Alexandre Alcaïs - Academia.edu (original) (raw)

Papers by Alexandre Alcaïs

Disseminated disease in children and pulmonary disease in adults constitute two major epidemiolog... more Disseminated disease in children and pulmonary disease in adults constitute two major epidemiological and clinical forms of tuberculosis. Paradoxically, only a small fraction of infected individuals develop clinical tuberculosis, typically one form of the disease or the other. Mendelian and complex genetic predispositions to tuberculosis were reported recently in children and adults, respectively. Here, we argue that tuberculosis and its clinical expression largely reflect the underlying human genetic background.

Current opinion in immunology, 2014

Infectious diseases are the result of the exposure of susceptible hosts to pathogenic microbes. G... more Infectious diseases are the result of the exposure of susceptible hosts to pathogenic microbes. Genetic factors are important determinants of host susceptibility and efforts are being made to establish the molecular identity of such genetic susceptibility variants by genome-wide association studies. Results obtained to date partly confirm already known genetic vulnerabilities, but also point to new and unexpected mechanisms of susceptibility that extend from classical innate and acquired immunity to weaknesses in constitutional resistance. These studies also revealed an overlap in genetic control between infectious disease and other common immune and inflammatory disorders.

Seminars in Immunology, 2006

The elucidation of the genetic control of susceptibility to common infectious diseases is expecte... more The elucidation of the genetic control of susceptibility to common infectious diseases is expected to provide new and more effective tools for prevention and control of some of the most pressings health needs on a global scale. A major advantage of whole genome based genetic approaches is that no a priori assumptions about mechanisms of pathogenesis need to be made in these studies. Hence, genetic studies can identify previously unrecognized pathways of disease susceptibility and tag critical pathogenic events for further biochemical, immunological or physiological analysis. We have applied this strategy to leprosy, a disease that still claims 400,000 new cases each year. We identified genetic variants in the shared promoter region of the PARK2 and PACRG genes as major risk factors of leprosy susceptibility. Both encoded proteins are part of the cellular ubiquitination system. Specifically, PARK2, the cause of early onset Parkinson's disease, is an E3 ligase that likely is involved in controlled proteolysis, the cellular anti-oxidants response and the regulation of innate immune responsiveness. In addition, numerous E3 ligases have recently been shown to be critical regulators of immunity. While the specific role of PARK2/PACRG in leprosy pathogenesis remains unknown, a number of experimentally testable scenarios can be developed to further explore the role of these proteins in anti-Mycobacterium leprae host responsiveness.

Current opinion in immunology, 2005

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects an estimated ... more Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects an estimated 700,000 new individuals each year. A strong contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability observed between individuals exposed to M. leprae. As there is no relevant animal model for human leprosy, forward genetics is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. With respect to genome-wide screens, a major breakthrough has been reported this year; variants in the regulatory region shared by PARK2 and PACRG have been identified as being common risk factors for leprosy.

Clinical Infectious Diseases, 2014

Mycobacterium ulcerans is known to cause Buruli ulcer (BU), a necrotizing skin disease leading to... more Mycobacterium ulcerans is known to cause Buruli ulcer (BU), a necrotizing skin disease leading to extensive cutaneous and subcutaneous destruction and functional limitations. However, M. ulcerans infections are not limited to skin, and osteomyelitis, still poorly described in the literature, occurs in numerous young patients in Africa. In a retrospective matched case-control study conducted in a highly endemic area in Benin, we analyzed demographic, clinical, biological, and radiological features in all patients with M. ulcerans infections with bone involvement, identified from a cohort of 1257 patients with polymerase chain reaction-proved M. ulcerans infections. The 81 patients studied had a median age of 11 years (interquartile range, 7-16 years) and were predominantly male (male-female ratio, 2:1). Osteomyelitis was observed beneath active BU lesions (60.5%) or at a distance from active or apparently healed BU lesions (14.8%) but also in patients without a history of BU skin lesions (24.7%). These lesions had an insidious course, with nonspecific clinical findings leading to delayed diagnosis. A comparison with findings in 243 age- and sex-matched patients with BU without osteomyelitis showed that case patients were less likely to have received BCG immunization than controls (33.3% vs 52.7%; P = .01). They were also at higher risk of longer hospital stay (118 vs 69 days; P = .001), surgery (92.6% vs 63.0%; P = .001), and long-term crippling sequelae (55.6% vs 15.2%; P < .001). This study highlighted the difficulties associated with diagnosis of M. ulcerans osteomyelitis, with one-fourth of patients having no apparent history of BU skin lesions, including during the current course of illness. Delays in treatment contributed to the high proportion (55.6%) of patients with crippling sequelae.

