Download Host genetics and parasitic infections

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10.1111/1469-0691.12793
Host genetics and parasitic infections
V. D. Mangano1,2 and D. Modiano1,2
1) Department of Public Health and Infectious Diseases and 2) Istituto Pasteur, Fondazione Cenci Bolognetti, University of Rome ‘La Sapienza’, Rome, Italy
Abstract
Parasites still impose a high death and disability burden on human populations, and are therefore likely to act as selective factors for genetic
adaptations. Genetic epidemiological investigation of parasitic diseases is aimed at disentangling the mechanisms underlying immunity and
pathogenesis by looking for associations or linkages between loci and susceptibility phenotypes. Until recently, most studies used a
candidate gene approach and were relatively underpowered, with few attempts at replicating findings in different populations. However, in
the last 5 years, genome-wide and/or multicentre studies have been conducted for severe malaria, visceral leishmaniasis, and cardiac Chagas
disease, providing some novel important insights. Furthermore, studies of helminth infections have repeatedly shown the involvement of
common loci in regulating susceptibility to distinct diseases such as schistosomiasis, ascariasis, trichuriasis, and onchocherciasis. As more
studies are conducted, evidence is increasing that at least some of the identified susceptibility loci are shared not only among parasitic
diseases but also with immunological disorders such as allergy or autoimmune disease, suggesting that parasites may have played a role in
driving the evolution of the immune system.
Keywords: Genetic epidemiology, genome-wide association studies, leishmaniasis, lymphatic filariasis, malaria, onchocerciasis,
schistosomiasis, soil-transmitted helminth diseases, trypanosomiasis
Article published online: 1 October 2014
Clin Microbiol Infect 2014; 20: 1265–1275
Corresponding authors: D. Modiano and V. D. Mangano, Dept. of
Public Health and Infectious Diseases, Sapienza University of Rome,
Piazzale Aldo Moro 5, 00185 Rome, Italy
E-mails: [email protected],
[email protected]
The MalariaGEN Consortium. Reappraisal of known malaria resistance loci in a large multicentre study. Under revision by Nature
Genetics[1].
Introduction
Parasitic diseases represent a very important public health
problem, mainly in the tropical and subtropical regions of the
world (Table 1). The heaviest death toll is imposed by malaria,
with approximately 600 thousand reported fatalities every
year. However, parasites can cause not only acute and lethal
illnesses but also chronic diseases with diverse impacts ranging
from compromised organic functions to malnutrition, impaired
growth and learning abilities, and increased susceptibility to
other infections.
It is therefore likely that all major parasites play a role as
selective factors in shaping the evolution of the human
genome, promoting a rise in the frequency of protective
alleles (e.g. for malaria [2]). Actually, for many parasitic
diseases, a heritable component has been demonstrated.
Evidence has been gained with a variety of approaches,
including twin studies, observation of familial clustering,
pedigree-based variance component analysis and segregation
analysis, and studies of ethnic groups that share the same
environmental exposure but show different susceptibilities [2–
10]. Although parasitic diseases are clearly of multifactorial
origin, the genetic architecture underlying susceptibility varies,
with two possible extremes being represented by malaria, in
which the genetic component is more probably explained by
the additive effect of many loci with small to modest
penetrance [11], and Schistosoma infection, in which one major
locus with high penetrance seems to be involved [12].
