Heavy smoking and lung cancer: are women at higher risk? Result of the ICARE study.

BACKGROUND: Whether women are more or equally susceptible to the carcinogenic effects of cigarette smoke on the lungs compared with men is a matter of controversy. Using a large French population-based case-control study, we compared the lung cancer risk associated with cigarette smoking by gender. METHODS: The study included 2276 male and 650 female cases and 2780 male and 775 female controls. Lifetime smoking exposure was represented by the comprehensive smoking index (CSI), which combines the duration, intensity and time since cessation of smoking habits. The analysis was conducted among the ever smokers. All of the models were adjusted for age, department (a regional administrative unit), education and occupational exposures. RESULTS: Overall, we found that the lung cancer risk was similar among men and women. However, we found that women had a two-fold greater risk associated with a one-unit increase in CSI than men of developing either small cell carcinoma (OR=15.9, 95% confidence interval (95% CI) 7.6, 33.3 and 6.6, 95% CI 5.1, 8.5, respectively; P<0.05) or squamous cell carcinoma (OR=13.1, 95% CI 6.3, 27.3 and 6.1, 95% CI 5.0, 7.3, respectively; P<0.05). The association was similar between men and women for adenocarcinoma. CONCLUSION: Our findings suggest that heavy smoking might confer to women a higher risk of lung cancer as compared with men.

UDP-glucuronosyltransferase UGT1A7 genetic polymorphisms in hepatocellular carcinoma: a differential impact according to seropositivity of HBV or HCV markers?

BACKGROUND: We conducted a case-control study to evaluate the role of UDP-glucuronosyltransferase 1A7 (UGT1A7) polymorphisms in the onset of hepatocellular carcinoma (HCC). METHODS: The study included 165 patients with HCC, 134 with cirrhosis and 142 controls without liver disease, matched for age and hospital. All were men younger than 75 years. HCC and cirrhosis patients were stratified according to time since cirrhosis diagnosis. RESULTS: We found a positive association between the UGT1A7*3/*3 genotype and HCC when the comparison was restricted to patients whose disease was of viral origin [OR = 3.4 (0.3-45)] but a negative association when it included only alcoholic patients [OR = 0.1 (0.02-0.6), p = 0.01]. CONCLUSION: Our study shows that UGT1A7 may play a role in hepatocellular carcinogenesis and that this role may differ according to the primary cause of the cirrhosis.

Relation between inducibility of CYP1A1, GSTM1 and lung cancer in a French population.

Smoking is the principal cause of lung cancer. However, not all smokers will develop this disease. Individual susceptibility to chemically induced cancer may be explained in part by genetic differences in the activation and detoxification of procarcinogens. The activation phase of polycyclic aromatic hydrocarbon (PAH) metabolism is governed by the enzyme CYP1A1, induced by PAH when it enters the body. The extent to which PAH induces CYP1A1 activity varies greatly from one subject to another. CYP1A1 inducibility has long been associated, although inconsistently, with an increased risk of lung cancer. In 1982, Kouri corroborated Kellerman's results with a new method for measuring inducibility, but few studies have reported using this method. The glutathione S-transferases (GSTs) are involved in the detoxification phase of PAH, and the allelic deletion of GSTM1 has been also associated with an increased risk of lung cancer. We conducted a case-control study to examine the risk of lung cancer related, separately and together, to CYP1A1 inducibility, GSTM1 polymorphism and cigarette smoking in a French population. The 611 subjects were 310 incident lung cancer cases and 301 hospital control subjects. We were able to constitute a DNA bank for 552 subjects (89.5%) and gather detailed information on smoking history for all of them. Inducibility could be measured for 195 cases and 183 control subjects. Results for GSTM1 polymorphism concern 247 cases and 254 control subjects. GSTM1 polymorphism and inducibility could both be assessed for 179 cases and 166 control subjects. The odds ratio related to inducibility was 1.7 [1.0-3.0] for medium and 3.1 (1.3-7.4) for hyper inducers. The association with GSTM1 was 1.6 (1.0-2.6). With a reference category of subjects who were both low inducers and GSTM1(+), we found an odds ratio for lung cancer of 8.1 (2-31) for the subjects with both risk factors [i.e. GSTM1(-) and hyper inducers]. Our data did not reveal evidence of interaction between smoking and inducibility. On the other hand, we found an interaction of 3.6 (0.6-21) between inducibility and GSTM1.

