Alcohol and Alcoholism Advance Access published online on January 18, 2008
Alcohol and Alcoholism, doi:10.1093/alcalc/agm155
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Cytogenetic effects of ethanol on chronic alcohol users
temirDepartment of Medical Biology and Genetics, Medical Faculty, Çukurova University, Adana, Turkey
* Author to whom correspondence should be addressed at: Department of Medical Biology and Genetics, Medical Faculty, Çukurova University, 01330, Balcali, Adana, Turkey. Tel: (+90) 322 3387140; Fax: (+90) 322 3386572; E-mail: osdemir{at}cu.edu.tr
Received 23 June 2007; first review notified 20 August 2007; in revised form 5 September 2007; accepted 11 September 2007
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ABSTRACT |
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Aim: Alcoholism is a significant public health problem that is also associated with a complex genetic trait. Fragile sites (FS) are potentially informative endpoints for the study of clinical disorders. We aimed to find chromosomal damages in chronic alcohol users for the purpose of finding the correlation between alcohol and chromosomal anomalies. Methods: The potential roles/effects of ethanol on chromosome(s) were assessed in this study by investigating its cytotoxic effects in lymphocyte cultures from chronic alcoholics and controls. Results: Alcoholics revealed a significantly higher frequency of FS and chromosomal aberrations (CA), and the FS clusters in specific chromosomal regions: 1q12, 1q21, 1q32, 2p13, 2q21, 2q31, 3p14, 3p25, 3q21, 4q21, 4q31, 5q31, 6p21, 7q22, 7q32, 9q13, 9q22, 10q22, 11q23, and 12q13. We also observed a significantly greater number of numerical and structural CA in alcoholics. The most frequent exchange types were deletions and polymorphic variations. CA could be due to the cumulative effect of both alcohol and smoking. The loci 1q12, 3p25, 4q31, 6p21, and 12q13 were not reported previously in alcoholics and may be hot spots for alcoholism. The overall FS frequencies were not statistically different between smoker and non-smoker controls, but smoking significantly increased the expression of 1p36, 3q21, and 5p15 sites. These sites have important clinical significance. Conclusions: Chronic alcohol abuse and the smoking habit can lead to chromosome damages that are especially influential on oncogenic regions, which may persist for a long time, and constitute a relevant factor of risk for the development of neoplasias.
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Introduction |
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Alcoholism is the outcome of complex interactions between the environment and multiple gene loci. Alcohol can act as a carcinogenic chemical, and it's genotoxic effects have been demonstrated in vivo and in vitro (Chang et al., 1992
). The toxic effects of alcohol are mediated at least partially by damaging DNA. DNA damages also show susceptibility to chromosomal fragile sites (FS), and if not repaired, may lead to chromosome damage, such as deletions within the FS, translocations, or other rearrangements involving breakage at a FS (Stein et al., 2002). FS are non-staining gaps and breaks in specific points of chromosomes. They are divided into two classes on the basis of their frequency in the general population: common FS (cFS) with a high frequency and rare FS (rFS) with a low frequency. Most rFS can be induced by thymidylate stress caused by medium deficiency in folic acid or thymidine. The rFS on chromosomes are archetypal dynamic mutations. They involve large expansions of the microsatellite CCG repeats or AT-rich minisatellites. cFS are predisposed chromosomal breakage regions. It is known that these sites extend over large regions and are associated with genes that exhibit late or delayed replication and contain regions with high variability. FS have been suggested to predispose to specific translocations and deletions in vivo. Chromosome translocations with breakpoints at FS may be useful in gene mapping.
A significant increase in the frequency of structural and numerical chromosomal aberrations (CA) has been observed in lymphocytes of chronic alcoholics as compared with controls (Obe et al., 1980; Obe and Andersoni, 1987; Huttner et al., 1999). Alcoholics also have a higher frequency of sister chromatid exchanges in their lymphocytes as compared with non-alcoholics (Lazutka et al., 1992). Some studies also confirmed that CA and micronuclei occur more frequently in lymphocytes of alcoholics than in age- and sex-matched controls (Castelli et al., 1999; Maffei et al., 2002).