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TABLE 1. Major human parasitic diseases
Disease
Phylum
Species
Malaria
Apicomplexa
Schistosomiasis
Platyhelminthes
Leishmaniasis
Sarcomastigophora
Hookworm disease
Nematoda
Lymphatic filariasis
Nematoda
African
trypanosomiasis
(sleeping sickness)
Ascariasis
Trichuriasis
Sarcomastigophora
Trypanosoma brucei
gambiense, T. b. rhodesiense
Nematoda
Nematoda
Onchocerciasis
(river blindness)
Nematoda
Ascaris lumbricoides
Trichuris trichura
(whipworm)
Onchocerca volvulus
American
trypanosomiasis
(Chagas disease)
Sarcomastigophora
Trypanosoma cruzii
a
Transmission
Distribution
Infections
Bite of female
mosquitoes
(Anopheles)
Tropical and
subtropical
areas
~258 million
Contaminated
fresh water d
Plasmodium falciparum,
P. malariae,
P. vivax,
P. ovale,
P. knowlesi
Schistosoma mansoni,
S. haematobium,
S. japonicum,
S. mekonji,
S. intercalatum
Leishmania species
Ancylostoma duodenalis,
Necator americanus
Wuchereria bancrofti,
Brugia malayi, B. timor
Deaths
b
DALYs
b
c
589 218
55 413 529
Tropical and
subtropical
areas
~243 million
23 313
3 971 096
Bite of female
sand flies
(Phlebotomus,
Lutzomya)
Contaminated soil
Tropical and
subtropical
areas
0.8–1.6 million
53 675
3 754 202
~740 million
3
3 158 856
Bite of female
mosquitoes (Aedes,
Anopheles, Culex,
Mansonia)
Bite of tsetse fly
(Glossina)
Tropical
areas
~120 million
5
2 740 426
Sub-Saharan
Africa
c
19 026
1 345 594
Contaminated soil
Contaminated soil
Worldwide
Worldwide
1.2 billions
~795 million
2991
0
1 253 785
629 901
Bite of blackfly
(Simulium)
Africa, foci
in Latin
America and
the Middle
East
Latin America
~26 million
1
564 059
7–8 million
7356
499 067
Bite of triatomine
bugs (Rhodnius,
Panstrongylus,
Triatoma)
Worldwide
e
~20 000
c
f
c
DALY, disability-adjusted life-year.
a
Data on infection cases are based on the most recent WHO reports on individual parasites (prevalent cases if not specified otherwise).
b
Data on deaths and DALYs are based on the WHO Global Health Observatory Data Repository for 2011.
c
Incident cases.
d
Biomphalaria, Bulinus, Neotricola and Oncomelania snails are intermediate hosts.
e
Highest prevalence in warm and moist climate areas, and areas with poor sanitation.
f
Highest prevalence in tropical and subtropical areas, and areas with poor sanitation.
Genetic epidemiology studies are aimed at identifying the
genetic factors responsible for heritability through association
or linkage with the phenotype of interest [13]. The identification of susceptibility loci can provide important insights into
the mechanisms of protective immunity and pathogenesis, and
genetic epidemiology studies can be therefore regarded as
observational studies of immunology in natura, complementary
to in vitro and in vivo experimental studies [14].
In recent years, major advances have been achieved in the
study of protozoa by the creation of consortia, namely
MalariaGEN [15] and LeishGEN [16], that have allowed the
collection of unprecedently large and multicentre samples, and
the standardization of case definitions and laboratory procedures. Furthermore, genome-wide association studies
(GWASs) of severe Plasmodium falciparum malaria [17–19],
visceral leishmaniasis (VL) [16] and Chagas disease [20] have
been conducted.
Regarding helminths, increasing evidence has emerged that a
common genetic basis exists for susceptibility to different
species, as will be discussed. Although no GWAS has been
conducted to date, an interesting new approach has been
proposed to identify candidate genes at the genome-wide level,
by searching for polymorphisms that show strong correlations
with the diversity of the prevalent helminth species in distinct
geographical areas [21]. The same approach has been
successful in identifying known loci involved in resistance to
protozoan infections [22].
An update per parasite in the field follows. Genetic epidemiology studies of susceptibility to parasitic diseases were
searched for in the existing literature with the following terms
and Boolean operators: ‘(genetic OR polymorphi*) AND
(association OR link* OR genome scan OR genome wide)
AND (parasitic disease OR parasite)’ [23]. Only articles written
in English for which abstracts were available and that described
studies based on human subjects were included in the search.
The search was frozen on 8 April 2014. Previous reviews on the
subject were also looked for, and particular emphasis has been
given in the following paragraphs to more recent studies.
Malaria
Malaria is caused by apicomplexan parasites of the genus
Plasmodium, which are transmitted by Anopheles blood-sucking
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Mangano and Modiano
female mosquitoes. The parasite develops intracellularly, with
a first latent stage of the life cycle within hepatocytes, and with
a later symptomatic stage within erythrocytes. The outcome of
an infection varies according to the immunity of the host and
environmental and parasite factors, and ranges from asymptomatic parasitaemia to uncomplicated disease characterized
by fever, chills and other mild symptoms, to severe complications. Five species infect humans: P. falciparum, P. vivax, P.
malariae, P. ovale, and P. knowlesi. P. falciparum has been long
recognized as the species imposing the largest burden,
representing 80–90% of infections in sub-Saharan Africa, and
causing severe and potentially lethal complications in susceptible children (cerebral malaria, severe malaria anaemia, and
respiratory distress) and pregnant women (pregnancy-associated malaria). However, evidence is accumulating that P. vivax
can also be responsible for severe malaria forms, and that
recurrent infections, including relapses, leave children chronically anaemic and more susceptible to other infections.