Genetic polymorphisms of cytochrome P450 2A6 in a case-control study on lung cancer in a French population.

Cytochrome P450 2A6 (CYP2A6) is involved in the C-oxidation of nicotine and in the metabolic activation of tobacco nitrosamines. Recent data have suggested that CYP2A6 genetic polymorphisms might play a role in tobacco dependence and consumption as well as in lung cancer risk. However, the previously published studies were based on a genotyping method that overestimated the frequencies of deficient alleles, leading to misclassification for the CYP2A6 genotype. In this study, we genotyped DNA from 244 lung cancer patients and from 250 control subjects for CYP2A6 (wild-type allele CYP2A6*1, and two deficient alleles: CYP2A6*2, and CYP2A6*4, the latter corresponding to a deletion of the gene) using a more specific procedure. In this Caucasian population, we found neither a relation between genetically impaired nicotine metabolism and cigarette consumption, nor any modification of lung cancer risk related to the presence of defective CYP2A6 alleles (odds ratio = 1.1, 95% confidence interval = 0.7-1.9).

Cytochrome P450 CYP2D6 gene polymorphism and lung cancer susceptibility in Caucasians.

Many studies have been performed in an attempt to establish a link between the polymorphism of the cytochrome P450 CYP2D6 gene and the incidence of lung cancer. Nevertheless, whether or not this genetic polymorphism has a role in the development of the disease remains unclear. Recently, new advances in our knowledge of the CYP2D6 gene and its locus (CYP2D) have been achieved. In particular, CYP2D6 was found to be highly polymorphic and multiple novel mutations and allelic variants of the gene have been identified. In addition, a number of CYP2D rearrangements, including those with amplification of the gene, have been demonstrated. Taking this new information into account, we have reconsidered the potential influence of CYP2D6 polymorphism in lung cancer susceptibility by performing a comparative analysis of the overall mutational spectrum of CYP2D6 and of the rearrangements of CYP2D in 249 patients with lung cancer and in 265 control individuals matched on age, sex, hospital and residence area. For this purpose, a strategy based on SSCP analysis of the entire coding sequence of CYP2D6 and on RFLP analysis of the gene locus was carried out in DNA samples from each individual. Forty mutations occurring in various combinations on 42 alleles of the gene and 82 different genotypes were identified. No significant difference in the distribution of the mutations, alleles or genotypes was observed between the two groups, except a particular genotype (CYP2D6*1A/*2), which was more common in the sub-group of moderate smokers (< 30 pack-years) suffering from small cell carcinoma (Odds Ratio (OR) 3.6, 95% CI 1.1-11.9). When the phenotype was predicted according to genotype, only a trend toward a higher frequency of ultrarapid metabolizers in patients was obtained. In spite of a complete analysis of the CYP2D6 gene and its locus, this case-control study provides elements against an influence of the CYP2D6 polymorphism on lung cancer susceptibility.

Organic solvent exposure may increase the risk of glomerular nephropathies with chronic renal failure.

BACKGROUND: Several studies have suggested that exposure to organic solvents is associated with glomerular nephropathies (GN), but this relationship remains controversial. METHODS: A case-control study of 298 biopsy-proven cases and 298 hospital controls, matched for year of birth, sex, origin, and place of residence, was conducted between 1989 and 1991 in five hospitals in the Paris area: 82 cases of membranous glomerulopathy were included; 100, nephrotic syndrome with either minimal change nephropathy or focal and segmental hyalinosis (MCN/FSH); and 116, IgA nephropathy (IgA N). Subjects were interviewed about their lifelong occupational and non-occupational activities. A 'blind' assessment of type, level, and duration of solvent exposure was carried out by two industrial hygienists. Human leucocyte antigen (HLA) phenotypes were determined. RESULTS: Among males, a clear association, which was not explained by social class, was observed between chronic renal failure and high exposure to solvents for both MCN/FSH (OR = 7.7, 95% CI: 1.4-41.6) and IgA N (OR = 3.5, 95% CI: 1.0-11.8). The odds ratios increased with duration of exposure. No relationship was observed between such exposure and GN cases with normal renal function. No evidence was found that the HLA phenotype plays a role in the association between solvent exposure and the disease. CONCLUSIONS: These results support the hypothesis of a causal relationship between high solvent exposure, which concerned 15% of the males in this study, and the development of GN with chronic renal failure.