To further confirm these earlier reports and to identify any additional susceptibility loci for alcohol dependence, we performed a cytogenetic analysis of alcoholics, with the aim of finding chromosomal FS and CA related to dependence on ethanol.
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Materials and Methods |
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Study population
The study involved 80 chronic alcohol users and 58 controls. Alcoholics were selected from a psychiatric and neurologic diseases hospital located in Adana, Turkey, between October 2001 and December 2004. Alcoholics (all males) were identified through alcohol treatment programmes at this hospital. They were invited to participate and were asked to complete the semi-structured assessment form for the study. The subjects were diagnosed by clinical interview, as having severe alcohol dependence, according to the DSM-III-R alcohol-dependence diagnosis (American Psychiatric Association, 1994
). The age of the patients ranged from 19 to 66 years, with a mean age of 41.5 ± 9.3 years. The alcoholics included in the study suffered from alcohol dependence syndrome and had received periodic psychotherapy sessions and clinical examinations for the treatment of alcohol-related diseases. After informed consent, each participant was extensively interviewed, providing important detailed information for the study. Sex, age, smoking, work-related exposure to hazardous agents, dietary habits, use of therapeutic drugs, health problems, and alcohol consumption were all reported. All patients were smokers, the number of cigarettes smoked daily ranged from 30 to 40 for 10 years or more. None of the subjects had known genetic disorders, a history of severe medical illness, or occupational chemical exposure. The alcoholics had a daily intake of pure alcohol of >70 g (Turkish raki, beer, and spirits) and can be considered as heavy alcoholic beverage drinkers (Muller et al., 1999). None of them had a deficient diet or had a major change in dietary habits during their alcohol dependence. They were taking two diazem tablets and other SSRI (Selective Serotonine Reuptake Ynhibitors) per day according to their psychotic levels. Controls numbering 58 healthy volunteers (20 smokers and 38 non-smokers), who presented absence of continued alcohol, were matched for age and sex. Ages of the controls ranged from 19 to 65 years with a mean age of 40.4 ± 10.1 years. They were from the same ethnic groups and lived in the same geographic areas as the patients. None of the controls had a deficient diet. Twenty of them smoked, on average, 20 cigarettes a day (range, 3–40 cigarettes) for an average 18 years (range, 5–40 years). The study was granted ethical approval by the local health committee.
Cytogenetic analysis
Peripheral blood was taken from each subject for culture. Each sample was examined for expression of folate-sensitive FS in the Genetics Laboratory of the Department of Medical Biology and Genetics, Faculty of Medicine, Çukurova University. A 0.3-ml blood sample was incubated at 37°C for 72 h in a folic acid-free medium (RPMI-1640, Sigma R6767 without folic acid) supplemented with 4% fetal calf serum, phytohemagglutinin, L-Glutamin, streptomycin, and penicillin. Standard cytogenetic techniques were used for harvesting and slide preparation. Three slides were prepared for each subject. The slides were stained only with Giemsa before examination in order to avoid missing any gaps. For detailed analysis of the FS, some slides were prepared by trypsin G-banding and 50 metaphases/individuals were analysed on coded slides for structural CA, such as chromatid and chromosome breaks, deletions, acentric fragments, di-centric chromosomes, tetraploids, quadriradial exchange figures, and chromosomal exchanges. Fragilities and gaps were also scored, but excluded from the final percentage of cells with CA. All gaps and breaks were recorded according to the ISCN (1985). The classification of FS was done according to the nomenclature established in human gene mapping HGM 11 (McAlpine et al., 1991).
For statistical analysis, the SPSS 11.0 software programme was used. The 
2 test was applied to determine the significance of the difference between the alcoholic and the control groups in FS frequency, and in the number of subjects with fragility at specific sites.
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Results |
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A total of 80 alcoholics and 58 controls were analysed cytogenetically. In patients, the aberrations were found in 1444 (36.1%) abnormal cells of 3974 cells analysed. In the control group, the aberrations were found in 324 (11.4%) abnormal cells among 2850 analysed cells. There was a significant difference in the total number of FS expressed and in the number of abnormal cells between alcoholics and all controls by the
2 test (P < 0.001). The alcoholics had a higher incidence of FS. The number of aberrations per person was also higher than in the control group (P < 0.001), but the difference was not statistically significant between the smoker-control and non-smoker-control groups (P > 0.05) (Fig. 1).