Many studies have been conducted on the human genetic
factors affecting susceptibility to malaria phenotypes, reporting
associations at candidate genes or linkages to genomic regions
with infection prevalence and levels, antibody responses to
malaria antigens, and uncomplicated and severe malaria. A
comprehensive description of these data has been provided
previously [2,3,24]. A significant proportion of studies have
analysed associations of erythrocyte factors with severe
P. falciparum malaria, and have obtained some very consistent
results, the most notable being protection conferred by
haemoglobin S (Table S1). However, these may represent only
a small fraction of the heritable component of malaria
susceptibility [11]. Furthermore, for most other loci, few
attempts had been made until recently to replicate initial
findings in different populations, and when this was done,
results were often conflicting, with likely explanations ranging
from heterogeneity in study design, including phenotype
definition, to heterogeneity in the haplotype structure of the
study populations [15]. In the last 5 years, the field has
experienced a dramatic change, as both hypothesis-free
GWASs and multicentre replication studies have been performed.
Three GWASs have been conducted in the Gambia [17],
in Ghana [18], and in a multicentre sample from the Gambia,
Kenya, and Malawi [19]. The authors proposed methodological strategies such as genotype imputation based on
sequences from reference panels and meta-analysis methods
allowing for heterogeneity, to overcome some of the
challenges posed by the high diversity of African populations
[25,26]. All three studies were able to identify significant
associations at the known malaria resistance loci HBB [27]
and ABO [28,29], and a novel important locus, APT2B4, was
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also identified. Other weaker or sub-phenotype-specific
signals are of considerable interest and deserve further
investigation [30].
A meta-analysis of association with 55 single-nucleotide
polymorphisms (SNPs) at 27 previously reported malaria
resistance loci has also been recently conducted in approximately 20 000 severe malaria cases and controls from 12
different locations in Africa, Asia, and Oceania. Highly significant associations were observed for haemoglobin S and C at
HBB and at ABO, CD40L [31], and ATP2B4 [18,19], whereas
weaker associations were observed at CD36 [32–35], IL1A
[36], and IRF1 [37,38]. For the G6PD variant that is most
commonly associated with enzyme deficiency in Africa [39–
41], an inverse association with the two main syndromes of
severe malaria was observed, i.e. a reduced risk of cerebral
malaria and an increased risk of severe malarial anaemia,
providing a possible explanation for previous contrasting
findings (The MalariaGEN Consortium, submitted).
A new malaria resistance locus, APT2B4, has been consistently
and robustly identified by recent studies. This gene encodes for
the major Ca2+ pump of erythrocytes, and it is therefore likely
that variants affecting the protein’s structure or expression
could have an important impact on Ca2+ homeostasis and, in
turn, on parasite survival within the host cell.
Leishmaniasis
Leishmaniasis is a disease caused by 21 different species of the
genus Leishmania and transmitted by the bite of female
phlebotomine sand flies. The tissue stage of the parasite, the
amastigote, invades and multiplies within macrophages and
other mononuclear phagocytic cells. The infection can either
be asymptomatic or develop into cutaneous leishmaniasis (CL),
mucocutaneous leishmaniasis (MCL), or VL, depending on
parasite, host and ecological factors.
The availability of an experimental mouse model for
leishmaniasis has been very useful for the identification of
genes and pathways involved in protective immune responses,
in the control of lesion growth, and in parasite load.
CL
CL is the most common form of leishmaniasis, and causes
nodules or ulcers at the sites of sand fly bites, which may heal
spontaneously or leave lifelong scars. MCL is a complication of
CL in which parasites colonize the mucosal tract via the
lymphatic system, and leads to partial or total destruction of
mucous membranes of the nose, mouth, and throat, leading to
disfigurement, secondary infections, and compromised nutritional and respiratory functions.
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Host loci affecting CL or MCL have uniquely been
investigated through candidate gene studies, and those showing significant associations are reported in Table S2.
Recently, a role for polymorphisms at loci encoding
products involved in the wound-healing response has emerged
from association studies. Linkage studies of MCL in mice have
shown that resistance to Leishmania major and wound healing
are controlled by FL1 [9]. In humans, associations of opposite
alleles of FL1 with CL and MCL have been demonstrated
[42,43]. FL1 is a transcription factor that represses CTGF
(encoding connective tissue growth factor) expression via
transforming growth factor-b signalling, thereby affecting
collagen synthesis. Polymorphisms at loci involved in this
pathway have been investigated, and significant results have
been obtained for associations with CL at FL1, CTGF, TGFBR2,
SMAD2, and SMAD7, and for associations with ML at SMAD3
and SMAD6 [44].