GSTM1, smoking and lung cancer: a case-control study.

BACKGROUND: We conducted a case-control study to examine the risk of lung cancer in relation to GSTM1 polymorphism and cigarette smoking (primarily of black tobacco) in a French population. METHODS: The 611 subjects were 301 incident lung cancer cases and 310 hospital controls. We were able to constitute a DNA bank for 547 subjects (89.5%) and gather detailed information on smoking history for all of them. Results presented here concern 247 cases and 254 controls. RESULTS: Taking non- or light smokers as the reference category, we estimated odds ratios (OR) of 4.2 (95% CI: 2.6-6.7) and 5.2 (95% CI: 3.3-8.3) for the medium and heavy smokers respectively. On the other hand we estimated that the crude OR associating GSTM1 with lung cancer was 1.3 (95% CI: 0.9-1.8). Furthermore our data do not depart significantly from a multiplicative model of the combined effects of smoking and GSTM1 deficiency. CONCLUSIONS: We conclude that smoking and the GSTM1 gene are each a risk factor for lung cancer, and that their combined effect does not differ significantly from that of a multiplicative model.

Influence of renal biomarker variability on the design and interpretation of occupational or environmental studies.

OBJECTIVES: To quantify and identify sources of within- and between-subject variability of microalbumin, N-acetyl-beta-D-glucosaminidase (NAG) and alanine aminopeptidase (AAP), three biomarkers used for early detection of renal injury, and to assess the consequences of this variability for the design and power of epidemiological studies. METHODS: Urinary excretion of microalbumin, NAG, AAP and creatinine as well as blood pressure (BP) were measured three times over a 2-year period among 142 healthy male workers. To minimise physiopathological and analytical sources of variation, standardised methods were used for urine collection and assays, and severe exclusion criteria were applied. At the first and third examinations, subjects completed the same questionnaire, providing information about their personal characteristics, tobacco and alcohol consumption, and health. A linear mixed model was used to estimate the within- and between-subject variance components and to analyse the relation between subjects' characteristics and the biomarkers. RESULTS: No change in the mean value of any of the biomarkers was observed over the 2-year period. Intra-class correlation coefficients between repeated measurements were 0.53, 0.57 and 0.56 for microalbumin, NAG and AAP, respectively; the between-subject variance was slightly higher than the within-subject variance. Subjects' age, BP, body mass index and smoking and drinking habits explained 7.2%, 12.5% and 4.2% of the total variance of microalbumin, NAG and AAP, respectively. CONCLUSIONS: In this healthy population of male workers, day-to-day differences in biomarker values appeared to be nearly as great as differences between subjects. The within-subject variance of these biomarkers is not high enough to justify systematic repeated measurements in epidemiological surveys. But, in some situations where the number of subjects is limited, measuring the subjects twice may improve study power by reducing the total variance by about 25% for each biomarker. Taking the above covariates into account would slightly improve study power and the accuracy of parameter estimates for NAG, but would add little to the analysis of microalbumin and AAP.

Risk of fatal industrial accidents and death from other external causes among asphalt workers.

The hypothesis that asphalt workers are at increased risk of mortality from industrial accidents and other external causes was tested. Mortality rates for external and violent causes of death in a cohort of asphalt industry employees from seven European countries and Israel were compared to that of the general population. There was no evidence that mortality from external causes was increased among long term employees in asphalt application and mixing. There was an increased risk for mortality due to external causes among short term workers. However, none of the fatal accidents among short term workers appear to have occurred during employment in the studied asphalt companies. Overall, no evidence was found supporting the hypothesis that asphalt workers are at increased risk of fatal industrial or road accidents. Mortality from other external causes did not increase in this population as a whole, but increased risks among short term workers deserve further attention.

