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1.  Parental Smoking and Risk of Childhood Brain Tumors by Functional Polymorphisms in Polycyclic Aromatic Hydrocarbon Metabolism Genes 
PLoS ONE  2013;8(11):e79110.
A recent meta-analysis suggested an association between exposure to paternal smoking during pregnancy and childhood brain tumor risk, but no studies have evaluated whether this association differs by polymorphisms in genes that metabolize tobacco-smoke chemicals.
We assessed 9 functional polymorphisms in 6 genes that affect the metabolism of polycyclic aromatic hydrocarbons (PAH) to evaluate potential interactions with parental smoking during pregnancy in a population-based case-control study of childhood brain tumors. Cases (N = 202) were ≤10 years old, diagnosed from 1984–1991 and identified in three Surveillance, Epidemiology, and End Results (SEER) registries in the western U.S. Controls in the same regions (N = 286) were frequency matched by age, sex, and study center. DNA for genotyping was obtained from archived newborn dried blood spots.
We found positive interaction odds ratios (ORs) for both maternal and paternal smoking during pregnancy, EPHX1 H139R, and childhood brain tumors (Pinteraction = 0.02; 0.10), such that children with the high-risk (greater PAH activation) genotype were at a higher risk of brain tumors relative to children with the low-risk genotype when exposed to tobacco smoke during pregnancy. A dose-response pattern for paternal smoking was observed among children with the EPHX1 H139R high-risk genotype only (ORno exposure = 1.0; OR≤3 hours/day = 1.32, 95% CI: 0.52–3.34; OR>3hours/day = 3.18, 95% CI: 0.92–11.0; Ptrend = 0.07).
Parental smoking during pregnancy may be a risk factor for childhood brain tumors among genetically susceptible children who more rapidly activate PAH in tobacco smoke.
PMCID: PMC3832498  PMID: 24260161
2.  Paternal Smoking and Risk of Childhood Acute Lymphoblastic Leukemia: Systematic Review and Meta-Analysis 
Journal of Oncology  2011;2011:854584.
Objective. To investigate the association between paternal smoking and childhood acute lymphoblastic leukemia (ALL). Method. We identified 18 published epidemiologic studies that reported data on both paternal smoking and childhood ALL risk. We performed a meta-analysis and analyzed dose-response relationships on ALL risk for smoking during preconception, during pregnancy, after birth, and ever smoking. Results. The summary odds ratio (OR) of childhood ALL associated with paternal smoking was 1.11 (95% Confidence Interval (CI): 1.05–1.18, I2 = 18%) during any time period, 1.25 (95% CI: 1.08–1.46, I2 = 53%) preconception; 1.24 (95% CI: 1.07–1.43, I2 = 54%) during pregnancy, and 1.24 (95% CI: 0.96–1.60, I2 = 64%) after birth, with a dose-response relationship between childhood ALL and paternal smoking preconception or after birth. Conclusion. The evidence supports a positive association between childhood ALL and paternal ever smoking and at each exposure time period examined. Future epidemiologic studies should assess paternal smoking during well-defined exposure windows and should include biomarkers to assess smoking exposure and toxicological mechanisms.
PMCID: PMC3132639  PMID: 21765828
3.  Risk of childhood cancer and adult lung cancer after childhood exposure to passive smoke: A meta-analysis. 
We identified more than 30 studies on the association between exposure to maternal tobacco smoke during pregnancy and cancer in childhood. We combined their results in meta-analyses based on a random effects model. The results of the meta-analyses suggest a small increase in risk of all neoplasms [relative risk (RR) 1.10; 95% confidence interval (CI), 1.03-1.19; based on 12 studies], but not of specific neoplasms such as leukemia (RR 1.05; CI, 0.82-1.34; 8 studies) and central nervous system tumors (RR 1.04; CI, 0.92-1. 18; 12 studies). Results for other specific neoplasms were sparse, but the available data did not suggest a strong association for any type of tumor. No clear evidence of dose response was present in the studies that addressed this issue. The results on exposure to maternal tobacco smoke before or after pregnancy are too sparse to allow a conclusion. The results on exposure to paternal tobacco smoke suggest an association with brain tumors (RR 1.22; CI, 1.05-1. 40; based on 10 studies) and lymphomas (RR 2.08; CI, 1.08-3.98; 4 studies). The data are too sparse for the other neoplasms, although the results of a few recent large studies are compatible with a weak carcinogenic effect of paternal smoke. For exposure from either maternal or paternal smoke, bias and confounding cannot yet be ruled out. Further studies are needed to confirm the hypothesis that parental tobacco smoke, from the father in particular, is a risk factor of childhood cancer. Results on the risk of lung cancer in adulthood and childhood passive smoking exposure are available from 11 studies: they do not provide evidence of an increased risk (summary RR 0.91; CI, 0.80-1.05).
PMCID: PMC1637845  PMID: 10620527
4.  Birth weight and other perinatal characteristics and childhood leukemia in California 
Cancer epidemiology  2012;36(6):e359-e365.
We conducted a large registry-based study in California to investigate the association of perinatal factors and childhood leukemia with analysis of two major subtypes, acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML).
We linked California cancer and birth registries to obtain information on 5788 cases and 5788 controls matched on age and sex (1:1). We examined the association of birth weight, gestational age, birth and pregnancy order, parental ages, and specific conditions during pregnancy and risk of total leukemia, ALL and AML using conditional logistic regression, with adjustment for potential confounders.
The odds ratio (OR) per 1000 gram increase in birth weight was 1.11 for both total leukemia and ALL. The OR were highest for babies weighing ≥4,500g with reference <2,500g: 1.59 (95% CI: 1.05-2.40) and 1.70 (95% CI: 1.08-2.68) for total leukemia and ALL, respectively. For AML, increase in risk was also observed but the estimate was imprecise due to small numbers. Compared to average-for-gestational age (AGA), large-for-gestational age (LGA) babies were at slightly increased risk of total childhood leukemia (OR=1.10) and both ALL and AML (OR=1.07 and OR=1.13, respectively) but estimates were imprecise. Being small-forgestational age (SGA) was associated with reduced risk of childhood leukemia (OR=0.81, 95% CI: 0.67-0.97) and ALL (OR=0.77, 95% CI: 0.63-0.94), but not AML. Being first-born was associated with decreased risk of AML only (OR=0.70; 95% CI: 0.53-0.93). Compared to children with paternal age <25 years, children with paternal age between 35 and 45 years were at increased risk of total childhood leukemia (OR=1.12; 95% CI: 1.04-1.40) and ALL (OR=1.23; 95% CI: 1.04-1.47). None of conditions during pregnancy examined or maternal age were associated with increased risk of childhood leukemia or its subtypes.