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The distribution of FS according to each chromosome is shown in Table 1. Analysis of the distribution of fragile points on chromosomes revealed that the fragilities were clustered on certain loci of chromosomes 1–7 and 9–12 in the alcoholic group. Among these expressed FS, there was a significant higher frequency of 20 fragile regions in decreasing order at 5q31, 1q32, 1q21, 3p14, 7q22, 3p25, 2q31, 4q31, 11q23, 3q21, 9q13, 1q12, 2p13, 12q13, 10q22, 6p21, 4q21, 9q22, 7q32, and 2q21 in alcoholics than in all controls by the
2 test (P < 0.001–0.029) (Table 1) (Fig. 2). A number of different regions were identified in one or more individuals from per-individual analysis. Among these expressed FS, the 2q21, 3p25, 3p14, 3q21, 6p21, 7q32, 9q13, 9q22, 10q22, and 11q23 loci were never expressed in the smoker-control group (Table 1). These 10 regions were considered as being connected with alcohol. Within the control group, statistical analysis showed that the frequency of total anomalies was not significantly different in the smoker controls compared with the non-smoker controls (P = 0.871), however, only 1p36, 3q21 and 5p15 fragile regions were found to be significantly higher in the smokers (P < 0.039–0.047). Duration of smoking had no effect on the FS frequencies in the alcoholics or controls (P > 0.05).
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Table 2 summarizes the CA and lifestyle characteristics of the study population. The frequencies of FS were not associated with the duration of alcohol exposure in years (P > 0.05). In addition, no significant correlation was found between the age of subjects of both groups and the FS frequencies (P > 0.05). There was a significant difference in the total number of chromosome breaks and number of cells with breaks between patients and controls as determined by the
2 test (P < 0.001). Both structural and numerical changes were observed in 38 cases (47.5%). The number of cells with breaks, and the genomic damage frequencies, were higher in the patients (Table 1). The chromosome breaks were more frequent than the chromatid-type breaks. Chromosomes 9 and 22 were found to be the most frequent structural abnormalities (Table 2). The polymorphic variations of the heterochromatic regions and pericentric inversion of chromosome 9 [inv(9)(p11;q13)] were found in 24 (30%) of 80 alcoholics, which was nearly two times higher than in the controls (14%). We observed a significantly greater number of single-cell translocations in alcoholics (Table 2), 3 (27%) of 11 deletions had the breakpoint at 22q12–13. The other deletions observed the breakpoints at 1q31, 2q31, 4p, 10p11, 13p, and Xq24 (Table 2). Numerical changes were seen in one or three cells of 70 alcoholics. In patient 65, a Klinefelter's karyotype, 47,XXY, was present in 3% of the cells, and the del(3)(p14 
ter) was found in one cell. The others (mar, min, ace) were seen only in one of 50 cells. Patients 4, 11, 14, 16, 25, 39, 40, 52, 53, 57, 63, 64, and 75 had multiple anomalies. Interestingly, acentric fragments, marker chromosomes, and minute fragments were observed only among patients. The heterochromatin loss of the Y chromosome, 46,XY,Yqh–, was observed in one patient (P75). This may confirm a breakpoint on the q arm of the Y chromosome. Nearly 62% (36/58) of alcoholics had a family history of alcoholism (father: 72.2, mother: 2.8, brother: 30.6, and the first-degree relatives: 36.1% respectively). The average number of years of regular alcohol use was about 20 (Table 2).
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Discussion |
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The characterization of FS has demonstrated that they are associated with genes that relate to tumorigenesis and behavioural disorders (Gericke, 1998
; Arrieta et al., 2002). Identification of the basis of instability at FS and the related genes provides an entree to understanding the important aspects of chromosomal instability, which is a prominent feature of alcoholism. It has been proposed that free radicals formed in association with the metabolism of ethanol may lead to the formation of chromosome damage in individuals with heavy alcohol consumption over many years (Burim et al., 2004). The results obtained in the present study indicate that alcoholics had a higher incidence of FS. It may be considered that the expression of FS could be an indicator of chromosomal instability within the genome of alcoholics. The FS were found in specific regions of chromosomes 1–7 and 9–12 in our patients (Table 1) (Fig. 2).