Immunologic and renal markers among photogravure printers exposed to toluene.

OBJECTIVES: This study assessed immunologic and early renal effects of chronic toluene exposure. METHODS: In a longitudinal study of 92 printers and 74 referents, 145 subjects had pre- and poststudy samples of blood and urine taken for the following measurements: immunoglobulin E (IgE), antiglomerular basement membrane (anti-GBM) and antilaminin (anti-LAM) antibodies in blood; creatinine and beta2-microglobulin in blood and urine; and microalbumin, N-acetyl-b-D-glucosaminidase (NAG) and alanine-aminopeptidase in urine. Creatinine clearance was calculated according to the Cockroft-Gault formula. Eight-hour personal air samples were collected twice to assess present exposure to toluene. A job-exposure matrix was developed to estimate past cumulative exposure. Information about potential confounders was recorded by questionnaire. Multiple regression analysis was performed to study dose-effect relations adjusted for age and smoking. RESULTS: No subject was positive for anti-GBM antibodies, and only 12 were positive for anti-LAM. No relation was observed between the markers studied and present exposure to toluene except that creatinine clearance was higher among the exposed subjects than among the referents. A dose-response relation was observed between cumulative toluene exposure and both IgE and NAG excretion. No interaction was observed between hypertension and exposure, but the relationship with NAG did not persist when subjects with hypertension were excluded. Past or present exposure did not alter the 2-year trend of any marker studied. CONCLUSIONS: According to the results of this study, toluene at 50 ppm is not related to detectable renal dysfunction. The increased IgE levels associated with present and past exposure require further investigation.

[Glomerular nephropathies and exposure to organic solvents--a case-control study]. / Néphropathies glomérulaires et exposition aux solvants organiques-- Etude cas-témoins.

Several studies have suggested that exposure to organic solvents is associated with glomerular nephropathies (GN), but this relationship remains controversial. A case-control study of 298 biopsy-proven cases and 298 hospital controls, matched for year of birth, sex, origin, and place of residence, was conducted between 1989 and 1991 in five hospitals in the Paris area : 82 cases of membranous glomerulopathy were included ; 100, nephrotic syndrome with either minimal change nephropathy or focal and segmental hyalinosis (MCN/FSH); and 116, IgA nephropathy (IgA N). Subjects were interviewed about their lifelong occupational and non-occupational activities. Type, level, and duration of solvent exposure were assessed blind with respect to case-control status by two industrial hygienists. HLA phenotypes were determined. Among males, a clear association, which was not explained by social class, was observed between chronic renal failure and high exposure to solvents for both MCN/FSH (OR = 7.7, 95% CI 1.4-41.6) and IgA N (OR = 3.5, 95% CI 1.0-11.8). The odds ratios increased with duration of exposure. No relationship was observed between such exposure and GN cases with normal renal function. No evidence was found that the HLA phenotype plays a role in the solvent exposure-disease association. These results support the hypothesis of a causal relationship between high solvent exposure, which concerned 15% of the males in this study, and the development of GN with chronic renal failure.

The role of fat, animal protein and some vitamin consumption in breast cancer: a case control study in southern France.

