Showing papers by "Florence Demenais published in 2000"

Genome Screen for Asthma and Related Phenotypes in the French EGEA Study

Abstract: A genome-wide search was conducted in 107 nuclear families with at least two siblings with asthma, as part of the French EGEA study. A two-stage analysis strategy was applied to the 107 families divided into two independent subsets of 46 and 61 families, where all regions detected in the first set of families were tested for replication in the second set. In addition, all regions reported by published genome scans in different populations were examined in the total sample. A total of 254 markers were typed in the first set of families and 70% of them in the second set. Linkage was investigated by model-free methods for asthma and four asthma-related phenotypes: bronchial responsiveness (BR), skin test response, total immunoglobulin E (IgE) levels, and eosinophil count. The two-stage analysis led to the detection of three regions: 11p13 for IgE, 12q24 for eosinophils, and 17q12-21 for asthma and skin tests. Among the regions reported by published genome screens, seven were found in the 107 French EGEA families: three being already detected by the two-stage analysis, 11p13 (p = 0.005), 12q24 (p = 0.0008), and 17q12-21 (p = 0.001), and four additional ones, 1p31 (p = 0.005) for asthma, 11q13 (p = 0.006) for IgE, 13q31 (p = 0.001) for eosinophils, and 19q13 (p = 0.02) for BR.

Gene-Covariate Interaction between Dysplastic Nevi and the CDKN2A Gene in American Melanoma-prone Families

Abstract: The CDKN2A gene has been implicated in cutaneous malignant melanoma pathogenesis. Although CDKN2A mutations confer substantial risk for melanoma, clinicoepidemiological covariates including dysplastic nevi (DN), total nevi, and solar injury also enhance melanoma risk. To examine the relationship between CDKN2A and these three risk factors, we conducted combined segregation/linkage analysis using the class D regressive logistic model, as implemented in the computer program REGRESS. Genetic and covariate data were collected on 20 American melanoma-prone families, 13 of which had cosegregating CDKN2A mutations. Two types of analyses were conducted. The missing-indicator method used a missing-value indicator, set to 1 for unknown and 0 for known covariate status, and a second variable set to 1 for exposed and 0 for unexposed or unknown. The second method, complete-cases method, coded subjects with missing covariates as unknown for the affection status. The results for both analyses were very similar. Overall, there was a significant improvement in the likelihood when DN, total nevi or both covariates were added to the base model, which included dominant transmission of the CDKN2A gene and a linear increase of risk with the logarithm of age on the logit scale. In contrast, inclusion of solar injury did not significantly improve the likelihood for the base model. Significant evidence for a gene-covariate interaction was detected between DN and CDKN2A when DN was the only covariate in the model (missing-indicator method or complete-cases method) or when both DN and total nevi were in the model (complete-cases method only). Interestingly, in both methods, the odds ratio (OR) for DN was greater in subjects without mutations (OR, 20.1; 95% confidence interval, 4.8-92.8) versus those with CDKN2A mutations (OR, 3.3; 95% confidence interval, 1.1-10.0; complete-cases method). The CDKN2A-DN interaction illustrates the complex etiology of melanoma and needs to be confirmed in a larger sample of families.

Patterns of familial aggregation of three melanoma risk factors: great number of naevi, light phototype and high degree of sun exposure

Abstract: Background Besides melanoma susceptibility genes and shared environmental exposures, part of the familial clustering of cutaneous malignant melanoma (CMM) might be due to familial aggregation of melanoma-associated phenotypes. Our goal was to assess the patterns of familial aggregation of three melanoma risk factors: great number of naevi (GNN), light phototype (LP) and high degree of sun exposure (HDSE). Methods Familial aggregation of GNN, LP and HDSE was investigated in 66 French families with at least two CMM cases and was measured by the asssociation of the relatives’ traits with the probands’ traits, using the generalized estimating equations approach. The probands were the melanoma cases leading to ascertainment of the families, subdivided into cases (with the trait studied) and controls (without the trait). Results We found significant evidence for familial aggregation of GNN only among sibs (OR = 3.7, 95% CI : 1.4‐10.5, P = 0.01), of LP among blood relatives (OR = 3.8, 95% CI : 1.8‐8.0, P = 0.004) and of HDSE among blood relatives (OR = 4.5, 95% CI : 2.1‐9.9, P , 0.001) and spouses (OR = 44.3, 95% CI : 5.1‐382.2, P , 10 ‐3 ). These results suggest that genetic factors might account for the clustering of GNN and LP and shared environment for the aggregation of HDSE. The GNN clustering was lower in families with increasing numbers of CMM (o3 cases) or presence of p16 mutations, the opposite being observed for LP and HDSE. Moreover, the familial aggregation of LP was significantly lower in families with highly sunexposed members. Conclusion Melanoma might not only result from specific genetic and environmental factors but also from those underlying melanoma-associated traits involving complex gene-gene and gene-environment interactions.

Segregation analysis of IgE levels in 335 French families (EGEA) using different strategies to correct for the ascertainment through a correlated trait (asthma).

Abstract: The main objective of this study was to search for a major gene controlling total serum immunoglobulin E (IgE) levels, an intermediate phenotype for asthma and allergy. We studied 335 French nuclear families of the EGEA study (Epidemiological study of the Genetics and Environment of Asthma), ascertained through asthmatic probands (123 are parents in the family, 212 children). Segregation analyses were performed by regressive models, which can take into account a major gene effect, various sources of familial covariation (genetic and/or environmental) as well as measured risk factors (i.e., age, sex, smoking habits). Different strategies were considered to account for the mode of ascertainment of the families through a correlated trait (asthma): the ascertainment mode was either ignored (strategy A) or taken into account by adjusting IgE levels for the position in the family, i.e., probands, blood relatives, spouses (strategy B) or excluding the asthmatic children-probands and computing the likelihood of each family conditionally on parents' IgE levels (strategy C). Whereas a major gene effect could not be detected with strategy A, strategies B and C showed evidence for the transmission of a dominant major gene for high IgE levels, which was more significant with strategy B. This gene does not interact with any of the covariates and is responsible for ≈15% of IgE variation (the allele frequency is 0.65). Genet. Epidemiol. 18:128–142, 2000. © 2000 Wiley-Liss, Inc.