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and smoker control group 
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means 10 aberrations and, 
means 1 aberration for alcoholics and smoker control groups.Specifically, FS expression at 5q31 was observed to be most frequent, followed by 1q (q32, q21, and q12) in our patients (Table 2) (Fig. 2). Some tumor suppressor genes on 5q31 are important in hematological transformation (Le Beau et al., 1993
; Dubourg et al., 2002). In previous studies, the 1p22–p21 and 1p31–p21 regions were reported to include and harbour susceptibility genes for alcohol dependence (Reich et al., 1998). We found three FS, at band p13, q21, and q31 on chromosome 2 that were significantly overexpressed in alcoholics (P = 0.001–0.006). The strongest evidence for loci linked to alcohol dependence was at band 2p11–13 on chromosome 2 (Bierut et al., 1998a,b). The fra(3)(p25), fra(3)(q21), specifically, 3p14 sites were significantly expressed in the alcoholics (P = 0.001) (Table 1) (Fig. 2). The 3p14 site is an interesting region and the most active cFS in the human genome and expressed when cells are exposed to folate stress (Smeets et al., 1986). Rearrangements at 3p14.2 occur frequently in most human cancers (Sozzi et al., 1997; Corbin et al., 2002). However, previous studies have indicated a higher frequency of FS at 3p14.2 in autistic populations (Li et al., 1993; Telvi et al., 1994). The FS of 4q21 and 4q31 in alcoholics are also seen commonly in our study. The alcohol dehydrogenase (ADH) gene locus exists in a cluster on the 4q21 region (Osier et al., 2002). So, all studies referred here and in our study demonstrated that some genes located on chromosome 1–5 may be associated with alcohol dependence, and because of the oncogenes on these chromosomes, tumorigenesis and/or cirrhosis may occur in alcohol users.
We also observed the fragility at 7q22 to be the most frequent, followed by 7q32 in alcoholics. Reich et al. (1998) reported a higher load score at pter–qter regions of chromosome 7 in affected sib-pair analysis with alcohol dependence. The FS on 9q13 and 9q22 were particularly interesting because these regions have also been previously reported to be linked to alcohol dependence in the American population (Bergen et al., 2003; Ma et al., 2003). The FS on 11q23 site was significantly expressed in our patients. This band contains a cancer breakpoint (Holmquist, 1992). Progress in the analysis of the 11q has demonstrated that a gene for neural cell adhesion molecule (NCAM) is localized at 11q23 (Berube et al., 1990; Panicker et al., 2003). NCAM had been shown to be important in the development of neural networks and myelination (Bhat and Silberberg, 1990; Ono et al., 1994). Abnormal myelination may be an important cause of the psychomotor retardation in alcoholic patients. Together, these results are consistent with the hypothesis that these interesting regions could play a role in the pathogenesis of alcoholism, tumorigenesis and behavioural disorders, and may provide much more genetic information relevant to alcoholism. Among these expressed FS, those at the 2q21, 3p25, 3p14, 3q21, 6p21, 7q32, 9q13, 9q22, 10q22, and 11q23 loci were never expressed in the smokers control group (Table 1), and thus, they were considered as being connected with alcoholism. However, the loci 1q12, 3p25, 4q31, 6p21, and 12q13 expressed in our patients were not reported previously in alcoholics. These sites may be new hot spots for alcoholism.
The fragility of the chromosome may be related to abnormalities in replication, resulting in single-strand DNA gaps, which, if not repaired, may lead to chromosome damage such as deletions within the FS, or translocations or other rearrangements involving breakage at a FS (Stein et al., 2002). An increase in CA, break-type aberrations, and deletions, was observed for alcoholics when compared with the control group. The increase in fragility may increase the risk for breakage or deletion in alcoholics. Greater numbers of deletions and inversions in alcoholics can be attributed to chronic and excessive consumption of alcoholic beverages. The elevated frequencies found in alcoholics of both FS and CA can be attributed to several factors. Acetaldehyde causes many toxic effects associated with excess intake of ethanol (Lieber, 1998). It plays an important role in the production of DNA single-strand breaks (Singh et al., 1995). Furthermore, acetaldehyde induces gene mutations in cultured human lymphocytes (He and Lambert, 1990).