The role of the consumption of fat, animal protein and vitamins on breast-cancer risk was investigated in a hospital-based case-control study of 924 patients (409 cases and 515 controls) in Montpellier (France). A dietary history questionnaire, administered by interview, comprising 55 key food items as well as beverage consumption, and including food frequencies and portion sizes, was used to measure the intake of total fat and its constituents, animal protein, retinol, beta-carotene, vitamin E and alcohol consumption. The questionnaire also elicited information on relevant medical history and personal characteristics. All food items which showed significantly elevated odds ratio (high-fat cheese, desserts and chocolate and processed pork meat) in a multivariate analysis contained a high proportion of animal fat. This is reflected in the nutrient analysis, which showed a significant linear trend as well as an elevated odds ratio for the highest tertile of consumption of total fat [OR3 = 1.6 (1.1-2.2)], animal fat [OR3 = 1.6 (1.1-2.2)], saturated fat [OR3 = 1.9 (1.3-2.6)] and mono-unsaturated fat [OR3 = 1.7 (1.2-2.5)]. For post-menopausal women, there is a particularly strong association with saturated fat [OR3 = 3.3 (1.4-7.8)] in a multivariate analysis including all other significant nutrients. There is no evidence of an increase of risk with the intake of animal protein and no evidence of risk reduction with increased consumption of vegetables, beta-carotene or vitamin E. Along with some recent studies, our results give support to the hypothesis that dietary fat is a risk factor in breast carcinogenesis.

Age, blood pressure and smoking effects on chronic renal failure in primary glomerular nephropathies.

BACKGROUND: Smoking is a known risk factor for renal damage in diabetic patients, but its relationship to other renal diseases is less clear. To assess its effect in primary glomerular nephropathy (GN), we used data from a case control study designed to assess several environmental risk factors. METHODS: This study included 295 biopsy-proven GN cases, 80 membranous nephropathy, 116 IgA nephropathy, and 99 nephrotic syndrome with either minimal change nephropathy or focal segmental hyalinosis, and 242 matched hospital controls, with diseases unrelated to smoking. Subjects were interviewed about their smoking history. Chronic renal failure (CRF), defined by serum creatinine> 150 micromol/L, was present in 74 cases (57 men and 17 women). Logistic regression was used to estimate odds ratios (ORs) adjusted for age and social class. RESULTS: In men, the percentage of ever-smokers did not differ between GN cases (60%) and controls [65%, OR = 0.9 (95% Confidence Interval 0.6-1.4)], but was significantly higher among cases with CRF (75%) than those without [55%, OR = 2.4 (1.2-4.5)]. Dose-effect relationships were observed with both the daily and cumulative dose; this relationship was stronger in the comparison of cases with CRF and those without CRF than in the comparison of cases with CRF with controls: OR = 1.9 versus 1.3 (20 cigarettes/day); OR = 1.9 versus 1.4 (15 pack years). Interactions between age, hypertension, and smoking were observed in the risk of CRF: smoking was significantly related to CRF among cases who were older than 40 years and/or hypertensive, but not among those cases younger than 40 or normotensive. The results did not significantly differ among the three histologic types. No relationship was shown between smoking and CRF in women. CONCLUSION: This study provides additional support for the hypothesis that smoking is related to GN severity, particularly in the at-risk groups of men older than 40 and/or hypertensive patients. These findings should be corroborated by further observations in other populations.

[Assessment of the use of hemoglobin AIc in diabetes mellitus screening]. / Evaluation de l'utilisation de l'hémoglobine AIc dans le dépistage du diabète sucré.

A population of 495 volunteer subjects who applied to the screening diabetes Centre of Hôtel-Dieu hospital in Paris has been studied and divided into two samples. In the first 300 subjects sample the sensitivity and the specificity of different fasting blood glucose threshold values, of different glycosylated hemoglobin threshold levels and of various combinations of the above mentioned parameter have been evaluated as a test for diabetes diagnosis defined by a 2-hr OGTT value greater than or equal to 200 mg/dl. The predictive values for both positive and negative diagnosis were also evaluated. The combination of a fasting blood glucose greater than or equal to 120 mg/dl with a glycosylated hemoglobin greater than 5.8% was found to be the best association with a good relative specificity (97.9%), a fair sensitivity (64.7%) and a fair predictive value for a positive diagnosis (64.7%). A second sample includes 195 subjects. These were classified according to either the above criterion or either the 2-hr OGTT value greater than or equal to 200 mg/dl. A great majority of subjects (95.4%) was classified in concordance by the two methods. The characteristics of the subjects that were identically classified as diabetic subjects (n = 5) were compared to those of differently classified subjects (n = 9). Longitudinal surveys are needed in order to assess the validity of HbA1c measurement as a tool for diabetes screening by reference to unquestionable criteria of the disease.

