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F Demenais

Publications and source records attributed to F Demenais.

At least 55 records · Page 3Linked to original sources
PubMed1996

Genetic and epidemiological risk factors for a malignant melanoma-predisposing phenotype: the great number of nevi.

Multiple genetic and epidemiological factors are involved in the etiology of cutaneous malignant melanoma. The phenotype defined by a great number of nevi (GNN) is consistently reported as being a major risk factor for melanoma and is likely to be under genetic control. As part of a large genetic and epidemiologic survey of melanoma in France, our goal was to understand the pattern of inheritance of GNN in 295 nuclear families ascertained through 295 melanoma probands. The GNN phenotype was defined as having 50 or more nevi vs. less than 50 nevi. Four percent of the 295 families included at least 2 GNN cases. We found that sun exposure during holidays and propensity to sunburns were significantly associated with GNN, independent of the occurrence of melanoma. Four segregation analyses of GNN were conducted, using the class D regressive logistic model, which differed according to the sampling procedure chosen (with and without the melanoma probands) and the inclusion or not of the significant risk factors. Three of these analyses led to the detection of a recessive-like major factor, which did not fit a Mendelian pattern of inheritance in two of them. Our results are discussed with respect to the low familial clustering of GNN, the type of analysis conducted, the characteristics of the model used, and the complexity of the mechanisms underlying the GNN phenotype.

Female↗
PubMed1996

The relationship of body mass index to reproductive factors in pre- and postmenopausal African-American women with and without breast cancer.

To date, there are virtually no existing data on the relationship between obesity, menopausal status, and breast cancer in African-Americans. Therefore, the present study was designed to test the following hypotheses in an African-American population: (1) there exists a positive association between BMI and breast cancer among postmenopausal women; (2) there exists an inverse association between BMI and breast cancer among premenopausal women; and (3) similar associations between BMI and reproductive factors exist for both pre- and postmenopausal breast cancer cases. The study population comprised 357 African-American women (n = 193 breast cancer cases; n = 164 controls). No significant differences were observed between premenopausal cases and controls for BMI, obesity categories, and reproductive factors. Among the postmenopausal women, the cases had significantly lower weight and BMI levels than the controls. Age at first pregnancy and parity were significantly lower among postmenopausal cases than their controls. No significant associations were revealed between body mass index and breast cancer for pre- and postmenopausal women. In the present study, early age at menarche was the only reproductive factor that was an independent predictor of BMI for both pre- and postmenopausal women, irrespective of breast cancer status. Also, these findings strongly suggest the need to consider reproductive factors, particularly age at menarche, as a covariate of BMI and other obesity-related diseases.

Adult↗
PubMed1996

Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach.

The changes in the type of haemoglobin (Hb) produced during embryonic, fetal and adult life, have served as a paradigm for understanding the developmental regulation of human genes. A genetically determined persistence of fetal Hb synthesis has an ameliorating effect on beta thalassaemia and sickle cell anaemia, globally the commonest single gene disorders. The search for the putative gene(s) controlling the level of fetal Hb production has been extremely difficult because this trait may be influenced by several factors. We have studied a large kindred with hereditary persistence of fetal haemoglobin (HPFH). Using a genetic mapping strategy and statistical methods that account simultaneously for the effects of several genetic factors, we have demonstrated that in addition to the two factors (beta thalassaemia and Xmn I-G gamma site) on chromosome 11p, there is a third major genetic determinant for fetal Hb production localized on chromosome 6q.

Chromosomes, Human, Pair 11↗
PubMed1996

Indication for linkage of the human OB gene region with extreme obesity.

Obesity is one of the most significant risk factors for hypertension, coronary heart disease, and NIDDM (Frayn KN, Coppack SW: Insulin resistance, adipose tissue and coronary heart disease. Clin Sci 82:1-8, 1992; Kaplan NM: The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 149:1514-1520, 1989). While family segregation, adoption, and twin studies have indicated that degree of adiposity has a significant genetic component (Stunkard AJ, Harris JR, Pedersen NL, McClearn GE: The body-mass index of twins who have been reared apart. N Engl J Med 322:1483-1487, 1990; Bouchard C, Despres J-P, Mauriege P: Genetic and nongenetic determinants of regional fat distribution. Endocr Rev 14:72-93, 1993), the genes and predisposing mutations remain poorly understood. This is in contrast to several well-defined genetic models for obesity in rodents, particularly the mouse obese (ob) gene, in which loss-of-function mutations cause severe obesity. Recent studies have demonstrated a substantial reduction in body fat when recombinant ob protein (leptin) is administered to mice. To test the relevance of these observations to human obesity, the location of the human homologue (OB) was established by radiation hybrid mapping and eight microsatellite markers spanning the OB gene region (7q3l.3) were genotyped in 101 obese French families. Affected-sib-pair analyses for extreme obesity, defined by BMI >35 kg/m2, revealed suggestive evidence for linkage to three markers located within 2 cM of the OB gene (D7S514, D7S680, and D7S530). The OB gene is therefore a candidate for genetic predisposition to extreme obesity in a subset of these families.