The frequency of inv(9)(p11;q13), 9qh+, 1qh+ and Yqh+ in our study was found to be 25 and 19% in the alcoholics and control group, respectively (Table 2). These are usually considered as polymorphisms, but their clinical consequences remain unclear. It could be estimated that the incidence of inv(9) in Asian populations is approximately 1.5%. Previous studies indicate that the inv(9) may be etiologically linked to schizophrenia (Kunugi et al., 1999; Miyaoka et al., 1999). We identified three alcoholics (3.75%) with 22q12–13 deletions. Previous studies confirmed an association between psychiatric illness and 22q11.2 deletions (Bassett and Chow, 1999; Nicolson et al., 1999; Demirhan and Tastemir, 2003). Various assays have shown that alcohol can induce chromosome mis-segregations (He and Lambert, 1990). Likewise, numerical chromosome changes were also seen frequently in our patients. On the other hand, diet may be a factor that determines chromosome damage in humans. None of our patients had a deficient diet or had major change in dietary habits during their alcohol dependence, but the concentrations of mineral and vitamins in the plasma of alcoholics were not measured. Thus, it has not been possible to rule out the influence of micronutrients on both FS and CA frequencies. With respect to the influence of age on genetic damage, we did not find a relationship between age and the percentage of FS in our study. Cigarette smoking is common among persons with alcohol dependence. Approximately 80% of alcohol-dependent patients are reported to be cigarette smokers (DiFranza and Guerrera, 1990; Miller and Gold, 1998). In fact, all our patients are heavy cigarette smokers (Table 2). Heavy cigarette usage is a predictor of unrecognized alcohol dependence (Djousse et al., 2002). Some reports have suggested that cigarette smoking can affect chromosome damage (da Cruz et al., 1994; Prabhavathi et al., 2000). The increased FS and CA frequency observed in the alcoholics compared with controls can be caused by ethanol combined with cigarette smoking in this study. A synergistic effect has been reported between alcohol consumption and smoking in humans (Castelli et al., 1999). Our patients were also maintained on anti-depressant drugs for treatment of depression and drinking cessation. The primary mechanism of action of anti-depressant drugs in alcohol cessation is thought to be via the drug's effect on dopamine neurotransmission and/or acetylcholine receptors.
Alcohol dependence is strongly familial and has been reported more commonly in males than females. In the present study we found that 62% of alcohol users have a family history of alcohol abuse and a family relation between alcohol dependence and alcohol use disorders, and a relation between paternal alcoholism (72%) and alcohol use disorders in offspring. It seems that children of alcoholics are at increased risk for attachment difficulties. Although attachment itself might not be genetically determined, it might serve to moderate high genetic risk for the development of alcoholism in offspring of alcoholics (Jacob et al., 2003).
In the present study, the smoking control group exhibited a higher frequency of total CA expression compared with that of the non-smoking control group (P < 0.001), but except for 1p36, 3q21 and 5p15 regions, the overall difference was not statistically significant (P > 0.05) (Fig. 1). In the smoking control group, FS at 1p36, 3q21 and 5p15 regions were significantly increased. These regions may be evidence for a common genetic factor that contributes to smoking. Previous studies demonstrated that a significant increase was found in the frequency of CA and FS between smokers and non-smokers (Prabhavathi et al., 2000; Stein et al., 2002; Zhang et al., 2004). Active tobacco exposure increases chromosomal FS expression and damage, in particular, at three critical sites in our smoking controls. These three regions have been previously identified as potential susceptibility loci for several cancers and may have susceptibility loci that are specific for the development of habitual smoking. The 1p36 band is a cancer breakpoint (Holmquist, 1992). Reciprocal translocations between 3q21 and other chromosomes are well documented in myelodysplastic syndrome and leukemia (Cambrin et al., 1986; Testoni et al., 1999). Previous studies have shown that the 5p15 region exhibits frequent genetic changes in bronchial epithelial cells in long-term smokers, and in invasive cervical carcinoma, and that these changes arise early during carcinogenesis (Arias–Pulido et al., 2002; Romeo et al., 2003). It is interesting that the tobacco compounds were particularly interactive with cancer loci but not with the other loci.
