An increased risk of developing acute leukemia has been associated with exposure to tobacco smoke (1), a known source of carcinogenic NAT22 substrates such as arylamines and hydroxylamines. Polymorphic status at the NAT2 locus may mediate this risk. To address whether acetylator status may mediate the risk of developing acute leukemia, we have analyzed a population-based case-control study of 557 acute leukemia samples and 952 matched controls (1) using PCR-based methods to define acetylator status. Furthermore, we have gone on to examine how this risk is affected by smoking status and by status as primary or secondary AML, defined clinically or by cytogenetics. We hypothesize that polymorphic status at the NAT2 locus confers risk for adult acute leukemia, and the risk may be particularly increased for smokers.

The cases were comprised of a group Caucasian patients who were 16 to 69 years of age and newly diagnosed with acute leukemia between April 1, 1991, and December 31, 1996. For every participating case, two controls of the same sex, year of birth, and ethnic origin were selected from the same general practice of the case.

PCR-RFLP methods were used to identify four of the most common NAT2 alleles by the method of Smith et al. (2). The wild-type or functional allele NAT2*4 and the low-activity alleles NAT2*5A, NAT2*5B, NAT2*5C, NAT2*6, and NAT2*7. Individuals homozygous for the NAT2*4 allele and individuals heterozygous for NAT2*4 in combination with a low-activity allele (NAT2*5A, NAT2*5B, NAT2*5C, NAT2*6, or NAT2*7) were classified as fast acetylators. Individuals with any combination of the low-activity alleles were classified as slow acetylators.

Odds ratios and 95% confidence intervals for a matched analysis were calculated using conditional logistic regression. Analysis was conducted using STATA (Stata Corporation). AML cases were divided into de novo and secondary, depending on whether they had received chemo- or radiotherapy previously. Subgroup analyses were performed for cell lineage and FAB classification types. Cytogenetic abnormalities among AML cases were classified hierarchically into one of the following groups: (a) normal, reciprocal translocations associated with good prognosis; that is, the t(15;17), t(8;21), or inv (16); or (b) partial or complete deletion of chromosomes 5, 7, 12 or 17, translocation, inversion, or deletion of chromosomes 3q21 or 11q23, or trisomy 8, 11, or 21. Other cytogenetic abnormalities were not otherwise classified. For each subgroup, odd ratios were estimated relative to the cases’ matched controls. The interaction between NAT2 genotypes and never/ever smoking status at 2 years before diagnosis of acute leukemia was tested.

No significant differences in NAT2 allele frequency compared with controls were seen for acute leukemia, AML, or ALL, and allele frequencies were unaffected by age or gender distribution within any of these groups (data not shown). When genotypes were examined, again, no significant effects were observed in the main diagnostic groups, nor when stratifying by de novo and secondary AML, FAB classifiction type, or cytogenetic groups (Table 1). No interaction was evident between NAT2 acetylator status and smoking for acute leukemia (χ2 = 0.90; P = 0.34), AML, or ALL was seen (data not shown).

This is the largest case-control study ever to examine the association of NAT2 genotype status and adult acute leukemia. As such, the statistical power to detect differences, should they exist, is higher than in any other study published to date. Nonetheless, the interpretation of small deviations in risk is still problematic; for the total data, the present investigation has sufficient power (80%) to detect risks >1.5 and <0.7.

Our results provide no evidence to support the hypothesis that chemicals such as arylamines, whose metabolism is affected by acetylator status, are associated with adult acute leukemia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

        
1

To whom requests for reprints should be addressed, at Academic Unit of Haematology and Oncology, Algernon Firth Building, University of Leeds, Leeds, LS2 9JT, United Kingdom.

        
2

The abbreviations used are: NAT2, N-acetyl transferase 2; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; FAB, French-American-British.

