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DRUG METABOLISM AND DISPOSITION
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics
DMD 29:479–483, 2001
Vol. 29, No. 4, Part 2
290105/893757
Printed in U.S.A.
GENETICS OF SUSCEPTIBILITY TO INFECTIOUS DISEASES: TUBERCULOSIS AND
LEPROSY AS EXAMPLES
SANDRINE MARQUET
AND
ERWIN SCHURR
McGill Centre for the Study of Host Resistance, McGill University Health Centre Research Institute, Montreal General Hospital, Montreal,
Québec, Canada
This paper is available online at http://dmd.aspetjournals.org
Mouse Models
One approach to identify human disease resistance and susceptibility genes is to identify murine resistance/susceptibility genes. In this
strategy, it is assumed that the basic pathology of the infectious
disease is similar in the animal model and the human host. Consequently, orthologous genes in mouse and humans are assumed to be
important for variable susceptibility/resistance to infection with the
same pathogen. Experimental models present several advantages,
including the ease of control of the environment, the ready access to
strains of defined and genetically homogenous backgrounds, the availability of genetically engineered animals, and the breeding at will of
appropriately chosen progenitor strains. A well known example for a
susceptibility gene that has been identified in the mouse is the “natural
resistance associated macrophage protein 1” (Nramp1). Natural resistance to infection with several intracellular pathogens belonging to the
genera Mycobacterium, Leishmania, and Salmonella has been shown
to be under control of a single G169D amino acid substitution in the
Nramp1 protein (Vidal et al., 1995, 1996). A potential problem of the
cross-species homology approach is that allelic variants of orthologues can be highly divergent among two species. Hence, the most
powerful use of mouse models is the identification of genes and their
respective biochemical pathways that are involved in disease susceptibility rather than the identification of specific susceptibility/resistance gene variants.
Send reprint requests to: Erwin Schurr, Ph.D., Associate Professor, Montreal
General Hospital Research Institute, Rm. L11-521, 1650 Cedar Ave., Montréal,
QC, H3G 1A4 Canada. E-mail: [email protected]
Candidate Gene Approach
Candidate genes are generally selected on the basis of their known
or speculated relevance to disease pathogenesis and the presence of
intragenic polymorphisms of possible biological significance. Candidate genes can also be derived based on experiments in mouse models
of infectious diseases thereby exploiting the identification of murine
resistance/susceptibility loci. Variants within a candidate gene can be
analyzed in linkage studies (family studies) and/or in association
studies (case-control studies), but in most cases, association studies
are used to study the possible biological relevance of polymorphisms
in specific candidate genes. With a growing number of gene polymorphisms appearing in public databases each month, the candidate
gene strategy has gained tremendously in popularity. Nevertheless,
problems remain because it is unlikely that all genes important for
susceptibility can be found a priori, and genes with major effects but
unknown function can easily be missed. The interpretation of positive
results on genetic associations with infectious diseases is frequently
complicated by the lack of appropriate corrections for multiple comparisons. Moreover, undetected population admixture or poor choice
of control populations probably explain part of the difficulties in
reproducing significant marker disease associations.
An alternative approach that has been recently proposed is to scan
the whole human genome with a large number of single nucleotide
polymorphisms for whole genome association studies. The power to
detect marker-phenotype associations following this strategy is presently a matter of controversy. However, it is clear that several million
genotypes will need to be generated for such studies. Present genotyping techniques cannot be used for such a task, and until new
technologies become available, family studies offer a more efficient
and feasible strategy.
Total Genome Scanning
In this approach, a large number of microsatellites (around 300)
evenly spaced across the whole genome are used for linkage analysis
employing families with multiple sibs affected by the studied disease.
Two types of linkage analysis can be performed: parametric and
nonparametric analysis. Parametric linkage analysis by the lod score
method requires a defined model specifying the relationship between
the phenotype and the factors (environmental and genetic), which
have an effect on phenotype expression. For example, such a model
can be provided by complex segregation analysis. Genetic linkage
analysis tests whether the marker segregates with the disease in
pedigrees with multiple affected according to a Mendelian mode of
inheritance. The test is formulated as logarithm of the ratio L(␪)/
L(␪ ⫽ 0.5) or lod score, i.e., the likelihood of observing the experimentally determined segregation pattern at a given recombination
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In the majority of infectious diseases only a proportion of individuals exposed to a pathogen become infected and develop clinically
evident disease. At least in part, this interindividual variability is
determined by the combined effect of host proteins encoded by a
series of genes that control the quantity and quality of host-parasite
interaction and host immune responses. Identification of the most
important host susceptibility/resistance genes will allow a better understanding of infectious disease pathogenesis and likely facilitate the
development of new therapeutic strategies.
