[Application of genetic epidemiology to dissecting susceptibility to leprosy].
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Epidemiologic Studies↗
Biomedical subjects
A Alcaïs
Publications and source records attributed to A Alcaïs.
[Human mycobacterial infections: impact of host genetic factors].
Humans are exposed worldwide to a variety of environmental mycobacteria (EM) and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. Although rarely pathogenic, poorly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. M. tuberculosis and M. leprae are more virulent, causing tuberculosis, and leprosy, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. There is now accumulating evidence that the large interindividual variability of clinical outcome results in part from variability in the human genes that control host defense. We review here in current knowledge about genetic predisposition to common (leprosy and tuberculosis) and rare (BCG and EM infections) mycobacterial infections.
Genetic Predisposition to Disease↗
An autosome-wide search for loci underlying wheezing age of onset in German asthmatic children identifies a new region of interest on 6q24-q25.
While numerous familial studies of asthma have identified several distinct chromosomal regions, no linkage studies have been performed taking into account the age of onset of disease. Here, we performed a genome-wide scan to search for loci linked either to asthma or wheezing age of onset in a population of German asthmatic children by incorporating survival analysis techniques in the maximum-likelihood-binomial approach. In addition to several regions already reported in asthma, wheezing age of onset was found to be strongly linked to chromosome 6q24-q25 (lod score = 3.56). Interestingly, this region contains some candidates genes such as the gene coding for the IFN-gamma receptor ligand-binding chain.
Adolescent↗
[Human genetics of tuberculosis: a continuous spectrum of simple monogenic predisposition to complex polygenic heredity].
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Cation Transport Proteins↗
Incorporation of covariates in multipoint model-free linkage analysis of binary traits: how important are unaffecteds?
When the mode of inheritance is unknown, genetic linkage analysis of binary trait is commonly performed using affected-sib-pair approaches. When there is evidence that some covariates influence the phenotype, incorporation of this information is expected to increase the power of the analysis since it allows (1) a better specification of the phenotype and (2) to take into account unaffected subjects. Here, we show how to account for covariates in the sibship-oriented Maximum-Likelihood-Binomial (MLB) linkage method by means of Pearson's logistic regression residuals which are computed using phenotypic and covariate information on both affected and unaffected subjects. These residuals are subsequently analysed as a quantitative phenotype with the corresponding extension of the MLB approach which can be used without any assumption on the distribution of these residuals. Then, a large simulation study is performed to study the relative power of incorporating or not unaffected sibs. To this aim, two different strategies in the multipoint analysis of family data are compared: (1) using residuals of the whole sibships (ie both covariate and genotypic information on unaffecteds is needed), and (2) using affecteds only (no information on unaffecteds is needed), under different generating models according to genetic and covariate effects. The results show that there is a clear increment in the power to detect the susceptibility locus when making use of the information carried by unaffecteds, in particular for dominant mode of inheritance and when values of the covariates influencing the disease are shared by all the members of the family.
Analysis of Variance↗
Granulomatous reaction to intradermal injection of lepromin (Mitsuda reaction) is linked to the human NRAMP1 gene in Vietnamese leprosy sibships.
The Mitsuda test, which measures the specific immune response against intradermally injected lepromin, has a high prognostic value for susceptibility or resistance to the lepromatous form of leprosy. A sib-pair linkage analysis between the Mitsuda response and the NRAMP1 gene was done among 20 nuclear families with leprosy (totaling 118 sibs) from Ho Chi Minh City, Vietnam. All family subjects were genotyped for several intragenic and flanking NRAMP1 markers, leading to the definition of a fully informative NRAMP1 haplotype. Significant linkage was observed between NRAMP1 and Mitsuda reaction when considered either as a quantitative (P<.002) or as a categorical (P=.001) trait. Separate analyses among healthy and affected sibs showed evidence for linkage in both subsamples, indicating that linkage between the Mitsuda reaction and NRAMP1 is independent of leprosy status. These results support the view that NRAMP1 plays a regulatory role for the development of acquired antimycobacterial immune responses as determined by in vivo Mitsuda test reaction.
Carrier Proteins↗
Maximum-Likelihood-Binomial method for genetic model-free linkage analysis of quantitative traits in sibships.
Sib-pair linkage studies are widely used to investigate the genetic factors implicated in complex quantitative traits. To analyze these data, we propose a Maximum-Likelihood-Binomial (MLB) approach, which considers the sibship as a whole and relies on the idea of binomial distributions of parental alleles among offsprings. The method is based on the introduction of a latent binary variable capturing the linkage information between the observed quantitative trait and the marker, and the final likelihood can be expressed assuming a parametric distribution for the studied trait but also without any assumption on this distribution. The test for linkage is a simple likelihood ratio test involving a single parameter. The performances of the MLB method are assessed by a simulation study in different kinds of family samples. In the case of families with various sibship sizes, both MLB approaches (assuming or not a parametric distribution for the quantitative trait) provide very consistent results in terms of type I errors and yield power levels generally higher than those of the classical Haseman-Elston method. In the case of extremely discordant sib pairs, we analytically show that, for a common asymptotic type I error, the distribution-free MLB statistic is expected to be more powerful than the test proposed by Risch and Zhang [(1995) Science 268:1584-1589]. In samples including both extremely concordant and discordant sib-pairs, simulation studies show that the MLB approach is at least as powerful as the EDAC method [Gu et al. (1996) Genet Epidemiol 13:513-533]. This MLB method, which can be easily extended to perform multipoint analysis and to account for genetic heterogeneity, appears to be quite an interesting alternative for mapping quantitative trait loci in humans.