Alleles↗
PubMed1996

[The PROGENE study, the French project of genetic analysis of familial prostatic cancer: recruitment and analysis].

OBJECTIVES: To initiate a genetic linkage study in order to localize one or several predisposition gene(s) for hereditary prostatic cancer (PC), as various epidemiological studies have demonstrated a possible family aggregation in about 25% of cases. A family segregation study [14] has also shown that a genetic predisposition, with autosomal dominant transmission and high penetrance (88% at 85 years) could be responsible for 9% of all PC. METHODS: A national collection of families with at least 2 cases of PC allowed: 1) identification of families with hereditary forms of PC, 2) creation of a constitutional DNA bank after collecting blood samples from subjects belonging to these families, and 3) a simulation study of genetic linkage analysis prior to microsatellite genotyping. RESULTS: From July 1994 to September 1995, we included 67 families (180 cases of PC). Another 45 families are currently being included. 24 of these 67 families (89 PC, 54 survivors) satisfied at least one of the criteria defined in the study by CARTER et al. for hereditary forms of familial PC. Two families were also included as the 3 patients with PC were second degree relatives. A total of 26 families therefore presented a hereditary form, 18 of which (73 PC, 46 survivors) were considered to be informative for a genetic linkage study (lod score = 4 for theta = 0.001 with an 8 allele marker). The constitutional DNA of 271 individuals of these informative families was extracted from circulating cells obtained from blood samples, immortalized lymphocytes, and the genotyping was initiated for 216 microsatellite markers distributed throughout the genome, an average of every 20 cM. CONCLUSION: Although the recruitment allowed us to identify many informative families for an inherited risk of PC, the predictive study suggested a high probability for localization of a predisposition gene by genetic linkage analysis. It would therefore be possible to identify, within the families concerned, the subjects carrying the genetic anomaly and consequently at high-risk of PC. Finally, the demonstration of the locus would allow cloning and identification of the gene (s) involved.

Female↗
PubMed1996

Candidate gene approach of familial morbid obesity: linkage analysis of the glucocorticoid receptor gene.

BACKGROUND: Morbid obesity is a multifactorial disease, with a strong but almost unknown genetic component. Familial linkage studies using the candidate gene approach have been shown to be powerful tools for identifying susceptibility genes for inherited diseases. AIM OF THE STUDY: We have investigated the role of the Glucocorticoid Receptor gene (GRL) in morbid obesity. SUBJECTS: Eighty obese families were recruited through a multimedia campaign (42 families, sample 1) or from the department of nutrition of the Hotel Dieu hospital in Paris (38 families, sample 2). METHODS: A multipoint linkage analysis with markers on chromosome 5q placed the GRL gene between D5S658 and D5S436 at genetic distances of 3.5 and 5 centimorgans, respectively. Using this map, we have chosen seven polymorphic microsatellite markers located in the vicinity of the GRL gene locus for sib pair linkage analysis. In addition to the obesity status, different quantitative phenotypes associated with obesity and insulin resistance were used for analysis. RESULTS: In sample 1, the results show a tendency towards linkage between three markers (one bc/1 intragenic RFLP and two microsatellite markers) in the GRL region and obesity characterised by a BMI > 27. However, using this phenotype, we failed to replicate the results in the second set of families. When using a more precise phenotype (the individual coefficient of variation of the BMI compared to a sex and age matched French reference population (pop) defined as the Zscore (indBMI-popBMI/SD of popBMI), a tendency for linkage was found for one marker in sample 2 as well as in the whole sample. No linkage was found when using quantitative traits associated with obesity. CONCLUSION: The GRL locus does not appear to be a major locus for obesity, but we cannot exclude that this gene or gene located nearby may have some minor effects on the obese phenotype or may be involved in some subtypes of obesity. Larger cohorts of families are probably necessary to improve the power of such linkage analysis in this heterogeneous disease.