Several approaches can be used to map and identify a host infectious disease susceptibility gene. Three of the most widely used
strategies, i.e., mouse models, candidate gene approach, and genome
scanning, are briefly presented. To date, at least 11 genes have been
implicated in susceptibility/resistance to mycobacterial infection and a
short discussion of the experiments implicating individual genes in
infectious disease susceptibility is given.
480
MARQUET AND SCHURR
TABLE 1
Examples of significant associations or linkages between selected genes and risk of mycobacterial infectious diseases
Infectious Diseases
Leprosy
Genes Associated or Linked with Specific
Phenotype
MHC class II
HLA-DR (lepromatous and tuberculoid)
TNFA (lepromatous)
NRAMP1
(leprosy per se)
(in vivo, lepromin response)
VDR (lepromatous and tuberculoid)
Tuberculosis
MHC class II
HLA-DR2 (pulmonary tuberculosis)
HLA-DRB1 (pulmonary tuberculosis)
HLA-DQB1 (tuberculosis progression)
HLA-DQB1 (pulmonary tuberculosis)
NRAMP1 (pulmonary tuberculosis)
Atypical disseminated
mycobacterial infections
IFNgR1
IFNgR2
IL-12Rb1
IL-12p40
Indian (van Eden et al., 1980; Todd et al., 1990; Rani et al., 1993; Zerva et al., 1996;
Roy et al., 1997)
Brazilian (Visentainer et al., 1997)
Indian (Roy et al., 1997)
Vietnamese (Abel et al., 1998)
Vietnamese (Alcaïs et al., 2000)
Indian (Roy et al., 1999)
Indian (Brahmajothi et al., 1991); Indonesian (Bothamley et al., 1989)
Indian (Ravikumar et al., 1999)
Cambodian (Goldfeld et al., 1998)
Indian (Ravikumar et al., 1999)
Gambian (Bellamy et al., 1998)
Canadian Indian (Greenwood et al., 2000)
Gambian (Bellamy et al., 1999); Gujarati (Wilkinson et al., 2000)
Indian (Selvaraj et al., 1999)
Coloured (Hoal-van Helden et al., 1999)
Gujarati (Wilkinson et al., 1999)
Maltese (Newport et al., 1996)
Tunisian (Jouanguy et al., 1996),
Italian (Pierre-Audigier et al., 1997)
German, Pakistani, (Altare et al., 1998c)
Portuguese (Jouanguy et al., 1997)
English (Dorman and Holland, 1998; Altare et al., 1998c)
Moroccan, Turkish, Dutch, Cypriot (Altare et al., 1998a,b; de Jong et al., 1998)
Pakistani (Altare et al., 1998d)
frequency ␪ compared with the likelihood of the same segregation
pattern in the absence of linkage. The objective of parametric linkage
analysis is to estimate the recombination frequency (␪) and to test
whether ␪ is less than 0.5, which is the case when two loci are
genetically linked. The nonparametric approach evaluates the statistical significance of excess allele sharing for specific markers among
affected sibs and does not require information about the mode of
disease inheritance. The genome wide search has the advantage that
no a priori knowledge of the structure or function of susceptibility
genes is required. Hence, this approach provides the possibility of
identifying genes that modulate susceptibility to infectious diseases
that had previously not been suspected of playing such a biological
role. To date, no final results of a completed genome scan in human
mycobacterial diseases have been published. However, several such
genome scans are in progress.
Leprosy (HLA, NRAMP1, TNFA, VDR). For centuries, leprosy
has been associated with an enormous social stigma partly rooted in
the claim that leprosy “runs” in certain families. The social suffering
of affected and unaffected members of “lepromatous” families is a
powerful reminder of the occasional treacherous area in which genetic
research can lead. Today we know that environmental, pathogen, and
host factors are important for the spread of an infectious disease
through an exposed population. For leprosy, four genes have been
implicated in modulating susceptibility. To identify these genes, association and linkage studies have been used.