The Lancet Infectious Diseases, 2014

Journal of Infectious Diseases, 2014

Background. Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In ... more Background. Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R.

PLoS ONE, 2014

Over 95% of the adult population worldwide is infected with Epstein-Barr virus (EBV). EBV infecti... more Over 95% of the adult population worldwide is infected with Epstein-Barr virus (EBV). EBV infection is associated with the development of several cancers, including Hodgkin lymphoma (HL). Elevated levels of anti-EBV antibodies have been associated with increased risk of HL. There is growing evidence that genetic factors control the levels of antibodies against EBV antigens. Here, we conducted linkage and association studies to search for genetic factors influencing either anti-viral capsid antigen (VCA) or anti-Epstein Barr nuclear antigen-1 (EBNA-1) IgG levels in a unique cohort of 424 individuals of European origin from 119 French families recruited through a Hodgkin lymphoma (HL) patient. No major locus controlling anti-VCA antibody levels was identified. However, we found that the HLA region influenced anti-EBNA-1 IgG titers. Refined association studies in this region identified a cluster of HLA class II variants associated with anti-EBNA-1 IgG titers (e.g. p = 5610-5 for rs9268403). The major allele of rs9268403 conferring a predisposition to high anti-EBNA-1 antibody levels was also associated with an increased risk of HL (p = 0.02). In summary, this study shows that HLA class II variants influenced anti-EBNA-1 IgG titers in a European population. It further shows the role of the same variants in the risk of HL. Citation: Pedergnana V, Syx L, Cobat A, Guergnon J, Brice P, et al. (2014) Combined Linkage and Association Studies Show that HLA Class II Variants Control Levels of Antibodies against Epstein-Barr Virus Antigens. PLoS ONE 9(7): e102501.

Nature genetics, 2007

Host genetics has an important role in leprosy, and variants in the shared promoter region of PAR... more Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 yea...

The Journal of infectious diseases, Jan 15, 2015

A substantial proportion of subjects exposed to a contagious tuberculosis case display lack of tu... more A substantial proportion of subjects exposed to a contagious tuberculosis case display lack of tuberculin skin test (TST) reactivity. We previously mapped a major locus (TST1) controlling lack of TST reactivity in families from an area in South Africa where tuberculosis is hyperendemic. Here, we conducted a household tuberculosis contact study in a French area where the endemicity of tuberculosis is low. A genome-wide analysis of TST negativity identified a significant linkage signal (P < 3 × 10(-5)) in close vicinity of TST1. Combined analysis of the 2 samples increased evidence of linkage (P = 2.4 × 10(-6)), further implicating genetic factors located on 11p14-15. This region overlaps the TNF1 locus controlling mycobacteria-driven tumor necrosis factor α production.

We previously reported the clinical phenotype of two siblings with a novel inherited developmenta... more We previously reported the clinical phenotype of two siblings with a novel inherited developmental and immunodeficiency syn- drome consisting of severe intrauterine growth retardation and the impaired development of specific lymphoid lineages, including transient CD8 T lymphopenia and a persistent lack of blood NK cells. We describe here the elucidation of a plausible underlying pathogenic mechanism, with a cellular phenotype

Annales De Dermatologie Et De Venereologie, 2005

Ultrasound in Obstetrics and Gynecology, 2000

Objective To evaluate the changes in flow velocity waveforms in the transverse cerebral sinus in ... more Objective To evaluate the changes in flow velocity waveforms in the transverse cerebral sinus in growth-restricted fetuses and to correlate these changes with (1) flow velocity waveforms in the ductus venosus and (2) changes in computerized analysis of the fetal cardiotocogram.

PLoS ONE, 2011

Background and Objectives: In the last decade, autosomal recessive IL-

PLoS Genetics, 2009

Infectious diseases have been paramount among the threats to health and survival throughout human... more Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Tolllike receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs-activated by nucleic acids and particularly specialized in viral recognition-have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface-activated by compounds other than nucleic acids-have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatiallyvarying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease.