Our results suggest that high birth weight and LGA were associated with increased risk and SGA with decreased risk of total childhood leukemia and ALL, being first-born was associated with decreased risk of AML, and advanced paternal age was associated with increased risk of ALL. These findings suggest that associations of childhood leukemia and perinatal factors depend highly on subtype of leukemia.
PMCID: PMC4034745  PMID: 22926338
childhood leukemia; birth weight; birth order; parental age; perinatal factors; pregnancy complications
5.  Socioeconomic Status and Other Characteristics in Childhood Leukemia 
Leukemia is the most prevalent childhood cancer, and Acute Lymphoblastic Leukemia (ALL) constitutes 75% of all cases. Some epidemiological studies have shown a relationship between socioeconomic status (SES) and some childhood cancers. In the present study, an attempt was made to assess socioeconomical status in a case-control study.
Materials and Methods
In 2010, a case-control study was conducted on 100 cases of acute lymphoblastic leukemia aged 1 to14 years in Department of Pediatric Oncology of Dr.Sheikh Hospital in Mashhad – Iran and matched age and sex with 400 healthy controls. Data was collected by interview using a questionnaire. Ninety five percent confidence intervals were used to measure the relationship between childhood Acute Lymphoblastic Leukemia and parental education, income status, father's job (Socioeconomic status), number of children, birth score and paternal smoking.
There was a significant difference in parental education level, income status, and number of children, birth score, father's job and paternal smoking between two groups. Regression analysis showed that the risk of childhood ALL associated with paternal smoking, and father's high risk job. Fifty percent cases and thirty five percent of control groups located in upper lower and lower middle class of socioeconomic status, respectively. There is a meaningful different between socioeconomic status in two groups. But the risk of childhood ALL did not associate with socioeconomic status.
The results suggest that paternal smoking and father’s high risk job are related to risk of childhood leukemia. It should be considered for planning support.
PMCID: PMC3915441  PMID: 24575261
Child; Leukemia; Social Class
6.  Tobacco Smoke Exposure and the Risk of Childhood Acute Lymphoblastic and Myeloid Leukemias by Cytogenetic Subtype 
Tobacco smoke contains carcinogens known to damage somatic and germ cells. We investigated the effect tobacco smoke on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML), especially subtypes of pre-natal origin like ALL with translocation t(12;21) or high-hyperdiploidy (51–67 chromosomes).
We collected information on exposures to tobacco smoking before conception, during pregnancy, and after birth in 767 ALL cases, 135 AML cases, and 1,139 controls (1996–2008). Among cases, chromosome translocations, deletions, or aneuploidy were identified by conventional karyotype and fluorescence in-situ hybridization.
Multivariable regression analyses for ALL and AML overall showed no definite evidence of associations with self-reported (yes/no) parental prenatal active smoking and child's passive smoking. However, children with history of paternal prenatal smoking combined with postnatal passive smoking had a 1.5-fold increased risk of ALL (95% CI: 1.01–2.23), compared to those without smoking history (ORs for pre- or postnatal smoking only were close to one). This joint effect was seen for B-cell precursor ALL with t(12;21) (OR=2.08; 95% CI: 1.04–4.16), but not high hyperdiploid B-cell ALL. Similarly, child's passive smoking was associated with an elevated risk of AML with chromosome structural changes (OR=2.76; 95% CI: 1.01–7.58), but not aneuploidy.
our data suggest that exposure to tobacco smoking before were associated with increased risks of childhood ALL and AML; and risks varied by timing of exposure (before and/or after birth) and cytogenetic subtype, based on imprecise estimates.
Parents should limit exposures to tobacco smoke before and after the child's birth.
PMCID: PMC3769478  PMID: 23853208
Childhood leukemia; tobacco smoking; cytogenetics
7.  Parental smoking during pregnancy and risk of overweight and obesity in the daughter 
Emerging evidence suggests that prenatal exposures may affect long-term health outcomes. In utero exposure to smoking is associated with an increased risk of overweight and obesity in children and adolescents. However, few studies have examined how prenatal exposure to parental smoking influences risk of obesity in adulthood and whether these associations are independent of childhood and adolescent adiposity. The aim of the current study was to investigate whether prenatal exposure to parental smoking influences body size in adulthood and whether any association may be mediated by childhood and adolescent body size.
We investigated the association between parental smoking during pregnancy and risk of overweight and obesity in adulthood and at age 18, and adiposity during childhood among 35,370 participants in the Nurses’ Health Study II. Data on smoking during pregnancy and socioeconomic variables were provided by the mothers, and anthropometric data and adult risk factors were reported by participants.
After adjustment for socioeconomic and behavioral variables, maternal smoking during pregnancy was associated with adiposity at ages 5–10, age 18, and during adulthood. For age 18 overweight the ORs (95% CIs) for 1–14, 15–24, and 25+cigarettes/day were 1.13 (1.18–1.50), 1.40 (1.20–1.64), and 1.15 (0.79–1.69) and for obesity were 1.41 (1.14–1.75), 1.69 (1.31–2.18), and 2.36 (1.44–3.86). The corresponding ORs (95% CIs) for obesity in adulthood were 1.26 (1.16–1.37), 1.46 (1.30–1.63), and 1.43 (1.10–1.86). Risk of adiposity was not increased among daughters whose mothers stopped smoking during the first trimester (OR [95% CI] for overweight (1.03 [95% CI 0.90–1.17] and obesity (1.12 [95% CI 0.97–1.30]). Women whose fathers smoked during pregnancy were also at increased risk of overweight and obesity in adulthood with covariate-adjusted ORs (95% CIs) for obesity of 1.19 (1.11–1.29) for 1–14 cigarettes/day, 1.27 (1.18–1.37) for 15–24 cigarettes/day, and 1.40 (1.27–1.54) for 25+ cigarettes/day compared to fathers who did not smoke (ptrend<0.0001). Paternal smoking during pregnancy was also associated with an increased risk of obesity at age 18 among those whose fathers smoked 15 or more cigarettes/day but was not associated with childhood body size.
Maternal smoking during pregnancy was associated in a dose-response manner with overweight and obesity in the daughter through adolescence and adult life. Smoking cessation during the first trimester appears to mitigate this excess risk.