HLA. There is strong epidemiological evidence that genetic factors
influence susceptibility to leprosy per se and to leprosy type. The role
of major histocompatibility complex (MHC1) polymorphisms in the
determination of leprosy type, i.e., lepromatous or tuberculoid lep1
Abbreviations used are: MHC, major histocompatibility complex; MBL, mannose binding lectin; MBP, mannose binding protein; IL, interleukin; QTL, quantitative trait loci; BCG, Bacillus Calmette-Guérin; IFN␥, interferon ␥.
rosy, has been found in several linkage and association studies, but in
most studies only weak linkage or association was detected. This lack
of power in association studies is due at least in part to the relatively
small sample sizes used to detect allelic association and the high
diversity of HLA alleles, which requires multiple allele testings resulting in correction for multiple comparisons and concomitant loss of
power. However, a number of case-control studies of both polar types
of leprosy and HLA have shown a consistent HLA-DR2 association
particularly in Asian populations (Table 1) (van Eden et al., 1980;
Todd et al., 1990; Rani et al., 1993). This association has been
reconfirmed more recently in an Indian population comprised of 121
patients with lepromatous leprosy, 107 patients with tuberculoid leprosy, and 160 control subjects (Roy et al., 1997) and in a Brazilian
population (Visentainer et al., 1997). Further molecular analysis identified specific mutations in pocket 4 of the DRB1-encoded class II
molecule that are associated with increased susceptibility to tuberculoid leprosy (Zerva et al., 1996). However, these MHC effects seem
not sufficient to explain the entire host genetic susceptibility to
leprosy, and several studies were conducted on non-class I or -class II
MHC genes such as tumor necrosis factor (TNFA), natural resistance
associated macrophage protein 1 (NRAMP1), and vitamin D receptor
(VDR).
TNFA. In the same Indian population used to show the association
between HLA-DR2 and susceptibility to both poles of leprosy severity,
there is also a significant higher TNF2 allele frequency in the lepromatous group but not in the tuberculoid group (Table 1) (Roy et al.,
1997). The HLA-DR2 and TNF2 alleles are not in strong linkage
disequilibrium suggesting that association of lepromatous leprosy
with DR2 serotypes and TNF2 is independent despite the proximity of
the two loci.
NRAMP1. The possible role of NRAMP1 as a genetic factor in
leprosy has been extensively studied. However, the first direct evi-
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VDR (pulmonary tuberculosis)
MBL
(pulmonary tuberculosis)
(tuberculous meningitis)
IL-1RA/IL-1b (tuberculosis form)
Populations and References
GENETICS OF SUSCEPTIBILITY TO INFECTIOUS DISEASES
healthy controls. The polymorphic variants of the NRAMP1 gene
analyzed correspond to a dinucleotide CA repeat in the 5⬘ region, a
single nucleotide polymorphism in intron 4 (469 ⫹ 14G/C), a nonconservative single-base change at codon 543 (D543N), and a 4-base
pair deletion in the 3⬘ region. Combined analysis of the polymorphisms in intron 4 and in the 3⬘ region detected a strong association
with tuberculosis (P ⬍ 0.001; Bellamy et al., 1998). Subjects heterozygous for these two variants were four times overrepresented
among patients with tuberculosis as compared with those bearing the
most common NRAMP1 genotype (odds ratio: 4.07, 95% CI: 1.86 –
9.12). In a more recent genetic study of a tuberculosis outbreak in a
Canadian Aboriginal Community, NRAMP1 was strongly linked to
tuberculosis susceptibility (lod score 4.2) (Greenwood et al., 2000).
These reports confirm that NRAMP1 is important in modulating
susceptibility to tuberculosis and demonstrate that mouse models of
infectious disease can identify relevant candidate genes for human
disease.
VDR. Variations in the vitamin D receptor gene were analyzed in
the same Gambian population that was enrolled to demonstrate the
NRAMP1 association with tuberculosis. Homozygous patients for a
polymorphism at codon 352 (genotype tt) were significantly underrepresented among those with tuberculosis (P ⫽ 0.01; Bellamy et al.,
1999) suggesting a role of VDR in the pathogenesis of tuberculosis
(Table 1). Recently it has also been shown that serum vitamin D
deficiency may contribute to the high occurrence of tuberculosis
among Gujarati Asian subjects (P ⫽ 0.008) (Wilkinson et al., 2000).
Moreover, the VDR genotypes of 91 untreated tuberculosis patients
and 116 healthy people who had been sensitized to tuberculosis
indicated that VDR polymorphisms are involved in tuberculosis susceptibility (Wilkinson et al., 2000).