Nature Immunology, 2007

The field of human genetics of infectious diseases defines the genes and alleles rendering indivi... more The field of human genetics of infectious diseases defines the genes and alleles rendering individuals (clinical genetics) and populations (epidemiological genetics) vulnerable to infection, and studies those selected by previous infections (evolutionary genetics). These disciplines-clinical, epidemiological and evolutionary genetics-delineate the redundant and nonredundant functions of host defense genes for past and present survival in natura-in natural ecosystems governed by natural selection. These disciplines, in other words, assess the ecologically relevant and evolutionarily selected roles of human genes and alleles in protective immunity to diverse and evolving microorganisms. The genetic dissection of human immunity to infection in natura provides unique immunological insight, making it an indispensable complement to experimental immunology in vitro and in vivo in plants and animals.

Nature Genetics, 2005

Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of ... more Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNcR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNc. We then searched the Human Gene Mutation Database for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, we identified 142 candidate mutations (B1.4%) in 77 genes (B13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate.

Nature Genetics, 2003

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,00... more Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,000 persons each year 1 . Clinically, leprosy can be categorized as paucibacillary or multibacillary disease 2 . These clinical forms develop in persons that are intrinsically susceptible to leprosy per se, that is, leprosy independent of its specific clinical manifestation 3 . We report here on a genome-wide search for loci controlling susceptibility to leprosy per se in a panel of 86 families including 205 siblings affected with leprosy from Southern Vietnam. Using model-free linkage analysis, we found significant evidence for a susceptibility gene on chromosome region 6q25 (maximum likelihood binomial (MLB) lod score 4.31; P = 5 × 10 -6 ). We confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families. Of seven microsatellite markers underlying the linkage peak, alleles of two markers (D6S1035 and D6S305) showed strong evidence for association with leprosy (P = 6.7 × 10 -4 and P = 5.9 × 10 -5 , respectively).

Nature Genetics, 2007

Host genetics has an important role in leprosy, and variants in the shared promoter region of PAR... more Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning 1,2 . Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan 1 , located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the lowproducing lymphotoxin-a (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P ¼ 0.007 and P ¼ 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P ¼ 0.000024), which increased to 5.63 (P ¼ 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case-and population-specific factors in the dissection of susceptibility variants in complex diseases.

Disseminated disease in children and pulmonary disease in adults constitute two major epidemiolog... more Disseminated disease in children and pulmonary disease in adults constitute two major epidemiological and clinical forms of tuberculosis. Paradoxically, only a small fraction of infected individuals develop clinical tuberculosis, typically one form of the disease or the other. Mendelian and complex genetic predispositions to tuberculosis were reported recently in children and adults, respectively. Here, we argue that tuberculosis and its clinical expression largely reflect the underlying human genetic background.

Current opinion in immunology, 2014

Infectious diseases are the result of the exposure of susceptible hosts to pathogenic microbes. G... more Infectious diseases are the result of the exposure of susceptible hosts to pathogenic microbes. Genetic factors are important determinants of host susceptibility and efforts are being made to establish the molecular identity of such genetic susceptibility variants by genome-wide association studies. Results obtained to date partly confirm already known genetic vulnerabilities, but also point to new and unexpected mechanisms of susceptibility that extend from classical innate and acquired immunity to weaknesses in constitutional resistance. These studies also revealed an overlap in genetic control between infectious disease and other common immune and inflammatory disorders.

Seminars in Immunology, 2006

The elucidation of the genetic control of susceptibility to common infectious diseases is expecte... more The elucidation of the genetic control of susceptibility to common infectious diseases is expected to provide new and more effective tools for prevention and control of some of the most pressings health needs on a global scale. A major advantage of whole genome based genetic approaches is that no a priori assumptions about mechanisms of pathogenesis need to be made in these studies. Hence, genetic studies can identify previously unrecognized pathways of disease susceptibility and tag critical pathogenic events for further biochemical, immunological or physiological analysis. We have applied this strategy to leprosy, a disease that still claims 400,000 new cases each year. We identified genetic variants in the shared promoter region of the PARK2 and PACRG genes as major risk factors of leprosy susceptibility. Both encoded proteins are part of the cellular ubiquitination system. Specifically, PARK2, the cause of early onset Parkinson's disease, is an E3 ligase that likely is involved in controlled proteolysis, the cellular anti-oxidants response and the regulation of innate immune responsiveness. In addition, numerous E3 ligases have recently been shown to be critical regulators of immunity. While the specific role of PARK2/PACRG in leprosy pathogenesis remains unknown, a number of experimentally testable scenarios can be developed to further explore the role of these proteins in anti-Mycobacterium leprae host responsiveness.