VL
VL is a systemic disease resulting from invasion of the spleen
and liver by Leishmania parasites and that is 100% lethal within
2 years of infection when untreated.
In 2013, the LeishGEN Consortium reported the results of
the first GWAS of VL, which was conducted in large samples
of cases and controls (N = 2078) from India (Leishmania
donovani) and affected child family members (N = 1970) from
Brazil (Leishmania infantum chagasi). The HLA–DRB1–HLA–
DQA1 locus showed strong signals of association in both
populations, and the result was replicated in a second Indian
cohort (N = 1931). It is remarkable that common polymorphisms in this major histocompatibility complex (MHC) class II
region are risk factors for VL caused by different parasite
species in two different geographical regions [16].
Previous studies aimed at identifying VL susceptibility loci
have used either genome-wide linkage or candidate gene
approaches, and have typically been small and underpowered
(Table S2). Among those, studies of HLA alleles had provided
inconsistent association results [45]. On the other hand, the
LeishGEN GWAS did not provide evidence of association for
any of the loci that both linkage and association studies had
previously indicated to play a role in VL, e.g. SLC11A1.
This gene encodes solute carrier family 11a member 1, an
ion transporter with pleiotropic effects located on the
lysosomal compartment of macrophages, and was first identified by studies in mice as a major locus controlling the
proliferation of L. donovani but not of L. major [9]. In humans,
polymorphisms in SLC11A1 have shown associations with
susceptibility to different infections, including leprosy, tuberculosis, and human immunodeficiency virus infection, as well as
to autoimmune diseases [45]. With respect to VL, SLC11A1
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genetic variation has shown linkage and association with VL in
Sudanese samples [46,47] but not in Brazilian [48] and Indian
populations [49], suggesting that the lack of significant results
in the GWAS (where association was apparently tested only in
the Indian replication sample [16] is attributable to genetic
heterogeneity of the populations (both human and parasite)
under study, and stressing the need to conduct GWASs of VL
in African populations.
Trypanosomiasis
African trypanosomiasis
African trypanosomiasis is caused by extracellular protozoan
haemoflagellates belonging to the complex Trypanosoma brucei.
Two morphologically indistinguishable species cause diverse
patterns of sleeping sickness, a lethal disease, in humans, and
are distributed in West/Central and East/Southeast Africa,
respectively: T. b. gambiense and T. b. rhodesiense. Trypanosomes are transmitted to humans by the bite of tsetse flies of
the genus Glossina. From skin tissue, the parasites enter the
lymphatic system and then the bloodstream, and are able to
invade other body fluids such as spinal fluid. The pathology
includes the development of a chancre at the site of
inoculation, and symptoms such as fever, lymphadenopathy
and pruritus are linked to the haemolymphatic stage. The
severe form of the disease results from invasion of the central
nervous system, which leads to somnolence, loss of consciousness, coma, and eventually death.
Humans are immune to infection by a third member of the
complex, T. b. brucei. The biological mechanisms responsible
for this refractoriness have been beautifully reviewed by Pays
and Vanhollebeke [50]. Human serum has trypanolytic activity
mediated by complexes of apolipoprotein A-1, apolipoprotein L-1 (apoL1), and haptoglobin-related protein (Hpr). Lysis
of trypanosomes is caused by apoL1, which forms anionic
pores on the lysosome membrane of the parasite, while Hpr,
in association with haemoglobin, promotes the binding of
trypanolytic complexes to a haptoglobin–haemoglobin receptor on the parasite surface, and therefore the internalization
of apoL1. T. b. gambiense and T. b. rhodesiense have evolved a
mechanism to overcome this immunity, based on a serum
resistance-associated protein that binds and neutralizes
apoL1. Variants of APOL1 have been described that encode
proteins with increased abilities to lyse trypanosomes and
that are associated with chronic kidney disease in African
Americans [51]. The same variants have been shown to be
under natural selection in African populations exposed to
T. b. [51,52] and to be associated with resistance to T. b.
gambiense infection in a small sample of affected child–parent
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trios from The Congo [53]. Equivocal evidence of signatures
of selection at the HP-HPR gene region has been obtained,
although a geographical overlap exists between the frequency
of an HPR copy number variant and the distribution of human
african trypanosomiasis, and HPR duplication is under-transmitted, in combination with APOL1 variants, to infected
children [53]. Few other candidate gene association studies
have been conducted to date, but they have identified
associations at TNFA, IL10, IL6, and HLA-G [54–56].
