Showing papers by "Florence Demenais published in 2002"

Geographical Variation in the Penetrance of CDKN2A Mutations for Melanoma

Abstract: Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14APF protein, and population melanoma incidence rates. All statistical tests were two-sided. Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P = .003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.

Detection of putative functional angiotensinogen (AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis.

Abstract: Previous studies have suggested that angiotensinogen (AGT) gene variants are associated with increased plasma AGT levels, and may also contribute towards the inherited component of predisposition to essential hypertension in humans. To explore the potential functionality of several AGT polymorphisms and estimate their effects, together with other sources of familial correlations, on plasma AGT, we undertook a large study involving 545 healthy French volunteers in 130 nuclear families that include 285 offspring. Plasma AGT levels were measured in all participants, and bi-allelic AGT variants were analysed as candidate functional variants at three sites in the 5'-flanking region (C-532T, A-20C, G-6A), two sites in exon 2 (M235T, T174M) and two newly identified variant sites in the untranslated sequence of exon 5 and the 3'-flanking region (C+2054A, C+2127T) of the gene. Analysis with the class D regressive model showed significant effects influencing plasma AGT levels of all AGT polymorphisms tested, with the exception of T174M. The most significant result was found at C-532T (P=0.000001), which accounts for 4.3% of total plasma AGT variability in parents and 5.5% in offspring, with substantial residual familial correlations. Maximum likelihood estimates of haplotype frequencies and tests of linkage disequilibrium between each AGT polymorphism and a putative QTL are in agreement with a complete confounding of C-532T with the QTL, when taking into account sex and generation specific effects of the QTL. However, further combined segregation-linkage analyses showed significant evidence for additional effects of G-6A, M235T and C+2054A polymorphisms after accounting for C-532T, which supports a complex model with at least two functional variants within the AGT gene controlling AGT levels.

[Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA) - First results of a multi-disciplinary study].

Abstract: The French co-operative epidemiological study EGEA realised in 1991/95 combines a case control study and a study of the families of asthmatic cases. A synthesis of the results already obtained is presented. Smoking was related to IgE, even in asthmatics and was clearly related to the clinical severity of asthma, an aspect insufficiently taken into account. The relationships of occupational exposures to asthma have been assessed using a job exposure matrix. Segregation analyses on IgE have shown, after correction for the mode of ascertainment, the existence of a dominant major gene and familial residual correlation. A systematic genome screen realised in families with 2 asthmatic siblings showed linkage of various regions in the genome implicated to asthma or related phenotypes (1p, 11p, 11q, 12q, 13q, 17q, 19q), coherent with genome screens realised in other studies. Regarding candidate genes, no association was evidenced between asthma and the AF508 mutation of the cystic fibrosis gene. The analysis is still in progress by studies on the heterogeneity of asthma with refined genetic studies and by searching to integrate results regarding environmental and genetic factors and studying their interactions.

Interactions between genetic and reproductive factors in breast cancer risk in a population-based sample of African-American families.

Abstract: Incidence of breast cancer (BC) varies among ethnic groups, with higher rates in white than in African-American women. Until now, most epidemiological and genetic studies have been carried out in white women. To investigate whether interactions between genetic and reproductive risk factors may explain part of the ethnic disparity in BC incidence, a genetic epidemiology study was conducted, between 1989 and 1994, at the Howard University Cancer Center (Washington, DC), which led to the recruitment of 245 African-American families. Segregation analysis of BC was performed by use of the class D regressive logistic model that allows for censored data to account for a variable age of onset of disease, as implemented in the REGRESS program. Segregation analysis of BC was consistent with a putative dominant gene effect (P < 0.000001) and residual sister-dependence (P < 0.0001). This putative gene was found to interact significantly with age at menarche (P = 0.048), and an interaction with a history of spontaneous abortions was suggested (P = 0.08). A late age at menarche increased BC risk in gene carriers but had a protective effect in non-gene carriers. A history of spontaneous abortions had a protective effect in gene carriers and increased BC risk in non-gene carriers. Our findings agree partially with a similar analysis of French families showing a significant gene x parity interaction and a suggestive gene x age at menarche interaction. Investigating gene x risk factor interactions in different populations may have important implications for further biological investigations and for BC risk assessment.