In conclusion, the present data demonstrated that chronic alcohol exposure increases chromosomal damage both in terms of FS and CA. The results confirm that chromosome damage of chronic alcoholic individuals could be induced by chronic alcohol exposure and smoking. The FS were clustered in specific regions of chromosomes 1–7 and 9–12 in alcoholics. At the same time, the exposure to tobacco increases the potential for chromosome breakage at three cancer sites in the genome. These observations should stimulate more studies on these chromosomal regions at the molecular, cytogenetic, and population genetic level.
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ACKNOWLEDGEMENTS |
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This study was supported by Research Fund of Çukurova University, Adana, TURKEY, and, for his help, we would like to thank Dr. Niyazi Yurtseven, who is president of the Psychiatric and Neurologic Diseases Hospital in Adana.
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References |
|---|
|
TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (1994) 4th edn. Washington, DC: American Psychiatric Association.
An international system for human cytogenetics nomenclature (ISCN). Report of the Standing Committee on Human Cytogenetic Nomenclature Published in collaboration with ‘Cytogenetics and Cell Genetics’ with Inserted Table: The Normal Human Karyotype. G- and R-bands—Harnden D. G., Klinger H. P., eds. (1985) Basel: S. Karger AG.
Arias-Pulido H., Narayan G., Vargas H., et al. Mapping common deleted regions on 5p15 in cervical carcinoma and their occurrence in precancerous lesions. Molecular Cancer (2002) 1:3.[CrossRef][Medline]
Arrieta I., Nunez T., Martinez B., et al. Chromosomal fragility in a behavioral disorder. Behavior Genetics (2002) 32(6):397–412.[CrossRef][Web of Science][Medline]
Bassett A. S., Chow E. W. C. 22q11 deletion syndrome: a genetic subtype of schizophrenia. Biological Psychiatry (1999) 46:882–891.[CrossRef][Web of Science][Medline]
Bergen A. W., Yang X. R., Bai Y., et al. Genomic regions linked to alcohol consumption in the Framingham Heart Study. Biomed Central Genetics (2003) 4(1):101.
Berube D., Passage E., Mattei M. G., et al. Fine mapping of the long arm of human chromosome 11 by in situ hybridization using different translocations, including the t(11;22) of Ewing sarcoma. Cytogenetics and Cell Genetics (1990) 54(3–4):142–147.[Web of Science][Medline]
Bhat S., Silberberg D. H. Expression of neural cell adhesion molecule in dysmyelinating mutants. Brain Research (1990) 535(1):39–42.[CrossRef][Web of Science][Medline]
Bierut L. J., Dinwiddie S. H., Begleiter H., et al. Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. Archives of General Psychiatry (1998a) 55(11):982–988.
Bierut L., Rice J., Goate A., et al. Comorbid habitual smoking and alcohol dependence: a genomic survey. American Journal of Medical Genetics (1998b) 81:550–551.
Burim R. V., Canalle R., Takahashi C. S., et al. Clastogenic effect of ethanol in chronic and abstinent alcoholics. Mutation Research (2004) 560:187–198.[Web of Science][Medline]
Cambrin G. R., Mecucci C., Van Orshoven A., et al. Translocation t(1;3)(p36;q21) in malignant myeloid stem cell disorders. Cancer Genetics and Cytogenetics (1986) 22(1):75–81.[CrossRef][Web of Science][Medline]
Castelli E., Hrelia P., Maffei F., et al. Indicators of genetic damage in alcoholics: reversibility after alcohol abstinence. Hepatogastroenterology (1999) 46(27):1664–1668.[Medline]
Chang L. W., Daniel F. B., DeAngelo A. B. Analysis of DNA strand breaks in rodent liver in vivo, hepatocytes in primary culture, and a human cell line by chlorinated acetic acids and chlorinated acetaldehydes. Environmental and Molecular Mutagenesis (1992) 20:277–288.[Web of Science][Medline]
Corbin S., Neilly M. E., Espinosa R., et al. Identification of unstable sequences within the common fragile site at 3p14.2: implications for the mechanism of deletions within fragile histidine triad gene/common fragile site at 3p14.2 in tumors. Cancer Research (2002) 62(12):3477–3484.