American trypanosomiasis
American trypanosomiasis, or Chagas disease, is caused by
Trypanosoma cruzi transmitted by blood-sucking triatomine
bugs, and represents a major public health problem in many
Latin American countries. Parasites enter the host through the
wound or mucosal membranes, invade cells near the site of
inoculation, and then, thanks to multiplication of extracellular
stages in the bloodstream, new infection sites, mainly the heart
and the digestive muscle. A nodular lesion, or chagoma, may
appear at the site of inoculation, followed by an acute phase
during which a high number of parasites circulate in the blood,
which is mostly asymptomatic. Most cases then develop a
chronic form of the disease, which can either never develop
clinically or progress to patent and potentially fatal Chagas
disease, whose main manifestations are cardiomyopathy and
pathologies of the digestive tract.
Recently, a first GWAS of chronic Chagas cardiomyopathy
was conducted in a Brazilian cohort of 580 T. cruzi-seropositive donors (controls) and chronic Chagas cardiomyopathy
patients (cases) [20]. The strongest association signals have
been observed at SLCO1B1, encoding a membrane transporter
of the solute carrier family, which has been previously shown
to play a role in statin-induced myopathy [57]. The authors
also reported a further 28 loci with association signals for six
other Chagas disease-related traits. However, none of the
signals reached a genome-wide significance level, probably
because of the relatively small sample size and genetic
heterogeneity of the cohort. Otherwise, the host genetic
epidemiology of Chagas disease has been addressed by a
number of candidate gene association studies of limited sample
size, with a focus on genes involved in innate and adaptive
immune responses, many of which have shown an involvement
of human leukocyte antigen (HLA) class I and II molecules
(Table S3).
Schistosomiasis
Schistosomiasis is a chronic disease caused by helminth
trematodes (flatworms) of the genus Schistosoma that are
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disseminated in fresh water by snails and that infect humans by
active skin penetration. Female adult worms lay hundreds of
eggs per day in the blood vessels of the intestine (S. mansoni
and S. japonicum) and bladder (S. haematobium), and most of
the pathology is associated with the host reaction to eggs, as
the majority of these do not reach the lumen to be eliminated
with the faeces or urine, but remain trapped in the liver or in
the bladder and urethra, depending on the worm species.
S. mansoni and S. japonicum can therefore cause severe and
potentially lethal hepatic disease, whereas S. haematobium can
cause severe bladder and renal pathology. Genetic epidemiology studies of susceptibility to schistosomiasis have investigated, on the one hand, loci responsible for infection levels, as
the severity of the disease is related to the number of eggs laid,
and, on the other hand, loci involved in progression to severe
hepatic disease. In both cases, linkage studies have provided
evidence that few loci play a major role in susceptibility, and
the characterization of the responsible genes has been quite
successful.
Infection levels
A major locus accounting for much of the variability in
S. mansoni infection intensity in a Brazilian population was
mapped by a genome-wide linkage study to the 5q31–q33
region of the genome [58,59], and the results were replicated
in a Senegalese population [60]. Candidate gene association
studies were then performed for loci in this region, which
contains a Th2 cytokine gene cluster (IL4, IL5, and IL13). SNPs
at IL13 have been shown to be associated not only with
S. mansoni infection levels [61] and re-infection after treatment
[62], but also with intensity of infection with S. haematobium
[63–65]. Variation at STAT6, another locus implicated in Th2
signalling, has also shown an association with S. haematobium
infection levels [64]. Both IL13 and STAT6 SNPs have been
shown to affect gene expression [64,66,67] and to be
associated with total IgE levels [68,69], and with allergy [70],
asthma, and atopy [66,71,72]. Furthermore, the 5q31–q33
region has been implicated in the development of autoimmunity diseases such as Crohn’s disease [73]. Genetic studies
therefore strongly support the evidence from immunological
studies [74] regarding the importance of the host Th2-type
immune response in susceptibility to schistosomiasis and other
helminth infections. It is indeed remarkable that genetic
variation at IL13 and STAT6 has also been found to affect
susceptibility to Ascaris lumbricoides [68,75], suggesting, as
discussed by Hopkin [76], that helminth infections have played
an important role in selecting Th2-upregulating variants that
are responsible for allergy and related traits.