Paternal smoking was also associated with risk of overweight and obesity of the adult daughter and this association persisted after adjustment for maternal smoking.
PMCID: PMC3795801  PMID: 23736356
pregnancy; prenatal programming; cigarette smoking; obesity
8.  Effects of SNPs (CYP1B1*2 G355T, CYP1B1*3 C4326G, and CYP2E1*5 G-1293C), Smoking, and Drinking on Susceptibility to Laryngeal Cancer among Han Chinese 
PLoS ONE  2014;9(10):e106580.
This study was conducted to explore the effects of genetic polymorphisms (CYP1B1*2 G355T, CYP1B1*3 C4326G, and CYP2E1*5 G-1293C) and environmental factors (smoking and drinking) on susceptibility to laryngeal cancer in a Han Chinese study group.
This case-control study included 552 Han Chinese patients diagnosed with laryngeal cancer and 666 healthy control subjects of the same ethnicity, similar age, and gender. Genetic polymorphisms were examined using multi-PCR and Matrix Assisted Laser Desorption Ionization - Time of Flight (MALDI-TOF MS) methodology. The association of these genetic and environmental factors with susceptibility to laryngeal cancer was evaluated using a statistical approach.
The frequencies of all three polymorphisms in the patient cohort were significantly different from those in the control cohort. Compared to the control cohort, carriers of variant alleles of CYP1B1*2 355T and CYP2E1*5 -1293C showed a higher risk for developing laryngeal cancer (for CYP1B1*2 355T, adjusted OR = 2.657, P <0.001; for CYP2E1*5 -1293C, adjusted OR = 1.938, P <0.001), while carriers of mutation allele CYP1B1*3 4326G showed a lower risk (adjusted OR = 0.562, P <0.001). Joint effects of these polymorphisms were observed. When compared to haplotype G355C4326G−1293, haplotypes T355C4326G−1293 (adjusted OR = 1.809, P <0.001), G355C4326C−1293 (adjusted OR = 1.644, P = 0.044), and T355C4326C−1293 (adjusted OR = 3.104, P <0.001) were associated with a significantly higher laryngeal cancer risk. The adjusted ORs for non-smokers, non-drinkers, smokers, and drinkers with the GT/TT genotype at CYP1B1*2 G355T were 2.190 (P = 0.006), 2.008 (P = 0.001), 5.875 (P <0.001), and 4.518 (P <0.001), respectively.
CYP1B1*2 355T and CYP2E1*5 -1293C are associated with an increased laryngeal cancer risk, while CYP1B1*3 4326G is associated with a decreased risk. These polymorphisms showed joint effects on laryngeal cancer risk. Smoking and drinking showed collaborative effects with two high risk alleles (CYP1B1*2 355T and CYP1B1*3 4326G) for promoting laryngeal cancer risk.
PMCID: PMC4191961  PMID: 25299224
9.  Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population 
BMC Cancer  2007;7:206.
The distribution and the potential gene-gene and gene-environment interaction of selected metabolic genetic polymorphisms was investigated in relation to gastric cancer risk in an Italian population.
One hundred and seven cases and 254 hospital controls, matched by age and gender, were genotyped for CYP1A1, CYP2E1, mEH, GSTM1, GSTT1, NAT2 and SULT1A1 polymorphisms. Haplotype analysis was performed for EPHX1 exons 3 and 4, as well as CYP2E1 RsaI (*5 alleles) and CYP2E1 DraI (*5A or *6 alleles). The effect modification by alcohol and cigarette smoking was tested with the heterogeneity test, while the attributable proportion (AP) was used to measure the biological interaction from the gene-gene interaction analysis.
Gastric cancer risk was found to be associated with the inheritance of GSTT1 null genotype (OR = 2.10, 95%CI: 1.27–3.44) and the SULT1A1 His/His genotype (OR = 2.46, 95%CI: 1.03–5.90). No differences were observed for the haplotype distributions among cases and controls. For the first time an increased risk was detected among individuals carrying the *6 variant allele of CYP2E1 if ever-drinkers (OR = 3.70; 95%CI: 1.45–9.37) with respect to never-drinkers (OR = 0.18; 95% CI: 0.22–1.46) (p value of heterogeneity among the two estimates = 0.001). Similarly, the effect of SULT1A1 variant genotype resulted restricted to ever-smokers, with an OR of 2.58 (95%CI: 1.27–5.25) for the carriers of His allele among smokers, and an OR of 0.86 (95%CI: 0.45–1.64) among never-smokers (p value of heterogeneity among the two estimates = 0.03). The gene-gene interaction analyses demonstrated that individuals with combined GSTT1 null and NAT2 slow acetylators had an additional increased risk of gastric cancer, with an OR of 3.00 (95%CI: 1.52–5.93) and an AP of 52%.
GSTT1, SULT1A1 and NAT2 polymorphisms appear to modulate individual's susceptibility to gastric cancer in this Italian population, particularly when more than one unfavourable genotype is present, or when combined with cigarette smoke. The increased risk for the carriers of CYP2E1*5A or *6 alleles among drinkers need to be confirmed by larger prospective studies.
PMCID: PMC2194718  PMID: 17996038
10.  Cigarette smoking, genetic polymorphisms and colorectal cancer risk: the Fukuoka Colorectal Cancer Study 
BMC Cancer  2010;10:274.
It is uncertain whether smoking is related to colorectal cancer risk. Cytochrome P-450 CYP1A1, glutathione-S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1) are important enzymes in the metabolism of tobacco carcinogens, and functional genetic polymorphisms are known for these enzymes. We investigated the relation of cigarette smoking and related genetic polymorphisms to colorectal cancer risk, with special reference to the interaction between smoking and genetic polymorphism.
We used data from the Fukuoka Colorectal Cancer Study, a population-based case-control study, including 685 cases and 778 controls who gave informed consent to genetic analysis. Interview was conducted to assess lifestyle factors, and DNA was extracted from buffy coat.
In comparison with lifelong nonsmokers, the odds ratios (OR) of colorectal cancer for <400, 400-799 and ≥800 cigarette-years were 0.65 (95% confidence interval [CI], 0.45-0.89), 1.16 (0.83-1.62) and 1.14 (0.73-1.77), respectively. A decreased risk associated with light smoking was observed only for colon cancer, and rectal cancer showed an increased risk among those with ≥400 cigarette-years (OR 1.60, 95% CI 1.04-2.45). None of the polymorphisms under study was singly associated with colorectal cancer risk. Of the gene-gene interactions studied, the composite genotype of CYP1A1*2A or CYP1A1*2C and GSTT1 polymorphisms was associated with a decreased risk of colorectal cancer, showing a nearly statistically significant (Pinteraction = 0.06) or significant interaction (Pinteraction = 0.02). The composite genotypes of these two polymorphisms, however, showed no measurable interaction with cigarette smoking in relation to colorectal cancer risk.