Adult↗
PubMed1996

Indication for genetic linkage of the phosphoenolpyruvate carboxykinase (PCK1) gene region on chromosome 20q to non-insulin-dependent diabetes mellitus.

There is strong evidence that non-insulin-dependent-diabetes mellitus (NIDDM) has a polygenic mode of inheritance. Nevertheless, major gene effects may be involved in its pathogenesis, especially in forms with an early age of onset. We performed linkage analyses between 4 candidate genes for insulin resistance and NIDDM in a set of 55 multigenerational French Caucasian families, using the affected sib-pair approach. No significant results were obtained with glycogen synthase (GSY), insulin receptor substrate-1 (IRS-1) and apolipoprotein C-II (APOC-II) genes. However, a significant trend towards linkage was found between NIDDM and the phosphoenolpyruvate carboxykinase gene (PCK1) located on chromosome 20q (p = 0.005 for the mean estimated proportion of alleles shared identically by descent, mean IBD = 0.55), particularly among sib-pairs with diabetes diagnosed before the age of 46 years (p = 0.0003, mean IBD = 0.66). These results suggest that the PCK1 gene or a nearby locus contributes to the development of NIDDM in the French population.

Alleles↗
PubMed1995

Detection of a recessive major gene for high IgE levels acting independently of specific response to allergens.

The genetic control of the total IgE, the immunoglobulins E involved in allergy, remains still unclear. Although high IgE levels were found to be determined by a recessive major gene in several studies, other modes of inheritance were also reported. Moreover, at least two different genetic mechanisms controlling the IgE regulation have been suggested: one involved in the specific IgE response and the other one in the nonspecific response. To better understand the genetic mechanisms controlling IgE variation, we performed segregation analysis of IgE levels by ignoring or taking into account the specific response to allergens (SRA). Analyses were conducted using the class D regressive model, in a sample of 234 Australian nuclear families randomly selected during the winter months, when IgE levels are the lowest (basal). SRA, when included as a covariate in the model, was defined by one of the three following criteria: (1) raised specific IgE level for one or more allergens, (2) positive skin test for one or more allergens, and (3) at least one of the (1) or (2) criteria. When the presence of SRA is ignored, the familial transmission of total IgE level is compatible with the segregation of a recessive major gene and residual familial correlations. When the presence of SRA is accounted for in the analysis, whether defined by criteria (1), (2), or (3), there is still evidence for a recessive major gene controlling IgE levels but residual familial correlations are no longer significant. In addition, no interaction between this major gene and SRA is shown here. Our results suggest that this gene, which accounts for 28% of the variation of the trait, may be involved in the control of basal IgE production, independently of specific response to allergens.

Adolescent↗
PubMed1995

Complex segregation analysis of familial diseases with variable age of onset: comparison of different methods by a simulation study.

Standard methods of segregation analysis, such as originally developed in the unified model (UM) or the regressive logistic model (RLM) do not account for age of onset, and use instead age at examination. To take into account age of onset, models should be formulated using survival analysis concepts, as it was recently proposed with a model based on a logistic hazard function (LHM). A simulation study was conducted to compare the performances of the three methods (UM, RLM, and LHM) in analyzing generated familial data with variable age of onset. When the data were simulated under a polygenic hypothesis, all analysis models were robust with respect to the false conclusion of a major gene, if the tests of transmission probabilities were performed properly. When the data were generated under a major gene hypothesis, two main results were observed: 1) the use of the LHM markedly increased the power to detect a major gene, in particular when a genotype by age interaction was introduced in the model; and 2) in the situation of disease-specific mortality, the use of either UM (whether specific mortality was accounted for or not) or RLM led to both spurious conclusions and bias in parameter estimates. These latter results obtained with the UM and the RLM can be explained by the violation of one constraint of both models observed in a situation of disease-specific mortality, i.e., given all covariates, the probability of being affected and that of not being affected should sum to 1. The use of methods based on survival analysis concepts is recommended in the study of familial diseases with variable age of onset, especially in the case of a correlation between age of onset and age at examination which is induced by disease-specific mortality.

