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 theHFE 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).

Table 1.

Presence of the C282Y Mutation (%) in Patients and Newborn Controls

Group I Group II
All patients  17.1 (n = 117)  NS  30.4 (n = 135) P = .0005  (OR = 2.5)  
cALL  15.4 (n = 78)   NS  36.3 (n = 102) P = .00001 (OR = 3.2)  
All males  23.4 (n = 64)   P = .02  (OR = 2.2)  34.7 (n = 75)   P = .0002  (OR = 3.0)  
cALL (males)  24.4 (n = 41)   P = .035 (OR = 2.3)  45.5 (n = 55)  P < 5 × 10−6 (OR = 4.7)  
All females   9.4 (n = 53)   NS  23.3 (n = 60)  NS  
cALL (females)   5.4 (n = 37)   NS 25.5 (n = 47)   NS  
CONTROLS  12.3 (n = 415)  15.1 (n = 238) 
Group I Group II
All patients  17.1 (n = 117)  NS  30.4 (n = 135) P = .0005  (OR = 2.5)  
cALL  15.4 (n = 78)   NS  36.3 (n = 102) P = .00001 (OR = 3.2)  
All males  23.4 (n = 64)   P = .02  (OR = 2.2)  34.7 (n = 75)   P = .0002  (OR = 3.0)  
cALL (males)  24.4 (n = 41)   P = .035 (OR = 2.3)  45.5 (n = 55)  P < 5 × 10−6 (OR = 4.7)  
All females   9.4 (n = 53)   NS  23.3 (n = 60)  NS  
cALL (females)   5.4 (n = 37)   NS 25.5 (n = 47)   NS  
CONTROLS  12.3 (n = 415)  15.1 (n = 238) 

Includes both homozygous and heterozygous occurrences of the mutation. There was 1 homozygous subject in each of the patient and control groups; NS, nonsignificant; OR, odds ratio; P values <.05 are shown for comparisons between the frequency in the leukemic group and the overall control group. In the control groups, there was no difference between gender-specific frequencies, but they were different in the patients with cALL both in group I (P = .03) and group II (P = .04). The overall frequencies were not different between the 2 control groups (P = .30).

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.

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