Cigarette smoking may be associated with increased risk of rectal cancer, but not of colon cancer. The observed interactions between CYP1A1 and GSTT1 polymorphisms warrant further confirmation.
PMCID: PMC2906477  PMID: 20534171
11.  Childhood cancer and parental use of tobacco: findings from the inter-regional epidemiological study of childhood cancer (IRESCC) 
British Journal of Cancer  2001;84(1):141-146.
Parental smoking data have been re-abstracted from the interview records of the Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC) to test further the hypothesis that paternal cigarette smoking is a risk factor for the generality of childhood cancer. Reported cigarette smoking habits for the parents of 555 children diagnosed with cancer in the period 1980–1983 were compared, in two separate matched pairs analyses, with similar information for the parents of 555 children selected from GP lists (GP controls) and for the parents of 555 hospitalized children (hospital controls). When cases were compared with GP controls there was a statistically significant positive trend (P = 0.02) between the risk of childhood cancer and paternal daily consumption of cigarettes before the pregnancy; there was no significant trend for maternal smoking habit. When cases were compared with hospital controls there was a statistically significant negative trend (P< 0.001) between the risk of childhood cancer and maternal daily consumption of cigarettes before the pregnancy; there was no significant trend for paternal smoking habit. Neither of the significant trends could be explained by adjustment for socioeconomic grouping, ethnic origin or parental age at the birth of the child, or by simultaneous analysis of parental smoking habits. Relations between maternal consumption of cigarettes and birth weights suggested that (maternal) smoking data were equally reliable for case and control subjects, although comparisons with national data suggested that the hospital control parents were unusually heavy smokers. These findings give some support for the hypothesis that paternal cigarette smoking is a potential risk factor for the generality of childhood cancers. © 2001 Cancer Research Campaign http://www.
PMCID: PMC2363626  PMID: 11139329
childhood cancer; smoking; case-control study
12.  CYP2C9 Variants Increase Risk of Colorectal Adenoma Recurrence and Modify Associations with Smoking but Not Aspirin Treatment 
Cancer causes & control : CCC  2012;24(1):47-54.
The cytochrome P450 2C9 enzyme (CYP2C9) is involved in metabolism of endogenous compounds, drugs and procarcinogens. Two common nonsynonymous polymorphisms in CYP2C9 are associated with reduced enzyme activity: CYP2C9*2 (rs1799853, R144C) and CYP2C9*3 (rs1057910, I359L).
We investigated whether CYP2C9 genotype was associated with risk of colorectal adenoma and/or modified associations with aspirin treatment or cigarette smoking in a cohort of 928 participants in a randomized trial of aspirin chemoprevention. Generalized linear regression was used to compute relative risks (RRs) and 95% confidence intervals (95% CIs). Multiplicative interactions terms were used to assess effect modification.
CYP2C9 genotype was associated with increased risks for adenoma recurrence of 29% (RR=1.29, 95% CI =1.09–1.51) for ≥1 variant allele (CYP2C9*2 or *3) and 47% (RR=1.47, 95% CI=1.19–1.83) for ≥1 CYP2C9*3 allele. The risk for advanced lesions or multiple (≥3) adenomas was increased by 64% (RR=1.64, 95% CI=1.18–2.28) for ≥1 variant allele (CYP2C9*2 or *3) and 79% (RR=1.79, 95% CI=1.16–2.75) for ≥1 CYP2C9*3 allele. Genotype modified associations with smoking, but not aspirin treatment. The adenoma risk was increased by 26% (RR=1.26, 95% CI=0.99–1.58) for former smokers and 60% (RR=1.60, 95% CI=1.19–2.15) for current smokers among wild-type individuals, but there was no increased risk among individuals with ≥1 variant allele (CYP2C9*2 or *3) (Pinteraction=0.04).
Carriers of CYP2C9 variants with lower enzyme activity have increased overall risk of colorectal adenoma but reduced adenoma risk associated with cigarette smoking. These results may be due to effects on the synthesis of endogenous eicosanoids and/or reduced activation of procarcinogens in smoke by CYP2C9 variants.
PMCID: PMC3529799  PMID: 23081681
colorectal neoplasia; CYP2C9; smoking; aspirin; polymorphism
13.  Childhood Exposure to Secondhand Smoke and Functional Mannose Binding Lectin Polymorphisms Are Associated with Increased Lung Cancer Risk 
Exposure to secondhand smoke during adulthood has detrimental health effects, including increased lung cancer risk. Compared with adults, children may be more susceptible to secondhand smoke. This susceptibility may be exacerbated by alterations in inherited genetic variants of innate immunity genes. We hypothesized a positive association between childhood secondhand smoke exposure and lung cancer risk that would be modified by genetic polymorphisms in the mannose binding lectin-2 (MBL2) gene resulting in well-known functional changes in innate immunity.
Childhood secondhand smoke exposure and lung cancer risk was assessed among men and women in the ongoing National Cancer Institute-Maryland Lung Cancer (NCI-MD) study, which included 624 cases and 348 controls. Secondhand smoke history was collected via in-person interviews. DNA was used for genotyping the MBL2 gene. To replicate, we used an independent case-control study from Mayo Clinic consisting of 461 never smokers, made up of 172 cases and 289 controls. All statistical tests were two-sided.
In the NCI-MD study, secondhand smoke exposure during childhood was associated with increased lung cancer risk among never smokers [odds ratio (OR), 2.25; 95% confidence interval (95% CI), 1.04-4.90]. This was confirmed in the Mayo study (OR, 1.47; 95% CI, 1.00-2.15). A functional MBL2 haplotype associated with high circulating levels of MBL and increased MBL2 activity was associated with increased lung cancer risk among those exposed to childhood secondhand smoke in both the NCI-MD and Mayo studies (OR, 2.52; 95% CI, 1.13-5.60, and OR, 2.78; 95% CI, 1.18-3.85, respectively).
Secondhand smoke exposure during childhood is associated with increased lung cancer risk among never smokers, particularly among those possessing a haplotype corresponding to a known overactive complement pathway of the innate immune system.