Adult↗
PubMed1995

How can maximum likelihood methods reveal candidate gene effects on a quantitative trait?

Different maximum likelihood approaches were used to explore the role of candidate genes in the variability of quantitative trait Q1 while accounting for the effects of age, Q2, and Q3. Segregation analysis, under the class D regressive model, provides evidence for a Mendelian gene effect on the adjusted trait Q1. Results of gene mapping through lod-score analyses remain puzzling. Pairwise lod scores indicate a possible linkage with the candidate gene C5 which is excluded when using tightly linked informative marker loci. Finally, our combined segregation and linkage analysis clearly shows that a C5 linked gene is involved in Q1 variability. However, given the lod-score results within the C5 region, we postulate a more complex mechanism for Q1 than a single di-allelic C5 linked gene. The knowledge of the true model (C5 is MG1 and has three alleles) permits a partial explanation of our results. This study demonstrates the advantages of using complementary approaches to reveal the role of candidate genes in complex traits, and the value of simultaneous estimation of linkage and segregation parameters.

Alleles↗
PubMed1995

Linkage analyses of the MODY3 locus on chromosome 12q with late-onset NIDDM.

Non-insulin-dependent diabetes mellitus (NIDDM) is a clinically and genetically heterogeneous disorder. Maturity-onset diabetes of the young (MODY), an autosomal dominant form of NIDDM, has been used as a model for genetic studies of NIDDM. We recently reported linkage between markers on chromosome 12q and diabetes in 25% of our French MODY families. To evaluate if this gene is also implicated in late-onset NIDDM, we performed linkage studies between two markers of the MODY region and diabetes in 172 families with late-onset NIDDM. Both parametric and nonparametric methods were used in a total of 600 affected sib-pairs. Linkage was rejected in this population by all methods, implying that the MODY gene on chromosome 12q is not a major gene for late-onset NIDDM in this population. However, we cannot exclude a modifying role in a polygenic disorder or an important role in some families.

Adult↗
PubMed1995

Comparison between familial and nonfamilial melanoma in France.

BACKGROUND AND DESIGN: Five percent to 10% of cutaneous malignant melanomas (CMMs) occur in a familial setting. Clinical, epidemiologic, and genetic studies of familial CMM in different regions of the world have led to various results. To assess the characteristics of familial CMM in France, the clinical, histologic, and epidemiologic characteristics of 295 patients with CMM were recorded, and a comprehensive familial investigation was performed for each case. Patients with a family history of CMM were compared with nonfamilial cases. RESULTS: Cutaneous malignant melanoma occurred as a familial cancer in 22 (8%) of 295 patients. Among the multiple variables studied, those significantly associated with the familial occurrence of CMM were red hair, inability to tan, and presence of clinically atypical moles. When these variables were considered together in a multivariate analysis, only the association with red hair (P = .001) and atypical moles (P < .05) remained significant. In addition, the patients with familial melanoma exhibited the following tendencies: a younger age at diagnosis, a higher number of moles, and the development of multiple primary melanomas, but these results did not reach statistical significance. Factors relating to UV light exposure, histologic features of CMM, course of the disease, and occurrence of nonmelanoma cancers showed a similar distribution between familial and nonfamilial cases. CONCLUSION: A familial investigation should be performed for each patient with CMM in France, particularly when he or she exhibits phenotypic risk factors for CMM such as red hair and atypical moles.

Adult↗
PubMed1994

Detection of a major gene for heterocellular hereditary persistence of fetal hemoglobin after accounting for genetic modifiers.

"Heterocellular hereditary persistence of fetal hemoglobin" (HPFH) is the term used to describe the genetically determined persistence of fetal hemoglobin (Hb F) production into adult life, in the absence of any related hematological disorder. Whereas some forms are caused by mutations in the beta-globin gene cluster on chromosome 11, others segregate independently. While the latter are of particular interest with respect to the regulation of globin gene switching, it has not been possible to determine their chromosomal location, mainly because their mode of inheritance is not clear, but also because several other factors are known to modify Hb F production. We have examined a large Asian Indian pedigree which includes individuals with heterocellular HPFH associated with beta-thalassemia and/or alpha-thalassemia. Segregation analysis was conducted on the HPFH trait FC, defined to be the percentage of Hb F-containing cells (F-cells), using the class D regressive model. Our results provide evidence for the presence of a major gene, dominant or codominant, which controls the FC values with residual familial correlations. The major gene was detected when the effects of genetic modifiers, notably beta-thalassemia and the XmnI-G gamma polymorphism, are accounted for in the analysis. Linkage with the beta-globin gene cluster is excluded. The transmission of the FC values in this pedigree is informative enough to allow detection of linkage with an appropriate marker(s). The analytical approach outlined in this study, using simple regression to allow for genetic modifiers and thus allowing the mode of inheritance of a trait to be dissected out, may be useful as a model for segregation and linkage analyses of other complex phenotypes.

