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Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major public health problem worldwide, resulting in 8.7 million new cases and 1.4 million deaths each year. One third of the world's population is exposed to M. tuberculosis and, after exposure, most, but not all, individuals become infected. Among infected subjects, only a minority (∼10%) will eventually develop clinical disease, which is typically either a primary, often extra-pulmonary, TB in children, or a reactivation, pulmonary TB in adults. Considerable genetic epidemiological evidence has accumulated to support a major role for human genetic factors in the development of TB. Numerous association studies with various candidate genes have been conducted in pulmonary TB, with very few consistent results. Recent genome-wide association studies revealed only a modest role for two inter-genic polymorphisms. However, a first major locus for pulmonary TB was mapped to chromosome 8q12-q13 in a Moroccan population after a genome-wide linkage screen. Using a similar strategy, two other major loci controlling TB infection were recently identified. While the precise identification of these major genes is ongoing, the other fascinating observation of these last years was the demonstration that TB can also reflect a Mendelian predisposition. Following the findings obtained in the syndrome of Mendelian susceptibility to mycobacterial diseases, several children with complete IL-12Rβ1 deficiency, were found to have severe TB as their sole phenotype. Overall, these recent findings provide the proof of concept that the human genetics of TB involves a continuous spectrum from Mendelian to complex predisposition with intermediate major gene involvement. The understanding of the molecular genetic basis of TB will have fundamental immunological and medical implications, in particular for the development of new vaccines and treatments., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Only about 10% of individuals infected with Mycobacterium tuberculosis develop tuberculosis, yet there are over eight million new cases and two million deaths each year. Complex interactions between environmental factors (microbial and non microbial) and human factors (genetic and non genetic) determine the clinical outcome of M. tuberculosis infection, accounting for the lack of symptoms in most individuals and the development of disseminated disease in childhood or pulmonary disease in adulthood in a minority of cases, Epidemiological evidence points to a major role of human genetic factors in the development of tuberculosis. Numerous association studies of various candidate genes have been conducted, with variable results. The most consistent findings concern certain HLA class II alleles and variants of the natural resistance-associated macrophage protein 1 (NRAMP1) gene. The first major locus identified by genome-wide linkage screening was recently mapped to chromosome region 8q12-q13 in a Moroccan population, and precise identification of this major gene is ongoing. One fascinating finding in recent years is a Mendelian predisposition to tuberculosis. Tuberculosis was found to be the only phenotypic manifestation in several children with genetic defects of the IL-12/23-IFNgamma circuit, and particularly those with complete IL-12Rbeta1 deficiency The human genetics of tuberculosis shows a continuum from Mendelian to complex predisposition with intermediate effects of major genes. A more thorough understanding of the molecular genetic basis of tuberculosis will have fundamental immunological and medical implications, particularly for the development of new vaccines and treatments.

Herpes simplex virus type 1 (HSV1) is frequent but usually benign in childhood Between 40% and 60% of adolescents have circulating anti-HSV1 antibodies by the age of 16 years. However, HSV1 infection is occasionally associated with encephalitis (fever, seizures, frequently altered consciousness, elevated CSF protein levels and lymphocyte counts, and EEG and MRI abnormalities). The etiologic diagnosis is based on lumbar puncture and detection of the viral genome or specific antibodies in CSF. Despite antiviral treatment with acyclovir, there is a high risk of sequelae such as epilepsy and severe mental retardation. The response to microbial pathogens is largely influenced by the host's genetic background (factors of resistance and predisposition), including Mendelian monogenic determinants. During the period 1985-2004, we conducted a molecular study based on a candidate gene strategy in 85 children with HSV1 encephalitis. The children belonging to 51 families, of which 7 were consanguineous. Five different mutations have so far been identified in 8 of these families, affecting genes encoding either Toll-like receptor 3 (TLR3) or a protein involved in intracellular signal transduction from this receptor to the interferon "a gene promoter", preventing the synthesis of this key molecule in the anti-HSV1 immune response.

Fifty years ago, the first identification of a non Mendelian genetic contribution to the development of a common infectious disease, i.e. the association between malaria and sickle-cell trait, was shown using a supervised approach which tests a limited number of candidate genes selected by hypothesis. Since then, the few genes that were convincingly associated with susceptibility to human infectious diseases were identified following the same strategy. The study of leprosy has contributed to modifying this way of thinking. In the absence of a satisfying experimental model and because of the impossibility to grow the causative agent in vitro, the candidate gene approach has turned out to be of limited interest. Conversely, positional cloning led to the identification of two major genes involved in the control of the disease, establishing for the first time the oligogenic nature of a human genetic contribution to an infectious disease. It is likely that these major results obtained in leprosy and the recent burst of genomic tools will make the genome-wide screening (functional or positional) the main strategy of dissection of the genetic susceptibility to many common infectious diseases.

