal Hospital for Sick Children
Glasgow, UK
| |
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