MBL (or MBP). Mannose binding lectin (MBL) also called mannose binding protein (MBP) activates the classical complement pathway and phagocytosis leading to neutralization of the pathogen. To
investigate the role of MBL gene polymorphisms in tuberculosis
susceptibility, a recent study was carried out with Indian patients. Two
hundred and two pulmonary tuberculosis patients and 109 controls
were genotyped for three MBL (codons 52, 54, and 57) functional
variants affecting the structure of MBL and associated with low serum
levels. A significantly increased genotype frequency of mutant homozygotes was noted in pulmonary tuberculosis patients compared
with healthy controls (P ⫽ 0.008) (Table 1) (Selvaraj et al., 1999). On
the other hand, a protective effect of the G54D MBL allele on
tuberculous meningitis was noted in a South African population
(Hoal-van Helden et al., 1999).
IL-1Ra and IL-1b. The proinflamatory cytokine interleukin-1b (IL1b) and the interleukin-1 receptor antagonist (IL-1Ra), which is a
specific inhibitor of IL-1 activity, have been shown to be induced in
vitro by Mycobacterium tuberculosis. Moreover patients with tuberculosis present an elevated serum concentration of IL-1Ra and IL-1Ra
was identified as a marker of disease activity in tuberculosis (Juffermans et al., 1998). Within the IL-1b gene, two biallelic polymorphisms have been identified at positions ⫺511 and ⫹3953, respectively. An 86-base pair variable number of tandem repeats
polymorphism with five different alleles is found in the IL-1Ra gene.
Genetic analysis detected that the IL-1Ra VNTR allele A2 was associated with a higher production of IL-1Ra in response to M. tuberculosis infection. Indeed, individuals with the IL-1Ra A2⫹ allele produced 1.9-fold more IL-1Ra than patients with IL-1Ra A2- alleles
(Wilkinson et al., 1999). The two polymorphisms in IL-1b were not
clearly associated with the level of IL-1b production in vitro induced
by M. tuberculosis, although expression of mRNA for IL-1b was
slightly higher in patients with the IL-1b(⫹3953) A1⫹ allele (P ⫽
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dence for a role of NRAMP1 in susceptibility to leprosy was obtained
only recently in a large familial study in South Vietnam. Six NRAMP1
polymorphisms and four closely linked microsatellites were genotyped in 168 patients of 20 multiplex leprosy families, and significant
evidence for linkage was obtained (P ⬍ 0.005– 0.02; Abel et al., 1998)
(Table 1). Segregation analysis performed on 285 Vietnamese and 117
Chinese families detected evidence for a major codominant gene only
in the Vietnamese population suggesting that the control of susceptibility to leprosy could be genetically heterogeneous according to the
ethnic origin of the families. It is possible that genetic heterogeneity
will partly explain the lack of linkage between NRAMP1 and leprosy
susceptibility in previous reports (Shaw et al., 1993; Roger et al.,
1997).
VDR. The binding of the active form of vitamin D (1,25-dihydroxy
vitamin D) to the vitamin D receptor present on monocytes, macrophages, and activated lymphocytes plays an immunoregulatory role. A
single base polymorphism in codon 352 of the VDR gene can be
detected as TaqI restriction fragment polymorphism with the two
alleles designated “T” and “t”, respectively. The less common allele
“t” has been associated with higher levels of VDR mRNA expression
in transient transfection assays (Morrison et al., 1992). In a casecontrol study in Calcutta, the codon 352 TaqI VDR polymorphism was
found associated with lepromatous leprosy (P ⫽ 0.04) and tuberculoid
leprosy (P ⫽ 0.004; Roy et al., 1999) (Table 1). The frequency of the
tt genotype was significantly increased in tuberculoid patients (21.5%)
as compared with controls (7.8%). In contrast, the TT genotype
frequency was higher in the lepromatous leprosy group (52.4%)
compared with the controls (39.8%). However, in this population no
significant association was found between NRAMP1 polymorphisms
and leprosy susceptibility.
Tuberculosis (HLA, NRAMP, VDR, IL-1Ra, IL-1b). Numerous
studies have analyzed a possible contribution of genetic factors to
tuberculosis susceptibility. A consistent conclusion from twin, family,
and adoption studies was that the genetic background of the host is an
important control element for susceptibility to tuberculosis. Employing candidate gene studies a number of gene variants have been
identified that contribute to tuberculosis risk.