Table 1

Number of cases and controls, adjusted odds ratios, and 95% confidence intervals by lineage, by FAB or immunophenotye, and by cytogenetics for the rate of NAT2 acetylation

DiagnosisSlowaFastb
CaseControlCaseControlOR95% CI
Acute leukaemia 299 489 236 456 0.85 0.68–1.06 
AMLc 253 427 208 394 0.91 0.71–1.15 
 De novo 218 360 188 360 0.89 0.69–1.15 
 Secondary 35 62 17 33 0.83 0.40–1.73 
 AML M0 10 27 12 12 2.11 0.80–5.59 
 AML M1 42 75 36 64 1.00 0.55–1.82 
 AML M2 56 85 52 103 0.74 0.44–1.24 
 AML M3 33 52 22 40 1.23 0.57–2.63 
 AML M4 35 71 35 61 1.17 0.63–2.15 
 AML M5 24 36 15 32 0.59 0.25–1.41 
 AML M6 8 18 12 20 2.02 0.57–7.17 
 AML M7 4 4 1 2 0.77 0.04–13.8 
 Cytogenetically normal 84 151 67 125 1.00 0.66–1.53 
 t(15;17), t(8;21), inv(16) 44 70 42 76 0.91 0.51–1.62 
 5q/7q-, etc. 36 52 25 54 0.66 0.33–1.33 
 Other abnormality 33 49 23 48 0.67 0.33–1.36 
 Failed/Not tested 57 107 51 89 1.12 0.70–1.81 
ALL 42 58 26 55 0.66 0.37–1.20 
 ALL Bd 28 40 19 40 0.69 0.33–1.44 
 ALL Td 6 9 5 7 1.18 0.25–5.56 
DiagnosisSlowaFastb
CaseControlCaseControlOR95% CI
Acute leukaemia 299 489 236 456 0.85 0.68–1.06 
AMLc 253 427 208 394 0.91 0.71–1.15 
 De novo 218 360 188 360 0.89 0.69–1.15 
 Secondary 35 62 17 33 0.83 0.40–1.73 
 AML M0 10 27 12 12 2.11 0.80–5.59 
 AML M1 42 75 36 64 1.00 0.55–1.82 
 AML M2 56 85 52 103 0.74 0.44–1.24 
 AML M3 33 52 22 40 1.23 0.57–2.63 
 AML M4 35 71 35 61 1.17 0.63–2.15 
 AML M5 24 36 15 32 0.59 0.25–1.41 
 AML M6 8 18 12 20 2.02 0.57–7.17 
 AML M7 4 4 1 2 0.77 0.04–13.8 
 Cytogenetically normal 84 151 67 125 1.00 0.66–1.53 
 t(15;17), t(8;21), inv(16) 44 70 42 76 0.91 0.51–1.62 
 5q/7q-, etc. 36 52 25 54 0.66 0.33–1.33 
 Other abnormality 33 49 23 48 0.67 0.33–1.36 
 Failed/Not tested 57 107 51 89 1.12 0.70–1.81 
ALL 42 58 26 55 0.66 0.37–1.20 
 ALL Bd 28 40 19 40 0.69 0.33–1.44 
 ALL Td 6 9 5 7 1.18 0.25–5.56 
a

Slow acetylator defined as 5A*5A, 5A*6, 5A*7, 5B*5B, 5B*6, 5B*7, 5C*5C, 5C*6, 5C*7, 6*6, 6*7, or 7*7; fast acetylator defined as 4*4, 4*5A, 4*5B, 4*5C, 4*6, or 4*7.

b

OR, odds ratio; CI, confidence interval.

c

De novo AML, AML with no previous myelodysplastic syndrome, chronic myeloid leukemia, or radio/chemotherapy; secondary AML, AML diagnosed after myelodysplastic syndrome, chronic myeloid leukemia, or radio/chemotherapy.

d

ALL B, acute lymphoblastic leukemia B-cell lineage; ALL T, acute lymphoblastic T-cell lineage.

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