Current opinion in immunology, 2005

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects an estimated ... more Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects an estimated 700,000 new individuals each year. A strong contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability observed between individuals exposed to M. leprae. As there is no relevant animal model for human leprosy, forward genetics is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. With respect to genome-wide screens, a major breakthrough has been reported this year; variants in the regulatory region shared by PARK2 and PACRG have been identified as being common risk factors for leprosy.

Clinical Infectious Diseases, 2014

Mycobacterium ulcerans is known to cause Buruli ulcer (BU), a necrotizing skin disease leading to... more Mycobacterium ulcerans is known to cause Buruli ulcer (BU), a necrotizing skin disease leading to extensive cutaneous and subcutaneous destruction and functional limitations. However, M. ulcerans infections are not limited to skin, and osteomyelitis, still poorly described in the literature, occurs in numerous young patients in Africa. In a retrospective matched case-control study conducted in a highly endemic area in Benin, we analyzed demographic, clinical, biological, and radiological features in all patients with M. ulcerans infections with bone involvement, identified from a cohort of 1257 patients with polymerase chain reaction-proved M. ulcerans infections. The 81 patients studied had a median age of 11 years (interquartile range, 7-16 years) and were predominantly male (male-female ratio, 2:1). Osteomyelitis was observed beneath active BU lesions (60.5%) or at a distance from active or apparently healed BU lesions (14.8%) but also in patients without a history of BU skin lesions (24.7%). These lesions had an insidious course, with nonspecific clinical findings leading to delayed diagnosis. A comparison with findings in 243 age- and sex-matched patients with BU without osteomyelitis showed that case patients were less likely to have received BCG immunization than controls (33.3% vs 52.7%; P = .01). They were also at higher risk of longer hospital stay (118 vs 69 days; P = .001), surgery (92.6% vs 63.0%; P = .001), and long-term crippling sequelae (55.6% vs 15.2%; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001). This study highlighted the difficulties associated with diagnosis of M. ulcerans osteomyelitis, with one-fourth of patients having no apparent history of BU skin lesions, including during the current course of illness. Delays in treatment contributed to the high proportion (55.6%) of patients with crippling sequelae.

The Lancet Infectious Diseases, 2014

Journal of Infectious Diseases, 2014

Background. Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In ... more Background. Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R.

PLoS ONE, 2014

Over 95% of the adult population worldwide is infected with Epstein-Barr virus (EBV). EBV infecti... more Over 95% of the adult population worldwide is infected with Epstein-Barr virus (EBV). EBV infection is associated with the development of several cancers, including Hodgkin lymphoma (HL). Elevated levels of anti-EBV antibodies have been associated with increased risk of HL. There is growing evidence that genetic factors control the levels of antibodies against EBV antigens. Here, we conducted linkage and association studies to search for genetic factors influencing either anti-viral capsid antigen (VCA) or anti-Epstein Barr nuclear antigen-1 (EBNA-1) IgG levels in a unique cohort of 424 individuals of European origin from 119 French families recruited through a Hodgkin lymphoma (HL) patient. No major locus controlling anti-VCA antibody levels was identified. However, we found that the HLA region influenced anti-EBNA-1 IgG titers. Refined association studies in this region identified a cluster of HLA class II variants associated with anti-EBNA-1 IgG titers (e.g. p = 5610-5 for rs9268403). The major allele of rs9268403 conferring a predisposition to high anti-EBNA-1 antibody levels was also associated with an increased risk of HL (p = 0.02). In summary, this study shows that HLA class II variants influenced anti-EBNA-1 IgG titers in a European population. It further shows the role of the same variants in the risk of HL. Citation: Pedergnana V, Syx L, Cobat A, Guergnon J, Brice P, et al. (2014) Combined Linkage and Association Studies Show that HLA Class II Variants Control Levels of Antibodies against Epstein-Barr Virus Antigens. PLoS ONE 9(7): e102501.

Nature genetics, 2007

Host genetics has an important role in leprosy, and variants in the shared promoter region of PAR... more Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 yea...