Adolescent↗
PubMed1993

Genetic analysis of diabetes and insulitis in an interspecific cross of the nonobese diabetic mouse with Mus spretus.

The nonobese diabetic (NOD) mouse is a widely used model for genetic studies of insulin-dependent diabetes mellitus due to the similarities between the murine and human diseases. To aid in the localization and identification of diabetes-related susceptibility genes, we have constructed an interspecific backcross between NOD and Mus spretus (SEG/Pas) mice. Although no diabetic animals were observed in the first backcross generation of (SEG/Pas x NOD) x NOD (BC1), the incidence of insulitis (lymphocyte infiltration of the islets of Langerhans) exceeded 20% after injections of cyclophosphamide, a treatment that provokes an acute form of diabetes in NOD mice. Insulitis, a prediabetic condition, is a useful phenotype in studies of diabetes susceptibility. In the second backcross (BC2) generation, 8% of the animals became diabetic and 76% were found to have insulitis. Genetic mapping studies in the BC2 families confirmed the importance of the major histocompatibility complex region on the severity of insulitis and suggested that additional susceptibility loci were linked to markers on mouse chromosomes 3, 6, and 15. Mus spretus crosses have been an important tool in recent advances in murine genetics, and our results extend their usefulness to the study of a multifactorial disease.

Animals↗
PubMed1993

Use of the regressive models in linkage analysis of quantitative traits.

Use of the regressive models to account for residual familial correlations in linkage analysis of complex quantitative traits can increase the power to detect linkage. This is especially observed when the effect of the gene to be mapped is small or when the residual correlations are substantial.

Chromosome Mapping↗
PubMed1993

Linkage analysis and molecular scanning of glucokinase gene in NIDDM families.

Mutations in the glucokinase gene are a major cause of maturity-onset diabetes of the young. To evaluate the contribution of this gene to the development of late-onset NIDDM, linkage analyses between DNA polymorphisms at the glucokinase locus and NIDDM were performed in 79 multigenerational French families. In addition, all exons and the islet promoter region of glucokinase gene from 1 affected member from each family as well as from 17 unrelated women with previous gestational diabetes were amplified by polymerase chain reaction and screened for mutations by single-strand conformational polymorphism and DNA sequencing. Linkage of glucokinase and NIDDM was significantly rejected under all models tested. However, in 1 family, the lod score was 2.30, and we found a nucleotide substitution at the position -30 in the islet promoter region that cosegregated with diabetes. The proband of this family was a gestational diabetic individual. No other mutation in glucokinase was found in the 79 NIDDM families. We identified a missense mutation (TGG257-->CGG257) in exon 7 of glucokinase gene from 1 of 17 women with gestational diabetes, which was present in all diabetic members of her family. This family is likely to be a cryptic maturity-onset diabetes of the young, as 4 younger members, carrying this mutation, were subsequently found to be hyperglycemic. In conclusion, no evidence was obtained to incriminate glucokinase as a major gene for late age of onset NIDDM. Diabetic families with mutations in glucokinase must be carefully investigated, to differentiate cryptic maturity-onset diabetes of the young from late-onset NIDDM. Furthermore, pregnancy reveals diabetes in women carrying a glucokinase defect.

Adolescent↗
PubMed1993

Descriptive analysis of breast cancer in African-American women at Howard University Hospital, 1960-1987.

This article describes breast cancer cases seen at the Howard University Hospital from 1960 through 1987 using information from the database of the Tumor Registry, established in 1960. Clinical information at presentation is presented as well as a description of reproductive and demographic characteristics. Pre- and postmenopausal women are compared, revealing differences in reproductive experience. This may contribute to the increasing incidence of breast cancer seen among younger women in recent years. This is of particular interest because the classic excess of nulliparous women among breast cancer cases is not seen among the population described here.

Adult↗