Tuberculosis, caused by Mycobacterium tuberculosis, is the most common mycobacterial disease in the world and remains a leading public health problem. Numerous other mycobacterial species are present in the environment and are most often termed atypical or nontuberculous mycobacteria. Like the attenuated vaccine Bacille Calmette-Guérin (BCG) they are generally poorly virulent, even so they can be at the origin of severe infections if the host immune response is impaired. It has been clearly demonstrated that the intrinsic virulence of a mycobacterial species is not the only factor determining disease severity, which is illustrated by the observation that the majority of individuals infected with M. tuberculosis do not develop clinical disease. Numerous arguments suggest that disease severity depends largely on susceptibility/resistance determined by the host genetic make up. In the following review we will discuss the studies on the genes implicated in complex predisposition to tuberculosis and Mendelian predisposition to disease caused by less virulent mycobacteria, proposing a continuous spectrum between those two types of predisposition.

Human herpesvirus 8 (HHV-8), also called Kaposi's sarcoma-associated herpesvirus (KSHV), is not a ubiquitous virus. In countries with a low viral seroprevalence (< 5% in adult general population) as the USA, Northern Europe and Asia, the infection concerns essentially homosexual men. In this latter population, the viral transmission seems to occur during sex. In endemic countries (HHV-8 seroprevalence between 10-70% in the adult general population) as in the Mediterranean basin (Italy, Greece), and Africa (East and Central Africa), men, women and children are infected. In these countries, HHV-8 seroprevalence increases with age and often reaches adult rates before the end of puberty. Viral transmission, in general endemic populations, seems to occur from mother to child and between sibs whereas heterosexual transmission appears to concern essentially groups at risk for sexual transmitted diseases. Saliva is a major reservoir of HHV-8.

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.

The development of genetic epidemiology methods using recent human genetic mapping information together with the growing availability of candidate genes has led to major advances in the identification of host genes in human schistosomiasis. Two phenotypes have been studied so far in the infection by Schistosoma mansoni: infection levels by the parasite as measured by the faecal egg counts, and the severe hepatic fibrosis caused by S. mansoni assessed by ultrasound examination. The first study was performed on Brazilian pedigrees and provided strong evidence for a major gene controlling infection levels by S. mansoni denoted as SM1 which was mapped to chromosome 5q31-q33. This region contains several candidate genes involved in the regulation of the Th1/Th2 response, and the direct role of polymorphisms located within these genes is under investigation. The second study conducted in Sudan also showed the presence of a major gene influencing the development of severe hepatic fibrosis due to S. mansoni infection denoted as SM2. This gene is not located in the 5q31-q33 region, but maps to chromosome 6q22-q23 and is closely linked to the IFN-gamma R1 gene encoding the receptor of the strongly anti-fibrogenic cytokine Interferon-gamma. These findings indicate that two distinct genetic loci control human predisposition to schistosomiasis, SM1 located in the 5q31-q33 region which is likely to play a role in the Th1/Th2 differentiation, and SM2 in 6q22-q23 influencing disease progression with a possible involvement in the regulation of IFN-gamma.

The development of genetic epidemiology methods using recent human genetic map together with the growing availability of candidate genes have led to substantial advances in the identification of host genes in human malaria. Investigation of these genes has progressed along two complementary ways: 1) The search for genes influencing the severe malaria clinical phenotype by means of population based case-control studies which showed the protective role of several red cell genetic defects (sickle cell anemia, a-thalassaemia ...) and that some polymorphisms of the TNF-alpha promoter region could predispose to cerebral malaria; 2) The investigation of the genetic regulation of malaria-related biological phenotypes (infection levels, immune response) by means of familial studies which underlined the influence of the 5q31-q33 chromosomal region in the control of Plasmodium falciparum blood parasitemia and the role of major histocompatibility complex (MHC) and non-MHC genes in the regulation of humoral and cellular response to various malarial antigens. Ongoing studies will precise the role of these genes and probably reveal the existence of other genes not identified yet. The impact of these findings on the understanding of malaria pathogenesis and on the design of future preventive and therapeutic strategies should be considerable.