PMCID: PMC2951599  PMID: 19959685
14.  Parental risk factors and anorectal malformations: systematic review and meta-analysis 
Anorectal malformations (ARM) are rare forms of congenital uro-rectal anomalies with largely unknown causes. Besides genetic factors, prenatal exposures of the parents to nicotine, alcohol, caffeine, illicit drugs, occupational hazards, overweight/obesity and diabetes mellitus are suspected as environmental risk factors.
Relevant studies published until August 2010 were identified through systematic search in PubMed, EMBASE, ISI Web of Knowledge and the Cochrane Library databases. Furthermore, related and cross-referencing publications were reviewed. Pooled odds ratios (95% confidence intervals) were determined to quantify associations of maternal and paternal smoking, maternal alcohol consumption, underweight (body mass index [BMI] < 18.5), overweight (BMI 25-29.9), obesity (BMI ≥30) and maternal diabetes mellitus with ARM using meta-analyses.
22 studies that reported on the association between prenatal environmental risk factors and infants born with ARM were included in this review. These were conducted in the United States of America (n = 12), Spain (n = 2), Sweden (n = 2), the Netherlands (n = 2), Japan (n = 1), France (n = 1), Germany (n = 1) and Hungary (n = 1). However, only few of these studies reported on the same risk factors. Studies were heterogeneous with respect to case numbers, control types and adjustment for covariates. Consistently increased risks were observed for paternal smoking and maternal overweight, obesity and diabetes, but not for maternal smoking and alcohol consumption. In meta-analyses, pooled odds ratios (95% confidence intervals) for paternal smoking, maternal overweight, obesity, pre-gestational and gestational diabetes were 1.53 (1.04-2.26), 1.25 (1.07-1.47), 1.64 (1.35-2.00), 4.51 (2.55-7.97) and 1.81 (1.23-2.65), respectively.
Evidence on risk factors for ARM from epidemiological studies is still very limited. Nevertheless, the few available studies indicate paternal smoking and maternal overweight, obesity and diabetes to be associated with increased risks. Further, ideally large-scale multicentre and register-based studies are needed to clarify the role of key risk factors for the development of ARM.
PMCID: PMC3121580  PMID: 21586115
anorectal malformations; imperforate anus; anal atresia; birth defects; risk factors; pregnancy
15.  Environmental Tobacco Smoke in Relation to Bladder Cancer Risk – The Shanghai Bladder Cancer Study 
Environmental tobacco smoke (ETS) contains tobacco carcinogens. Hepatic cytochrome P450 (CYP) 1A2 and N-acetyltransferase (NAT2) are important isoenzymes in activation and detoxification, respectively, of tobacco carcinogens. Data on ETS and bladder cancer risk are sparse.
We examined the effects of ETS alone and combined with NAT2/CYP1A2 on bladder cancer risk among lifelong-nonsmokers in a case-control study involving 195 patients and 261 controls in Shanghai, China. A comprehensive history of ETS exposure was determined through in-person interviews while CYP1A2 and NAT2 phenotypes by a caffeine-based urinary assay.
ETS exposure was related to an overall statistically non-significant 38% increased bladder cancer risk. The risk increased with increasing number of cigarettes smoked by household members or number of hours per day at workplace where coworkers smoked. Compared with no ETS exposure, subjects living with smoking parents during childhood had an OR of 2.43 (95% CI=0.99–5.96) for bladder cancer. When all ETS sources were combined, the risk increased with increasing total ETS score (Ptrend = 0.03). The OR for high versus nil ETS exposure was 3.00 (95% CI =1.24–7.26). The increased risk with ETS was mainly seen among individuals possessing a CYP1A2 high efficiency and/or a NAT2 slow acetylation phenotype (Ptrend = 0.04).
ETS was associated with an increased bladder cancer risk for lifelong-nonsmokers. The association was stronger for people possessing the at-risk phenotypes of CYP1A2 and/or NAT2.
Reducing exposure to ETS for children and genetically more susceptible individuals could be more effective for bladder cancer prevention.
PMCID: PMC3003610  PMID: 21056942
16.  Variation in xenobiotic transport and metabolism genes, household chemical exposures, and risk of childhood acute lymphoblastic leukemia 
Cancer Causes & Control  2012;23(8):1367-1375.
Recent studies suggest that environmental exposures to pesticides, tobacco, and other xenobiotic chemicals may increase risk of childhood acute lymphoblastic leukemia (ALL). We sought to evaluate the role of genes involved in xenobiotic transport and metabolism in childhood ALL risk, both alone and in conjunction with household chemical exposures previously found to be associated with childhood ALL risk.
We conducted a population-based epidemiologic study of 377 cases and 448 controls in California, utilizing a haplotype-based approach to evaluate 42 xenobiotic transport and metabolism genes in conjunction with data on self-reported household chemical exposures.
We identified significant associations of childhood ALL risk with haplotypes of ABCB1, ARNT, CYP2C8, CYP1A2, CYP1B1, and IDH1. In addition, certain haplotypes showed significant joint effects with self-reported household chemical exposures on risk of childhood ALL. Specifically, elevated risks associated with use of paints in the home (ever) and indoor insecticides (pre-birth) were limited to subjects carrying specific haplotypes of CYP2C8 and ABCB1, respectively.
Our results provide support for a role of xenobiotic transport and metabolism pathways in risk of childhood ALL and indicate that genes in these pathways may modulate the risk of disease associated with use of common household chemicals. Additional studies are needed to confirm these findings and localize specific causal variants.
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-012-9947-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3390694  PMID: 22674224
Xenobiotic; Chemicals; California; Childhood cancer; Epidemiology
17.  Current and Former Smoking and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(9):e1001515.
In a meta-analysis of 32 observational studies involving 3,966,184 participants and 35,151 events, Suhua Wu and colleagues found that current, ever, and former smoking was associated with risk of venous thromboembolism.
Please see later in the article for the Editors' Summary
Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose–response relationship exists.
Methods and Findings
We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09–1.25) for ever smokers, 1.23 (95% CI 1.14–1.33) for current smokers, and 1.10 (95% CI 1.03–1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%–11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%–8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24–1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%–12.3%) for ever smoking, 5.8% (95% CI 3.6%–8.2%) for current smoking, and 2.7% (95% CI 0.8%–4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4–26.7) cases per 100,000 person-years.
Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE.