da Cruz A. D., McArthur A. G., Silva C. C., et al. Human micronucleus counts are correlated with age, smoking, and cesium-137 dose in the Goiania (Brazil) radiological accident. Mutation Research (1994) 313:57–68.[Web of Science][Medline]
Demirhan O., Tastemir D. Chromosome aberrations in a schizophrenia population. Schizophrenia Research (2003) 65:1–7.[CrossRef][Web of Science][Medline]
DiFranza J. R., Guerrera M. P. Alcoholism and smoking. Journal of Studies on Alcohol (1990) 51(2):130–135.[Web of Science][Medline]
Djousse L., Dorgan J. F., Zhang Y., et al. Alcohol consumption and risk of lung cancer: the Framingham Study. Journal of the National Cancer Institute (2002) 94(24):1877–1882.
Dubourg C., Toutain B., Helias C., et al. Evaluation of ETF1/eRF1, mapping to 5q31, as a candidate myeloid tumor suppressor gene. Cancer Genetics and Cytogenetics (2002) 134(1):33–37.[CrossRef][Web of Science][Medline]
Gericke G. S. Chromosomal fragility may be indicative of altered higher-order DNA organization as the underlying genetic diathesis in complex neurobehavioral disorders. Medical Hypotheses (1998) 50:319–326.[CrossRef][Web of Science][Medline]
He S. M., Lambert B. Acetaldehyde-induced mutation at hprt locus in human lymphocytes in vitro. Environmental and Molecular Mutagenesis (1990) 16:57–63.[Web of Science][Medline]
Holmquist G. P. Chromosome bands, their chromatin flavors, and their functional features. American Journal of Human Genetics (1992) 52:17–37.[Web of Science]
Huttner E., Matthies U., Nikolova T., et al. A follow-up study on chromosomal aberrations in lymphocytes of alcoholics during early, medium, and long-term abstinence. Alcoholism-Clinical and Experimental Research (1999) 23(2):344–348.
Jacob T., Waterman B., Heath A., et al. Genetic and environmental effects on offspring alcoholism: new insights using an offspring-of-twins design. Archives Of General Psychiatry (2003) 60(12):1265–1272.
Kunugi H., Lee K. B., Nanko S. Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9. Schizophrenia Research (1999) 40:43–47.[CrossRef][Web of Science][Medline]
Lazutka J. R., Dedonyte V., Lekevicius R. K. Sister chromatid exchanges in lymphocytes of normal and alcoholic subjects. Experientia (1992) 48:508–512.[CrossRef][Web of Science][Medline]
Le Beau M. M., Espinosa R., Neuman W. L., et al. Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. Proceedings of the National Academy of Sciences of the United States of America (1993) 90(12):5484–5488.
Li T. K., Lumeng L., Doolittle D. P. Selective breeding for alcohol preference and associated responses. Behavioral Genetics (1993) 23(2):163–170.[CrossRef][Web of Science][Medline]
Lieber C. S. Hepatic and other medical disorders of alcoholism: from pathogenesis to treatment. Journal of Studies on Alcohol (1998) 59:9–25.[Web of Science][Medline]
Ma J. Z., Zhang D., Dupont R. T., et al. Mapping susceptibility loci for alcohol consumption using number of grams of alcohol consumed per day as a phenotype measure. Biomed Central Genetics (2003) 4(1):104.