Genetic factors have clearly been shown to play a role in controlling malarial infection in animal models. There is now also increasing evidence for the genetic control of malaria in man. We carried out a segregation analysis based on blood parasite load phenotype for a population of the town of Bobo-Dioulasso (Burkina-Faso). This analysis demonstrated a strong genetic effect. Our results were not consistent with the segregation of a major gene and thus suggest that parasite load is under the control of minor genes. The genetic effect was stronger in children than in adults. We carried out a regression analysis in children and found that there was an association between the phenotype for blood parasite load and the q31-33 region of chromosome 5. We identified a gene in this region, Pfil1 (Plasmodium falciparum infection levels 1), which accounted for almost 50% of the variance in blood parasite load and which played a fundamental role in the control of infection. The 5q31-33 region contains several genes encoding cytokines that regulate T lymphocytes. The identification of genes controlling malarial infection opens up new possibilities for preventive and treatment strategies. It should be possible in the near future to identify individuals at risk of malaria, who would derive the greatest benefit from preventive and therapeutic measures. Finally, a deeper understanding of these genes controlling protective immune responses could be of value for the development of vaccines.

The capacity of certain individuals to resist certain diseases, including leprosy, has for a long time been considered as being influenced by genetic factors. The clinical and pathological spectrum of leprosy, epidemiological heterogeneity, both geographic and ethnic, in the prevalence of polar forms, may be explained by genetic differences in host resistance. While the specific genes in question have not been identified, recent studies suggest a genetic basis for differences in the capacity of macrophages in the host to reduce bacterial multiplication. Experimental models analyzing the reactions of antimycobacterial defence have underscored at existing differences in resistance or vulnerability to infection (M. bovis, BCG, M. lepraemurium, M. tuberculosis) were guided by a dominant gene which exists in two allelic forms, bcgr and bcg5. The bcgr allele confers resistance and is more dominant than the bcgs allele which represents greater vulnerability to infection. The murine candidate gene for the bcg gene has been named NRAMP (Natural Resistance-associated Macrophage Protein). Even though the exact function of NRAMP is not currently known, it has been demonstrated that this gene is expressed mainly in macrophages, and that it brings about increased bacteriostatic capacity in these cells. NRAMP is structurally homologous to the family of membranous proteins having a transport function linking ATP. NRAMP is similar to the membranous bacterial system transporting nitrites. The NRAMP protein is also involved as a signal of transduction during the activation of macrophages. It is therefore possible to conceive of genetic polymorphism at this locus intervening in specific and non-specific immune responses to infection. Apart from such potential polymorphism during the initial phase of infection, immunogenetic studies suggest that the polymorphism of class II HLA molecules could intervene in the evolution of secondary immune response to M. leprae. Knowing that HLA molecules are expressed in a co-dominant form, and attributing extraordinary allelic polymorphism to this locus, there may be a rather wide range of immune responses to the M. leprae antigens in subjects with discordant HLA and in populations which have varied genetic profiles. In general it has been acknowledged that HLA-DR isotypes are associated with protective response, while HLA-DQ isotypes are said to be associated with multibacillary lepromatous forms. The chief role of the HLA systems controlling cell-mediated immunity leads to the probability that differences in HLA haplotypes could contribute to the wide spectrum of immune responses observed in leprosy. Genetic determinants of resistance to leprosy cannot be described in a straightforward manner using a classic approach because the complex mechanisms of resistance, yet to be clarified and for which at least two loci are believed to be contributory, may be re-assessed like a multifactorial, multigenetic complex in which environmental events linked to the transmission of M. leprae, its duration, intensity and host factors, varying as a function of time, intervene. A close study of each element and better understanding of the physiological and pathological mechanisms of infection and disease are necessary in order to state the influence of genetic factors on each of them with greater precision.

Genetic epidemiology is a new tool for the study of malaria, with interesting incidence in the comprehension of host/parasite interrelations. The existence of a co-dominant major gene, with a mendelian transmission, controlling the levels of parasitemia has been found out. This allele has a frequency of 24% which means that about 6% of the population is predisposed to high parasitemias. These studies show the interest to integrate the existence of a genetical variability in the development and the evaluation of malaria control programmes. They are offering new perspectives in therapeutics and in the elaboration of vaccinal strategies.

Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates and megacolon in infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR. Recently, a gene for HSCR has been mapped to chromosome 10q11.2. No recombination was observed between the disease locus and the locus for the RET proto-oncogene, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. Here we report on nonsense and missense mutations in the extracellular domain of the RET protein (exons 2, 3, 5 and 6) in 6 unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A). Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.