[Longitudinal study of the changes in glycosylated hemoglobin in normal pregnancy]. / Etude longitudinale des variations de l'hémoglobine glycosylée au cours de la grossesse normale.

A longitudinal study of HbA1c levels during normal pregnancy was carried out on 54 women. Three measurements were systematically performed around the 14th, the 24th and the 33rd weeks of gestation. On average, an initial decrease was observed in the first period, followed by a significant increase in the second period. The latter increase was negatively related to age (r = -0.33; p less than 0.05) and to prepregnancy weight (r = -0.26; p = 0.06), but neither to the birth weight of the offspring nor to total weight gain. The variation of HbA1c in the first period was not related to any of these four factors.

CYP2D6 genotype and lung cancer risk according to histologic type and tobacco exposure.

Polymorphism for CYP2D6 was determined genetically as part of a hospital-based case-control study. The cases were males with a histologically confirmed lung cancer diagnosis, < 75 years old, and no previous cancer diagnosis. Male controls were matched for age, hospital and residence area. This study includes 301 cases and 310 controls. A DNA bank was established for 547 patients (89.5%), and genotypes for CYP2D6 were differentiated by the Heim and Meyer method for the DNA samples of 249 cases and 271 controls. Among the cases, the frequencies of homozygous for the wild-type (EM), heterozygous (HEM) and homozygous for the mutant alleles (PM) were 62%, 32% and 7%; among the controls: 57%, 37% and 6%. Using EM as the reference, and adjusting for age, hospital and residence, we estimated the odds ratios for the HEM group and the PM group at 0.8 (95% CI [0.5-1.2]) and 1.1 (95% CI [0.5-2.4]) respectively. The PM frequency among the cases of adenocarcinoma was twice as high as among the controls (OR = 1.8, 95% CI [0.7-4.9]). This result was not observed among squamous and small cell carcinoma (OR = 0.7, 95% CI [0.3-1.8]). Twelve different case-control studies on CYP2D6 and lung cancer have so far been performed; the ORs they estimate range from 0.1 to 2.0, with a median value of approximately 0.6. This result lends some support to the hypothesis that belonging to the PM group is associated with a slight protective effect against lung cancer, but does not take into account the possibility that results may vary according to histologic type. In this context, the suggestion of a positive relationship between CYP2D6 and adenocarcinoma seems to us to merit investigation.

Polymorphisms of human aryl hydrocarbon receptor (AhR) gene in a French population: relationship with CYP1A1 inducibility and lung cancer.

The Ah receptor (AhR) is a ligand-dependent transcription factor that positively regulates the expression of the CYP1A1 gene. We investigated the genetic polymorphisms of the AhR gene including the promoter, and examined the link between these polymorphisms, CYP1A1 inducibility and the lung cancer incidence. The AhR promoter region and the 11 exons of 30 subjects were screened. Among the three polymorphisms found, two [(2417)(A/G) ((157)G/A)] have never been described previously. The (1721)(G/A) and (2417)(A/G) are localized in exon 10 and lead to Arg(554)Lys and Met(786)Val substitutions, respectively. The other polymorphism was found in the 5'-untranslated region, resulting in the substitution of a G by an A at position 157 (157)(G/A). To evaluate the frequency of this allelic variant found, a DNA library of a case-control study of lung cancer (162 controls and 177 patients) was studied. There is no significant association between (1721)(G/A), (157)(G/A) and lung cancer: (1721)(G/A) and (157)(G/A) were detected at the same allele frequency of 0.086 and 0.25, respectively in both controls and patients. (2417)(A/G) was found in only one control of 100 (allele frequency 0.005). Statistical analysis did not show any relationship between both (1721)(G/A) and (157)(G/A) polymorphisms found and CYP1A1 inducibility. Considering the rareness of the (2417)(A/G) allelic variant we were not able to evaluate its association with inducibility. In conclusion, none of the polymorphisms were found to play a key role in the CYP1A1 inducibility or in the susceptibility to develop lung cancer.