Maffei F., Forti G. C., Castelli E., et al. Biomarkers to assess the genetic damage induced by alcohol abuse in human lymphocytes. Mutation Research (2002) 514:49–58.[Web of Science][Medline]
McAlpine P. J., Shows T. B., Boucheli C., et al. The 1991 catalog of mapped genes and report of the nomenclature committee, Human Gene Mapping 11. Cytogenetics and Cell Genetics (1991) 58:5–102.[Web of Science]
Miller N. S., Gold M. S. Comorbid cigarette and alcohol addiction: epidemiology and treatment. Journal of Addictive Diseases (1998) 17(1):55–66.[Web of Science][Medline]
Miyaoka T., Seno H., Itoga M., et al. A case of small cerebral cyst and pericentric inversion of chromosome 9 that developed schizophrenia-like psychosis. Psychiatry and Clinical Neurosciences (1999) 53(5):599–602.[Medline]
Muller P., Henn W., Niedermayer I., et al. Deletion of chromosome 1p and loss of expression of alkaline phosphatase indicate progression of meningiomas. Clinical Cancer Research (1999) 5(11):3569–3577.
Nicolson R., Giedd J. N., Lenane M., et al. Clinical and neurobiological correlates of cytogenetic abnormalities in childhood-onset schizophrenia. American Journal of Psychiatry (1999) 156:1575–1579.
Obe G., Andersoni D. International commission for protection against environmental mutagens and carcinogens. ICPEMC Working Paper No. 15/1. Genetic effects of ethanol. Mutation Research (1987) 186(3):177–200.[Web of Science][Medline]
Obe G., Gobel D., Engeln H., et al. Chromosomal aberrations in peripheral lymphocytes of alcoholics. Mutation Research (1980) 73:377–386.[Web of Science][Medline]
Ono J., Harada K., Hasegawa T., et al. Central nervous system abnormalities in chromosome deletion at 11q23. Clinical Genetics (1994) 45(6):325–329.[Web of Science][Medline]
Osier M. V., Pakstis A. J., Soodyall H., et al. A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity. American Journal of Human Genetics (2002) 71(1):84–99.[CrossRef][Web of Science][Medline]
Panicker A. K., Buhusi M., Thelen K., et al. Cellular signaling mechanisms of neural cell adhesion molecules. Frontiers in Bioscience (2003) 8:d900–d911.[Web of Science][Medline]
Prabhavathi P. A., Fatima S. K., Rao R. S., et al. Analysis of chromosomal aberration frequencies in the peripheral blood lymphocytes of smokers exposed to uranyl compounds. Mutation Research (2000) 466:37–41.[Web of Science][Medline]
Reich T., Edenberg H. J., Goate A., et al. Genome-wide search for genes affecting the risk for alcohol dependence. American Journal of Medical Genetics (1998) 81(3):207–215.[CrossRef][Web of Science][Medline]
Romeo M. S., Sokolova I. A., Morrison L. E., et al. Chromosomal abnormalities in non-small cell lung carcinomas and in bronchial epithelia of high-risk smokers detected by multi-target interphase fluorescence in situ hybridization. Journal of Molecular Diagnostics (2003) 5(2):103–112.
Singh N. P., Lai H., Khan A. Ethanol-induced single-strand DNA breaks in rat brain cells. Mutation Research (1995) 345:191–196.[CrossRef][Web of Science][Medline]
Smeets D. F., Scheres J. M., Hustinx T. W. The most common fragile site in man is 3p14. Human Genetics (1986) 72(3):215–220.[CrossRef][Web of Science][Medline]
Sozzi G., Tornielli S., Tagliabue E., et al. Absence of Fhit protein in primary lung tumors and cell lines with FHIT gene abnormalities. Cancer Research (1997) 57(23):5207–5212.
Stein C. K., Glover T. W., Palmer J. L., et al. Direct correlation between FRA3B expression and cigarette smoking. Genes Chromosomes & Cancer (2002) 34:333–340.[CrossRef][Web of Science][Medline]
Telvi L., Leboyer M., Chiron C., et al. Is Rett syndrome a chromosome breakage syndrome? American Journal of Medical Genetics (1994) 51(4):602–605.[CrossRef][Web of Science][Medline]
Testoni N., Borsaru G., Martinelli G., et al. 3q21 and 3q26 cytogenetic abnormalities in acute myeloblastic leukemia: biological and clinical features. Haematologica (1999) 84(8):690–694.
Zhang W., Wang C., Chen D., et al. Effect of smoking on chromosomes compared with that of radiation in the residents of a high-background radiation area in China. Journal of Radiation Research (2004) 45:441–446.[Medline]
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