Please see later in the article for the Editors' Summary
Editors' Summary
Blood normally flows throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. Occasionally, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep within the body, usually in a leg, is called deep vein thrombosis (DVT) and can cause pain, swelling, and redness in the affected limb. DVT can be treated with drugs that stop the blood clot from getting larger (anticoagulants) but, if left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are collectively known as venous thromboembolism (VTE). Risk factors for VTE include having an inherited blood clotting disorder, oral contraceptive use, prolonged inactivity (for example, during a long-haul plane flight), and having surgery. VTEs are present in about a third of all people who die in hospital and, in non-bedridden populations, about 10% of people die within 28 days of a first VTE event.
Why Was This Study Done?
Some but not all studies have reported that smoking is also a risk factor for VTE. A clear demonstration of a significant association (a relationship unlikely to have occurred by chance) between smoking and VTE might help to reduce the burden of VTE because smoking can potentially be reduced by encouraging individuals to quit smoking and through taxation policies and other measures designed to reduce tobacco consumption. In this systematic review and meta-analysis, the researchers examine the link between smoking and the risk of VTE in the general population and investigate whether heavy smokers have a higher risk of VTE than light smokers. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 32 observational studies (investigations that record a population's baseline characteristics and subsequent disease development) that provided data on smoking and VTE. Together, the studies involved nearly 4 million participants and recorded 35,151 VTE events. Compared with never smokers, ever smokers (current and former smokers combined) had a relative risk (RR) of developing VTE of 1.17. That is, ever smokers were 17% more likely to develop VTE than never smokers. For current smokers and former smokers, RRs were 1.23 and 1.10, respectively. Analysis of only studies that adjusted for body mass index (a measure of body fat and a known risk factor for conditions that affect the heart and circulation) yielded a slightly higher RR (1.30) for current smokers compared with never smokers. For ever smokers, the population attributable fraction (the proportional reduction in VTE that would accrue in the population if no one smoked) was 8.7%. Notably, the risk of VTE increased by 10.2% for every additional ten cigarettes smoked per day and by 6.1% for every additional ten pack-years. Thus, an individual who smoked one pack of cigarettes per day for 40 years had a 26.7% higher risk of developing VTE than someone who had never smoked. Finally, smoking was associated with an absolute risk increase of 24.3 cases of VTE per 100,000 person-years.
What Do These Findings Mean?
These findings indicate that cigarette smoking is associated with a statistically significant, slightly increased risk for VTE among the general population and reveal a dose-relationship between smoking and VTE risk. They cannot prove that smoking causes VTE—people who smoke may share other unknown characteristics (confounding factors) that are actually responsible for their increased risk of VTE. Indeed, these findings identify body mass index as a potential confounding factor that might affect the accuracy of estimates of the association between smoking and VTE risk. Although the risk of VTE associated with smoking is smaller than the risk associated with some well-established VTE risk factors, smoking is more common (globally, there are 1.1 billion smokers) and may act synergistically with some of these risk factors. Thus, smoking behavior should be considered when screening individuals for VTE and in the prevention of first and subsequent VTE events.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolism), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, and on pulmonary embolism; SmokeFree is a website provided by the UK National Health Service that offers advice on quitting smoking
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
The World Health Organization provides information about the dangers of tobacco (in several languages), from the US National Cancer Institute, offers online tools and resources to help people quit smoking
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and the dangers of smoking (in English and Spanish)
PMCID: PMC3775725  PMID: 24068896
18.  Paternal age at birth is associated with offspring leukocyte telomere length in the nurses' health study 
Human Reproduction (Oxford, England)  2012;27(12):3622-3631.
Is the association between paternal age at birth and offspring leukocyte telomere length (LTL) an artifact of early life socioeconomic status (SES)?
Indicators of early life SES did not alter the relationship between paternal age at birth and offspring LTL among a population of white female nurses.
Telomere length is considered a highly heritable trait. Recent studies report a positive correlation between paternal age at birth and offspring LTL. Maternal age at birth has also been positively associated with offspring LTL, but may stem from the strong correlation with paternal age at birth.
The Nurses' Health Study (NHS) is an ongoing prospective cohort study of 121 700 female registered nurses who were enrolled in 1976. Great effort goes into maintaining a high degree of follow-up among our cohort participants (>95% of potential person-years). In 1989–1990, a subset of 32 826 women provided blood samples from which we selected participants for several nested case–control studies of telomere length and incident chronic disease. We used existing LTL data on a total of 4250 disease-free women who also reported maternal and paternal age at birth for this study.
Nested case–control studies of stroke, myocardial infarction, cancers of the breast, endometrium, skin, pancreas and colon, as well as colon adenoma, were conducted within the blood sub-cohort. Each study used the following study design: for each case of a disease diagnosed after blood collection, a risk-set sampling scheme was used to select from one to three controls from the remaining participants in the blood sub-cohort who were free of that disease when the case was diagnosed. Controls were matched to cases by age at blood collection (±1 year), date of blood collection (±3 months), menopausal status, recent postmenopausal hormone use at blood collection (within 3 months, except for the myocardial infarction case–control study), as well as other factors carefully chosen for each individual study. The current analysis was limited to healthy controls. We also included existing LTL data from a small random sample of women participating in a cognitive sub-study. LTL was measured using the quantitative PCR-based method. Exposure and covariate information are extracted from biennial questionnaires completed by the participants.
We found a strong association between paternal age at birth and participant LTL (P = 1.6 × 10–5) that remained robust after controlling for indicators of early life SES. Maternal age at birth showed a weak inverse association with participant LTL after adjusting for age at blood collection and paternal age at birth (P = 0.01). We also noted a stronger association between paternal age at birth and participant LTL among premenopausal than among postmenopausal women (Pinteraction = 0.045). However, this observation may be due to chance as premenopausal women represented only 12.6% (N = 535) of the study population and LTL was not correlated with age at menopause, total or estrogen-only hormone therapy (HT) use suggesting that changes in in vivo estrogen exposure do not influence telomere length regulation.
The women in our study are not representative of the general US female population, with an underrepresentation of non-white and low social class groups. Although the interaction was not significant, we noted that the paternal age at birth association with offspring LTL appeared weaker among women whose parents did not own their home at the time of the participant's birth. As telomere dynamics may differ among individuals who are most socioeconomically deprived, SES indicators may have more of an influence on the relationship between paternal age at birth and offspring LTL in such populations.
As of yet, our and prior studies have not identified childhood or adult characteristics that confound the paternal age at birth association with offspring LTL, supporting the hypothesis that offspring may inherit the longer telomeres found in sperm of older men. The biological implications of the paternal age effect are unknown. A recent theory proposed that the inheritance of longer telomere from older men may be an adaptive signal of reproductive lifespan, while another theory links telomere length attrition to female reproductive senescence. However, we are unaware of any data to substantiate a relationship between paternal age at birth and daughter's fertility. Generalizability of our study results to other white female populations is supported by prior reports of paternal age at birth and offspring telomere length. Furthermore, a confounding relationship between paternal or maternal age at birth and SES was not observed in a study of SES and telomere length.