Asthme : dépistage et prévention chez l'enfant

Abstract: Les manifestations allergiques, l’asthme en particulier, sont de plus en plusfrequentes dans tous les pays industrialises. Il faut egalement remarquer quenon seulement la prevalence mais aussi la severite de l’asthme se sont fortementaccrues au cours des dernieres annees. Plusieurs etudes effectuees atravers le monde montrent que, depuis 1960, la frequence de l’asthme s’accroitd’environ 6 % a 10 % par an chez l’enfant, quels que soient le pays ou l’ethnieetudies. Elle est la premiere maladie chronique de l’enfant dans les paysdeveloppes. Cette augmentation ne semble pas proceder d’une modificationdes moyens de diagnostic ou d’une meilleure connaissance de l’affection.Si la prise en charge de l’asthme a nettement progresse depuis une vingtained’annees, du fait d’une meilleure connaissance des mecanismes physiopathologiquesde la maladie et de l’arrivee sur le marche de nouvelles therapeutiques,il reste cependant essentiel d’apprehender les facteurs a l’origine de saprogression foudroyante.Les facteurs a l’origine des maladies allergiques, et de l’asthme en particulier,sont de deux ordres, genetiques et environnementaux, d’importantes interactionsexistant entre eux. Si un certain nombre de genes candidats pourl’immunopathologie de l’asthme sont en cours d’identification, des modificationsde ces genes ne peuvent constituer une explication coherente pourrendre compte de l’augmentation de la prevalence de l’asthme observee cesvingt dernieres annees. Les facteurs environnementaux apparaissent commel’explication la plus plausible : la pollution de l’air et les modifications dumode de vie, d’une part, la disparition de facteurs de resistance (infections aucours de la petite enfance), d’autre part, sont en premiere ligne des responsablespossibles.L’asthme est defini comme une obstruction bronchique reversible, spontanementou sous l’effet de traitements bronchodilatateurs. Sur le plan physiopathologique,l’asthme est caracterise par une inflammation de la muqueusebronchique. Cette inflammation est constante, plus ou moins importanteselon le stade de gravite de la maladie.La prise en charge des asthmatiques a largement beneficie d’une meilleurecomprehension des mecanismes physiopathologiques impliques dans le developpementde la maladie. Cette meilleure connaissance a permis d’elaborerune strategie therapeutique coherente et de proposer des schemas de traitementsappropries aux differentes formes d’asthme.Cependant, si nous avons largement progresse dans la comprehension del’histoire naturelle et la prise en charge de l’asthme, il n’existe pas encore de traitement curateur de la maladie. C’est dire l’importance des mesures preventives,qui reposent avant tout sur l’education des patients, mais aussi desmedecins. La prevention primaire implique un processus dans lequel l’interventionprecede le developpement de la maladie. La prevention secondaire apour objectif de prevenir le developpement de la maladie chez un sujetpredispose, par exemple atopique. Pour les patients chez qui le diagnosticd’asthme a ete pose, la prevention tertiaire consiste en une modification del’environnement et la prescription d’un traitement pharmacologique adapte.Ce document constitue une bonne synthese des travaux les plus representatifsen epidemiologie, physiopathologie et clinique. Il indique les principalesrecommandations en prevention et education a la sante, a l’intention desdifferents acteurs impliques dans la prise en charge de cette pathologie, etpropose quelques pistes de recherche qui meriteraient d’etre developpees.

Regressive threshold model for familial analysis of complex diseases with variable age of onset

Abstract: Few models for segregation (or combined segregation-linkage) analysis have been developed to account for variable age of onset. The unified model (UM) can only take into account age at examination. In the logistic hazard model (LHM), Abel and Bonney ([1990] Genet. Epidemiol. 7:391-407) incorporated survival analysis concepts into the regressive logistic model of Bonney ([1986] Am. J. Med. Genet. 18:731-749), but interpretation of familial dependence parameters is difficult. In this article, we extended the regressive threshold model (RTM) proposed by Demenais ([1991] Am. J. Hum. Genet. 49:773-785) to account for a variable age of onset of complex diseases. This model assumes an underlying liability to disease and is more general than the original logistic formulation, since the phenotypes of each individual's antecedents can be adjusted for their own genotypes and covariate effects. The variation of risk with age can be expressed as a general step function, and variants of the model have been proposed by imposing different types of constraints among the time-dependent thresholds. The performances of the three models (UM, LHM, and RTM) were compared in the context of segregation analysis of family data generated with variable age of onset. All analysis models were robust with respect to false conclusion of a major gene, and the best results were obtained under RTM. The power to detect the major gene was higher under LHM than RTM, but the best fit of the estimated cumulative age-dependent penetrance with respect to the true value was obtained under RTM. This new model may thus prove helpful in contributing to identification of genes underlying complex diseases, since it can easily include linked marker loci and linkage disequilibrium.