HLA. A large number of associations of HLA type with tuberculosis
have been reported for different populations. However, a substantial
proportion of these tuberculosis associations could not be reproduced
in independent studies. One of the most consistent findings that has
been reproduced in several populations is that susceptibility to pulmonary tuberculosis appears associated with the HLA-DR2 serotype
(Table 1) (Bothamley et al., 1989; Brahmajothi et al., 1991). However, a two-stage case-control study has shown the importance of the
HLA-DQB1*0503 allele in tuberculosis progression (P ⫽ 0.005) in a
Cambodian population while no significant effect of HLA DR2 alleles
was detected (Goldfeld et al., 1998). A recent association study on 126
patients with pulmonary tuberculosis and 87 endemic controls from
India indicated that HLA-DRB1*1501 (P ⫽ 0.013) and HLADQB1*0601 (P ⫽ 0.008) were associated with pulmonary tuberculosis (Ravikumar et al., 1999). Interestingly, no connection has been
found between TNFA polymorphisms and tuberculosis risk (Shaw et
al., 1997). These results suggest that the variability in the major
histocompatibility complex and its relationship to tuberculosis susceptibility deserves further clarification, preferably using HLA analysis on the level of the nucleotide.
NRAMP1. Recently a large case-control study conducted in The
Gambia (West Africa) has shown that four alleles of NRAMP1 were
significantly associated with susceptibility to tuberculosis (Table 1)
(Bellamy et al., 1998). This genetic analysis was performed on 410
smear-test-positive tuberculosis patients and 417 ethnically matched
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MARQUET AND SCHURR
0.04). In a case-control study comprised of 114 healthy subjects and
89 patients with tuberculosis, no significant difference was found in
IL-1b and IL-1Ra allele or genotype frequencies between the two
groups. However, the IL-1Ra A2-/IL-1b (⫹3953) A1⫹ genotype combinations are overrepresented in patients with tuberculous pleurisy
(92%) compared with M. tuberculosis-sensitized control patients
(57%) or patients with other disease forms (56%) (Table 1). The
mechanistic basis underlying the above associations is unknown.
However, considering the relatively small number of individuals
enrolled in the study and the fact that the association with tuberculosis
type is of borderline significance if corrected for multiple comparisons, it is important that the results be repeated in distinct populations.
Genetic Analysis of Tuberculosis Mouse Models
Hypersusceptibility to Mycobacterial Infection
Genetic studies of patients with severe idiopathic disseminated
infections due to weakly pathogenic Mycobacteria revealed the presence of mutations in four different genes: IFNgRI, IFNgR2, IL-12Rb1,
and IL-12p40.
IFNgR1— complete and partial deficiency. In a Maltese family,
four children with recessive susceptibility to atypical mycobacterial
infection (M. fortuitum, M. chelonei, and M. avium) presented a
homozygous point mutation at nucleotide position 395 in the gene for
interferon gamma receptor 1 (IFNgR1) (Table 1). This mutation
introduced a stop codon leading to a truncated protein that lacks the
transmembrane and cytoplasmic domains of the receptor (Newport et
al., 1996). A second study indicated that one child with fatal disseminated BCG infection was homozygous for a frameshift deletion in
this gene (Jouanguy et al., 1996) with absence of expression of the
receptor at the cell surface. IFNgR1 deficiency has also been identified in a patient with disseminated M. smegmatis infection (PierreAudigier et al., 1997). These studies demonstrated that the IFNgR1
gene was responsible for the children’s immune deficiency and underline the importance of the IFN␥ pathway in immunity to mycobacterial infection. Moreover complete IFNgR1 deficiency appears to
be an autosomal immune disorder associated with severe and selective
infection by poorly pathogenic Mycobacteria, and a complete absence
of mature granuloma formation.
Partial IFNgR1 deficiency due to a homozygous missense mutation
has been found in two patients, one patient with disseminated infection after BCG vaccination and the second with clinical tuberculosis
without BCG vaccination (Table 1) (Jouanguy et al., 1997). Moreover, partial as opposed to complete IFNgR1 deficiency is associated
with mature granulomas and a milder course of mycobacterial infection. These studies suggested that ligation of IFN␥ to IFNgR is
essential for immunity against BCG and M. tuberculosis and that
subtle mutations in these genes may alter disease susceptibility on the
population level.
Conclusion
To identify susceptibility/resistance genes in infectious diseases
different strategies can be used. To date, candidate gene analysis has
been the method of choice in most studies. Contrary to genome-scan
analysis, this approach allows the possibility of identifying genes that
exert a small or moderate effect on susceptibility to infection. However, this approach is limited to known candidate genes, and the
results should be confirmed in independent studies. Another challenge
of candidate gene analysis is the identification of the causal mutation
of the disease. This can be relatively straightforward in the case of
major mutations but can be a difficult undertaking in the case of subtle
polymorphic variations. The characterization of the susceptibility
genes and their underlying causative mutations has important implications not only for a better understanding of disease pathogenesis but
also for the control and development of new therapeutic strategies for
infectious diseases.
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