This work was supported by the National Institutes of Health (grants numbers: CA87969, CA49449, CA065725, CA132190, CA139586, HL088521, CA140790, CA133914, CA132175, ES01664 to M.D.); and by the American Health Association Foundation. We have no competing interests to declare.
PMCID: PMC3501241  PMID: 22940768
epidemiology; telomere; paternal age; maternal age; social class
19.  Critical role of smoking and household dampness during childhood for adult phlegm and cough: a research example from a prospective cohort study in Great Britain 
BMJ Open  2014;4(4):e004807.
To examine independent associations between childhood exposures to smoking and household dampness, and phlegm and cough in adulthood.
A prospective cohort study.
7320 of the British cohort who were born during 1 week in 1970 and had complete data for childhood and adult information.
Main outcome measures
Experiences of phlegm and coughing over the previous 3 months were assessed using questions from the Medical Research Council (MRC) Questionnaire on respiratory symptoms when the cohort participants were 29 years of age. 4 response patterns (no symptoms, phlegm only, cough only, both symptoms present) were created based on the responses to these questions.
Childhood smoking and exposure to marked household dampness at age 10 were associated with phlegm (childhood smoking: relative risk ratio (RRR)=1.45, 95% CI 1.02 to 2.05; dampness: RRR=2.05, 95% CI 1.07 to 3.91) and co-occurring cough and phlegm (childhood smoking: RRR=1.35. 95% CI 1.08 to 1.67; dampness: RRR=2.73, 95% CI 1.88 to 3.99), while exposure to two or more adult smokers in the household was associated with cough-related symptoms (cough only: RRR=1.28, 95% CI 1.04 to 1.58; phlegm and cough: RRR=1.32, 95% CI 1.06 to 1.64). These associations were independent from adult smoking, childhood phlegm and cough, early social background and sex. Current smoking at age 29 contributed to all symptom patterns; however, a substantial association between household dampness and co-occurring phlegm and cough suggest long-term detrimental effects of childhood environmental exposures.
Our findings give support to current public health interventions for adult smoking and raise concerns about the long-term effects of a damp home environment on the respiratory health of children.
PMCID: PMC4010851  PMID: 24747796
BCS70; Household Dampness; Adult Respiratory Health; Life Course Study
20.  Polymorphisms in genes involved in the estrogen pathway and mammographic density 
BMC Cancer  2010;10:636.
Single nucleotide polymorphisms (SNPs) in genes involved in the estrogen pathway appear to be associated with breast cancer risk and possibly with mammographic density (MD), but little is known of these associations among premenopausal women. This study examines the association of 11 polymorphisms in five estrogen-related genes (estrogen receptors alpha and beta (ERα, ERβ), 17β-hydroxysteroid dehydrogenase 1 (HSD17B1), catechol-O-methyltransferase (COMT), cytochrome P450 1B1 (CYP1B1)) with premenopausal MD. Effect modification of four estrogen-related factors (parity, age at menarche, hormonal derivatives use and body mass index (BMI)) on this relation is also assessed.
Polymorphisms were genotyped in 741 premenopausal Caucasian women whose MD was measured in absolute density (AD, cm2) and percent density using a computer-assisted method. Multivariate linear models were used to examine the associations (Ptrend) and interactions (Pi).
None of the SNPs showed a statistically significant association with AD. However, each additional rare allele of rs1056836 CYP1B1 was associated with a reduction in AD among nulliparous women (Ptrend = 0.004), while no association was observed among parous women (Ptrend = 0.62; Pi = 0.02). An increase in the number of rare alleles of the HSD17B1 SNP (rs598126 and rs2010750) was associated with an increase in AD among women who never used hormonal derivatives (Ptrend = 0.06 and Ptrend = 0.04, respectively), but with a decrease in AD among past hormonal derivatives users (Ptrend = 0.04; Pi = 0.02 and Ptrend = 0.08; Pi = 0.01, respectively). Moreover, a negative association of rs598126 HSD17B1 SNP with AD was observed among women with higher BMI (>median) (Ptrend = 0.01; Pi = 0.02). A negative association between an increased number of rare alleles of COMT rs4680 SNP and AD was limited to women who never used hormonal derivatives (Ptrend = 0.02; Pi = 0.03) or with late age at menarche (>median) (Ptrend = 0.03; Pi = 0.02). No significant association was observed between polymorphisms in the ERα or ERβ genes and AD. Similar results, although less significant, were observed when MD was assessed in percent density.
SNPs located in CYP1B1, COMT or HSD17B1 genes seem to be associated with MD in some strata of estrogen-related factors. Our findings suggest that modifying effects of estrogen-related factors should be considered when evaluating associations of polymorphisms in estrogen-related genes with premenopausal mammographic density.
PMCID: PMC3000407  PMID: 21092186
21.  Parental smoking and childhood refractive error: the STARS study 
Eye  2012;26(10):1324-1328.
To assess the relationship between parental smoking and childhood refractive errors in Singapore Chinese children aged 6–72 months recruited through the STrabismus, Amblyopia, and Refractive errors in Singaporean children study.
A total of 4164 children were recruited, with a positive response rate of 72.3% (n=3009). Cycloplegic refraction measurements were obtained from all children by trained eye professionals. Parents underwent an interviewer-administered questionnaire with information on demographics, lifestyle, and parental smoking history being obtained.
Spherical equivalent readings were obtained for 87.7% of the children. In all, 52.1% were male (n=1375). The overall prevalence of myopia (at least −0.5 D) was 11.0%. Overall, 37.1% of the fathers interviewed gave a history of smoking. Among the mothers interviewed, 9.2% gave a history of smoking, 6.6% had smoked during the child's life, and 2.2% had smoked during the pregnancy. Maternal history of ever smoking, smoking during child's life, and smoking during pregnancy were associated with decreased odds ratio (OR) of childhood myopia (OR 0.50 (P=0.01), OR 0.39 (P=0.01), and OR 0.3 (P=0.14), respectively). Paternal history of smoking was associated with decreased OR of childhood myopia (OR of 0.72 (P=0.02)).