Alleles↗
Genetic model-free linkage analysis using the maximum-likelihood-binomial method for categorical traits.
Within the simulated data of the 11th Genetic Analysis Workshop, we searched for the genes controlling the disease. We analyzed 200 families from Studies 2 and 3 presenting both mild and severe forms of disease. Linkage analysis was performed using the recently developed genetic model-free maximum-likelihood-binomial (MLB) method which overcomes the problem of multiple sibs by considering the sibship as a whole. The MLB allowed us to consider the disease as either a binary (affected/unaffected) or an ordered categorical (differentiating the two forms of disease and including effects of environmental factors) phenotype. In both studies, two regions provided evidence for linkage at a significance level below 10(-4). One is located on chromosome 3 (from D3G041 to D3G047), and the other on chromosome 5 (from D5G034 to D5G041). In Study 2, the most significant results were obtained by combining both forms of disease, suggesting that they are under the same genetic control, while in Study 3, the stronger results were obtained when considering severe subjects alone, suggesting that only the severe form is under the control of both locus B and C. The subsequent knowledge of the true model allowed a posterior interpretation of our results, in particular the difference in optimal coding schemes observed between Studies 2 and 3, and the failure to locate locus A.
Alleles↗
Evidence for a major gene controlling susceptibility to tegumentary leishmaniasis in a recently exposed Bolivian population.
Tegumentary leishmaniasis due to Leishmania braziliensis is a parasitic disease that occurs in two stages after the infected sandfly bite: (1) a primary cutaneous lesion followed by (2) a secondary mucosal involvement generally resulting in severe facial deformities. In order to investigate the genetic and environmental factors involved in the development of the cutaneous lesion, a familial study was performed in a region of Bolivia in which the disease is endemic. Complete selection of 118 nuclear families (703 subjects, with 241 patients), each with at least one cutaneous affected subject, was achieved; 41 families were of native origin, and 77 (herein designated "migrant") recently had settled in the area. For the analysis, the trait under study was the time to onset of the primary cutaneous lesion. The start of the follow-up was birth, for native population, or date of arrival in the endemic area, for migrant population. Segregation analysis was performed by use of a model based on survival analysis methods that allows joint estimation of genetic and environmental effects and accounts for gene x covariate interactions. A significant effect of gender, home-forest distance, and forest-related activity was found. In the 77 migrant families there was evidence for a recessive major gene controlling the onset of the primary cutaneous lesion, with residual familial dependences and age x genotype interaction. Penetrance estimations show that young subjects are genetically more susceptible than older subjects, suggesting that this genetic component could concern mechanisms involved in the development of individual protection during childhood. There was also a significant genetic heterogeneity of the sample according to the native/migrant origin of the families, and no major-gene effect was found in the native subsample.
Adult↗
Radioiodine therapy of the autonomous thyroid nodule in patients with or without visible extranodular activity.
UNLABELLED: Patients with an autonomously functioning thyroid nodule (ATN) may be present with various clinical, biochemical and scintigraphic features. To optimize 131I dose planning and treatment timing in these patients, relationships between dosimetric data and clinical follow-up events must be established. METHODS: We retrospectively reviewed the records of 88 patients who received 131I (intended dose of 80 Gy) for an ATN, of whom 39 had evidence of extranodular activity (ENA) and 76 presented with overt thyrotoxicosis. In all of the patients, dosage calculation was monitored to estimate precisely both beta and gamma absorbed doses received by the ATN and the nodule-free lobe. The mean duration of follow-up was 75 mo (max 180) and always included biochemical thyroid tests. Finally, we compared the dosimetric profiles of four dosage schemes which had been normalized by simulation to ensure that the same absorbed dose threshold value was always delivered to the ATN. RESULTS: About 75% of the patients were cured at 6 mo for a mean 305 MBq administered. The absorbed doses delivered to the nodule-free lobe ranged from 12% (no ENA) to 86% (ENA) of the values delivered to the ATN, mainly in the form of beta irradiation. Life-table estimates for hypothyroidism and death were 9.6% and 22% at 75 mo, respectively. Hypothyroidism mainly developed in patients with nonsuppressed TSH levels but regardless of ENA, which often accounted for multifocal disease. CONCLUSION: We suggest that fixed doses bordering on 370 MBq are advizable in younger individuals and in patients with mild thyrotoxocosis, while 555 MBq-740 MBq can be administered in other patients and that ENA indicates multifocal autonomy in patients with toxic ATN and is a further indication for radioiodine treatment which should be begun as soon as possible to avoid the development of cardiac complications.
Aged↗
Linkage analysis of quantitative trait loci: sib pairs or sibships?
Sib pair linkage studies are now widely used to investigate the genetic factors implicated in complex quantitative traits. To increase the power of these approaches, it has been proposed to select extremely discordant (ED) sib pairs which are expected to contain the highest linkage information. However, it is known that sibships of larger size contain more linkage information than independent sib pairs. In this paper we compare, in terms of power and cost considerations, the ED strategy, which uses information on sib pairs only, to the recently developed 'Maximum Likelihood Binomial' sibship-oriented method performed on the whole sibships from which the ED sib pairs have been extracted. We show that the use of these whole sibships is an efficient alternative to approaches focusing on ED sib pairs only.
Algorithms↗