Elsevier

Leukemia Research

Volume 33, Issue 2, February 2009, Pages 250-258
Leukemia Research

Paternal smoking, genetic polymorphisms in CYP1A1 and childhood leukemia risk

https://doi.org/10.1016/j.leukres.2008.06.031Get rights and content

Abstract

We conducted a case–control study to evaluate the association between paternal smoking and childhood leukemia and to evaluate potential modification by polymorphisms in CYP1A1. Histologically confirmed childhood leukemia cases (n = 164) and non-cancer controls (n = 164) were recruited from three teaching hospitals in Seoul, Korea. Five single nucleotide polymorphisms in CYP1A1 (−17961T>C, −9893G>A, I462V, 1188C>T (*2A), and 11599C>G) were genotyped and haplotypes were estimated by the expectation-maximization method. We also conducted a meta-analysis of 12 studies that have reported the association between paternal smoking and childhood leukemia risk. Paternal smoking at home was associated with all leukemias (OR = 1.8, 95% CI = 1.1–2.8) and acute lymphoblastic leukemia (ALL) (2.0, 1.2–3.4). An increasing trend in risk was observed for pack-years smoked after birth (Ptrend = 0.06 and 0.02, respectively) and the number of smokers in the home during the child's life (Ptrend = 0.05 and 0.03, respectively). Among those without the CGACC haplotype, ALL risk was significantly increased by the father's smoking at home (2.8, 1.5–5.3) and the presence of at least one smoker in the home (2.3, 1.2–4.4), and the test for interaction was significant (Pinteraction = 0.03 and 0.02, respectively). The meta-analysis showed that overall paternal smoking (1.13, 1.04–1.24) and smoking before the pregnancy of the child (1.12, 1.04–1.21) were significantly associated with childhood leukemia risk. Our results suggest that paternal smoking is a risk factor for childhood leukemia and the effect may be modified by CYP1A1 genotype.

Introduction

Despite decreasing mortality rates over the past two decades, childhood cancer is the second most frequent cause of death after accidents and poisonings, among children aged 1 or older in Korea (about 4 per 100,000 person-years as of 2003). Although childhood leukemia is the most common childhood cancer with an incidence of 3.8 cases per 100,000 person-years in Korean children [1], no studies in Korea have evaluated environmental exposures as potential risk factors. Likewise, the risk factors in other study populations have not been well characterized with the exception of ionizing radiation.

Children may be particularly vulnerable to environmental toxicants because of their greater relative exposure, immature metabolism, and higher level of cell division and growth [2]. Cigarette smoke is a common environmental exposure for children, containing various carcinogens such as nitrosamines, polycyclic aromatic hydrocarbons (PAHs), heterocyclic amines, and radioactive compounds [3]. However, epidemiological evidence for a relationship between childhood leukemia and tobacco smoke exposure in utero or during the postnatal period is inconclusive [4], [5].

Although several case–control studies suggested that maternal smoking during pregnancy increases risk of childhood leukemia [6], [7], cohort studies have found inverse associations between maternal smoking during pregnancy and childhood leukemia [8], or no association [9], [10], [11]. Inverse associations were also observed between maternal smoking more than 10 cigarettes per day during pregnancy and childhood leukemia in case–control studies conducted in German and the U.K. [12], [13]. Paternal smoking, especially in the prenatal period, has been shown to increase childhood leukemia risk in a number of studies [7], [14], [15], [16], [17]. However, other studies found no significantly increased risk [12], [13], [18], [19], [20], [21].

In terms of postnatal smoking exposure, genetic variants of the child's enzymes (i.e., CYP1A1, CYP2D6, GSTM1/T1/P1, NAT1, and NAT2) involved in the oxidation activation and subsequent conjugation detoxification of carcinogens, such as PAHs and aromatic amines, may play a role in susceptibility to leukemogenesis in children. Presently, CYP1A1*2A[22], [23], [24], CYP2E1*5 [25], CYP2D6*3 [25], NAT1*4[23], NAT2 slow acetylator [23], GSTM1 null genotype [23], [24], [25], [26], and GSTP1*B [27], have been suggested to have effects on childhood leukemia risk. Furthermore, the most widely investigated polymorphism, the CYP1A1*2A (rs4646903, 1188C>T) which is potentially functional [28], has been reported to have a possible interactive effect with exposure to parental smoking [29], [30].

To better understand the role of smoking exposure and potential interactive effect with CYP1A1 polymorphisms in the development of childhood leukemia, we conducted a case–control study in Korea population using a haplotype approach to evaluate the association between CYP1A1 polymorphisms and childhood leukemia. We also conducted a meta-analysis to evaluate the association between paternal smoking and childhood leukemia risk.

Section snippets

Subjects

We conducted a hospital-based case–control study in Seoul, Korea. The protocol was reviewed and approved by the three participating hospitals (Seoul National University Hospital, Asan Medical Center and Samsung Medical Center). Histologically confirmed incident childhood leukemia cases (n = 176) aged 0–18 were recruited from these three teaching hospitals between May 2003 and May 2005. The histological subtypes of cases included acute lymphoblastic leukemia (ALL) (65%), acute myeloid leukemia

Results

Selected characteristics of the cases and controls are shown in Table 1. Childhood leukemia was more common in males (61.6%) compared to females (38.4%). The age distribution peaked at ages 3–4 (20.7%). Increasing birth weight was associated with increased childhood leukemia risk (Ptrend = 0.001). Duration of breast feeding, father's educational attainment, and family history of cancer were not significantly associated with childhood leukemia risk.

The lifetime smoking status of the father (never

Discussion

Our study suggests that paternal smoking increases the risk of childhood leukemia, especially ALL, and the effect may be modified by polymorphisms in CYP1A1, an enzyme which is responsible for activation of PAHs.

Many previous epidemiological studies found that prenatal paternal smoking is associated with increased risk of childhood leukemia [7], [14], [15], [16], [17]. Our meta-analysis of previous reports [7], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [29], showed that

Conflicts of Interest

None

Acknowledgements

We gratefully acknowledge the individuals who participated in the research and the clinicians who gave permission for us to approach their patients. This research was funded by Korea Electrotechnology Research Institute, Ministry of. Knowledge Economy (MKE) and by a grant of the Korea Health 21 R&D Project, Ministry of Health, Welfare and Family Affairs, Republic of Korea (A030001: 03-PJ10-PG13-GD01-0002).

Contribution. The principal investigators of the hospital-based case–control study in

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