The Journal of infectious diseases, Jan 15, 2015

A substantial proportion of subjects exposed to a contagious tuberculosis case display lack of tu... more A substantial proportion of subjects exposed to a contagious tuberculosis case display lack of tuberculin skin test (TST) reactivity. We previously mapped a major locus (TST1) controlling lack of TST reactivity in families from an area in South Africa where tuberculosis is hyperendemic. Here, we conducted a household tuberculosis contact study in a French area where the endemicity of tuberculosis is low. A genome-wide analysis of TST negativity identified a significant linkage signal (P < 3 × 10(-5)) in close vicinity of TST1. Combined analysis of the 2 samples increased evidence of linkage (P = 2.4 × 10(-6)), further implicating genetic factors located on 11p14-15. This region overlaps the TNF1 locus controlling mycobacteria-driven tumor necrosis factor α production.

We previously reported the clinical phenotype of two siblings with a novel inherited developmenta... more We previously reported the clinical phenotype of two siblings with a novel inherited developmental and immunodeficiency syn- drome consisting of severe intrauterine growth retardation and the impaired development of specific lymphoid lineages, including transient CD8 T lymphopenia and a persistent lack of blood NK cells. We describe here the elucidation of a plausible underlying pathogenic mechanism, with a cellular phenotype

Annales De Dermatologie Et De Venereologie, 2005

Ultrasound in Obstetrics and Gynecology, 2000

Objective To evaluate the changes in flow velocity waveforms in the transverse cerebral sinus in ... more Objective To evaluate the changes in flow velocity waveforms in the transverse cerebral sinus in growth-restricted fetuses and to correlate these changes with (1) flow velocity waveforms in the ductus venosus and (2) changes in computerized analysis of the fetal cardiotocogram.

PLoS ONE, 2011

Background and Objectives: In the last decade, autosomal recessive IL-

PLoS Genetics, 2009

Infectious diseases have been paramount among the threats to health and survival throughout human... more Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Tolllike receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs-activated by nucleic acids and particularly specialized in viral recognition-have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface-activated by compounds other than nucleic acids-have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatiallyvarying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease.

Nature Immunology, 2007

The field of human genetics of infectious diseases defines the genes and alleles rendering indivi... more The field of human genetics of infectious diseases defines the genes and alleles rendering individuals (clinical genetics) and populations (epidemiological genetics) vulnerable to infection, and studies those selected by previous infections (evolutionary genetics). These disciplines-clinical, epidemiological and evolutionary genetics-delineate the redundant and nonredundant functions of host defense genes for past and present survival in natura-in natural ecosystems governed by natural selection. These disciplines, in other words, assess the ecologically relevant and evolutionarily selected roles of human genes and alleles in protective immunity to diverse and evolving microorganisms. The genetic dissection of human immunity to infection in natura provides unique immunological insight, making it an indispensable complement to experimental immunology in vitro and in vivo in plants and animals.

Nature Genetics, 2005

Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of ... more Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNcR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNc. We then searched the Human Gene Mutation Database for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, we identified 142 candidate mutations (B1.4%) in 77 genes (B13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate.

Nature Genetics, 2003

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,00... more Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,000 persons each year 1 . Clinically, leprosy can be categorized as paucibacillary or multibacillary disease 2 . These clinical forms develop in persons that are intrinsically susceptible to leprosy per se, that is, leprosy independent of its specific clinical manifestation 3 . We report here on a genome-wide search for loci controlling susceptibility to leprosy per se in a panel of 86 families including 205 siblings affected with leprosy from Southern Vietnam. Using model-free linkage analysis, we found significant evidence for a susceptibility gene on chromosome region 6q25 (maximum likelihood binomial (MLB) lod score 4.31; P = 5 × 10 -6 ). We confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families. Of seven microsatellite markers underlying the linkage peak, alleles of two markers (D6S1035 and D6S305) showed strong evidence for association with leprosy (P = 6.7 × 10 -4 and P = 5.9 × 10 -5 , respectively).

Nature Genetics, 2007

Host genetics has an important role in leprosy, and variants in the shared promoter region of PAR... more Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning 1,2 . Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan 1 , located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the lowproducing lymphotoxin-a (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P ¼ 0.007 and P ¼ 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P ¼ 0.000024), which increased to 5.63 (P ¼ 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case-and population-specific factors in the dissection of susceptibility variants in complex diseases.