In light of this finding of an inverse association between parental smoking and childhood myopia, further studies are suggested to better understand the role of nicotinic acetylcholine receptor pharmacology in ocular development. This may pave the way for the development of targeted treatment strategies for prevention of myopia.
PMCID: PMC3470050  PMID: 22935668
myopia; smoking; parental
22.  X-Ray Repair Cross-Complementing Group 1 (XRCC1) Genetic Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia: A Meta-Analysis 
PLoS ONE  2012;7(4):e34897.
Recently, there have been a number of studies on the association between XRCC1 polymorphisms and childhood acute lymphoblastic leukemia (ALL) risk. However, the results of previous reports are inconsistent. Thus, we performed a meta-analysis to clarify the effects of XRCC1 variants on childhood ALL risk.
A meta-analysis was performed to examine the association between XRCC1 polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) and childhood ALL risk. We critically reviewed 7 studies with a total of 880 cases and 1311 controls for Arg399Gln polymorphism, 3 studies with a total of 345 cases and 554 controls for Arg280His polymorphism, and 6 studies with a total of 783 cases and 1180 controls for Arg194Trp polymorphism, respectively. Odds ratio (OR) and its 95% confidence interval (CI) were used.
Significant association between XRCC1 Arg399Gln polymorphism and childhood ALL risk was observed in total population analyses (ORadditive model = 1.501, 95% CI 1.112–2.026, POR = 0.008; ORdominant model = 1.316, 95% CI = 1.104–1.569, POR = 0.002) and Asian subgroup analyses (ORadditive model = 2.338, 95%CI = 1.254–4.359, POR = 0.008; ORdominant model = 2.108, 95%CI = 1.498–2.967, POR = 0.000). No association was detected in Caucasians, Metizo and mixed populations. Ethnicity was considered as a significant source of heterogeneity in the meta-regression model. For the other two XRCC1 polymorphisms, no association with childhood ALL risk was found.
The meta-analysis results suggested that XRCC1 Arg399Gln polymorphism might be associated with elevated childhood ALL risk among Asian population.
PMCID: PMC3329555  PMID: 22529951
23.  A Meta-Analysis of Parental Smoking and the Risk of Childhood Brain Tumors 
PLoS ONE  2014;9(7):e102910.
Previous studies regarding the association between parental smoking and the risk of childhood brain tumors (CBT) have reported inconsistent results. We performed a meta-analysis to summarize evidence on this association and to quantify the potential dose-response relationship.
A systematic literature search was conducted in the Medline and Embase databases. The summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Dose–response meta-analysis was also performed for studies that reported categorical risk estimates for a series of smoking exposure levels.
A total of 17 studies fulfilled the inclusion criteria. In the meta-analyses, the summary RRs (95% CIs) of CBT for maternal smoking during pregnancy, paternal smoking during pregnancy, maternal smoking before pregnancy, and paternal smoking before pregnancy were 0.96 (0.86–1.07), 1.09 (0.97–1.22), 0.93 (0.85–1.00), and 1.09 (1.00–1.20), respectively. Dose-response meta-analysis also showed no significant association between parental smoking and the risk of CBT.
Findings from our meta-analysis indicate that parental smoking may not be associated with a risk of CBT.
PMCID: PMC4109951  PMID: 25058491
24.  Tobacco Smoke and Risk of Childhood Acute Non-Lymphocytic Leukemia: Findings from the SETIL Study 
PLoS ONE  2014;9(11):e111028.
Parental smoking and exposure of the mother or the child to environmental tobacco smoke (ETS) as risk factors for Acute non-Lymphocytic Leukemia (AnLL) were investigated.
Incident cases of childhood AnLL were enrolled in 14 Italian Regions during 1998–2001. We estimated odds ratios (OR) and 95% confidence intervals (95%CI) conducting logistic regression models including 82 cases of AnLL and 1,044 controls. Inverse probability weighting was applied adjusting for: age; sex; provenience; birth order; birth weight; breastfeeding; parental educational level age, birth year, and occupational exposure to benzene.
Paternal smoke in the conception period was associated with AnLL (OR for ≥11 cigarettes/day  = 1.79, 95% CI 1.01–3.15; P trend 0.05). An apparent effect modification by maternal age was identified: only children of mothers aged below 30 presented increased risks. We found weak statistical evidence of an association of AnLL with maternal exposure to ETS (OR for exposure>3 hours/day  = 1.85, 95%CI 0.97–3.52; P trend 0.07). No association was observed between AnLL and either maternal smoking during pregnancy or child exposure to ETS.
This study is consistent with the hypothesis that paternal smoke is associated with AnLL. We observed statistical evidence of an association between maternal exposure to ETS and AnLL, but believe bias might have inflated our estimates.
PMCID: PMC4234298  PMID: 25401754
25.  Roles of Arginase variants, Atopy and Ozone in Childhood Asthma 
Arginases (encoded by ARG1 and ARG2 genes) may play an important role in asthma pathogenesis through effects on nitrosative stress. Arginase expression is upregulated in asthma and varies with T helper type-2 cytokine levels and oxidative stress.
We aimed to examine whether variants in these genes are associated with asthma, and whether atopy, and exposures to smoking and air pollution influence the associations.
Among non-Hispanic and Hispanic white participants of the Children’s Health Study (N=2,946), we characterized variation in each locus (including promoter region) with 6 tagSNPs for ARG1 and 10 for ARG2. Asthma was defined by parental report of physician-diagnosed asthma at study entry.
Both ARG1 and ARG2 genetic loci were significantly associated with asthma (global locus level p-values=0.02 and 0.04, respectively). Compared to the most common haplotype within each locus, one ARG1 haplotype was associated with reduced risk (odds ratio (OR) per haplotype copy=0.55; 95% confidence interval (CI): 0.36–0.84) and one ARG2 haplotype was associated with increased risk (OR per haplotype copy=1.35; 95% CI: 1.04–1.76) of asthma. The effect of the ARG1 haplotype that was significantly associated with asthma varied by child’s history of atopy and ambient ozone (Pinteraction=0.04 and 0.02, respectively). Among atopic children living in high ozone communities, those carrying the ARG1 haplotype had reduced asthma risk (OR per haplotype copy=0.12; 95% CI: 0.04–0.43; Pheterogeneity across atopy/ozone categories=0.008).
ARG1 and ARG2 loci are associated with childhood asthma. The association between ARG1 variation and asthma may depend on atopy and ambient ozone.
PMCID: PMC2913574  PMID: 19281908
air pollution; asthma genetics; atopy; gene-environment interaction; nitrosative stress

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