Suggestive evidence of linkage with S. mansoni infection levels
has been found for two further genome regions, 1p21–q23 and
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6p21–q21, by a re-analysis of data from Marquet et al. [77], but
no studies on the responsible genes have followed. Evidence for
a role of HLA (6p21) alleles in the control of infection intensity is
limited [7].
Severe hepatic disease
Linkage analysis performed in four candidate regions in a
Sudanese population has shown that a major locus in the
6q22–q23 region controls susceptibility to S. mansoni severe
hepatic fibrotic disease (HF), with a linkage peak close to
IFNGR1 [78], encoding the a-chain of the receptor for
interferon-c, a cytokine with potent antifibrogenic activity. A
family-based candidate gene association study conducted in
Egypt confirmed the involvement of IFNGR1 [79]. An important role for interferon-c in liver fibrosis has been further
supported by the association of SNPs in IFNG with HF in a
Sudanese population [80].
CTGF, encoding connective tissue growth factor, a profibrogenic molecule produced by hepatocytes, also lies in the
6q22–q23 region, and variants at this locus that alter
transcription factor binding have been shown to be associated
with HF in two independent samples from China (S. japonicum), and in Sudanese and Brazilian samples (S. mansoni).
Linkage disequilibrium analysis of the 6q22–q23 7-Mb region
surrounding CTGF conducted in the HapMap Chinese population did not reveal correlation patterns that could account
for the signals of association observed at this gene [81]. In this
study, only two IFNGR1 SNPs were tested for association in
one Chinese sample, with no significant results being obtained.
It therefore remains to be understood whether IFNGR1 and
CTGF SNPs independently affect susceptibility to HF, and
whether they interact and how.
Although the MHC region has not been identified by linkage
studies as a major susceptibility locus, many studies have
investigated the involvement of HLA class I and II alleles in liver
pathology caused by schistosomes, with variable results [7].
However, a recent meta-analysis identified risk and protective
HLA alleles, and the authors suggested the possible existence
of common antigenic moieties that would be presented to
pathogenic or protective T-cells, affecting the outcome of the
disease [82].
Soil-transmitted helminth diseases
Soil-transmitted helminth disases are chronic diseases of the
gastrointestinal tract caused by a group of parasitic nematode
worms that infect humans via parasite eggs or larvae that
thrive in the soil of the world’s tropical and subtropical
countries. Roundworms (Ascaris lumbricoides), whipworms
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(Trichuris trichiura) and hookworms (Necator americanus or
Ancylostoma duodenale) account for most of the burden
worldwide. Co-infection with all three worms is common,
especially in children, who suffer malnutrition, growth stunting,
and cognitive deficits [83].
Extensive genetic epidemiology studies of A. lumbricoides
infection intensity have been conducted in the Jiri population
from Nepal. Two genome-wide linkage scans have identified
quantitative trait loci (QTLs) in four different regions: 1p32,
8q23, 11p14, and 13q32–q34 [84,85]. SNPs at two genes
within the last of these regions, LIG4 and TNFSF13B, have
shown associations with levels of IgG and IgE against Ascaris in
a Colombian sample, suggesting that they could affect susceptibility to infection by promoting a protective humoral
response against the parasite [86]. Candidate gene association
studies of Ascaris infection intensity have shown significant
results not only for IL13 [75] and STAT6 [68,75], as previously
discussed, but also for IFNG [75]and ADRB2 (located in the
5q31–q33 region) [87] loci [6]. Recently, a large (N = 1353)
candidate gene association study was conducted in Brazil, and
showed that IL10 SNPs play a role in susceptibility to current
and chronic infection with both A. lumbricoides and T. trichiura.
The same study showed associations of IL10 SNPs with atopic
wheeze and total IgE levels, providing further evidence that
common genetic regulation underlies susceptibility to helminth
infection and allergy [88].
However, genome-wide linkage analysis of T. trichura
infection intensity, also performed in the Jiri population of
Nepal, provided evidence for QTLs in the 9p24 and 18p11
regions, and therefore distinct from those identified for Ascaris,
suggesting that the major loci influencing helminthic burden are
probably infection-specific [89].
To date, no studies have investigated the genetic epidemiology of hookworm susceptibility.
Filariasis
Lymphatic filariasis
Lymphatic filariasis is caused by the filarid nematodes Wuchereria bancrofti, Brugia malayi, and B. timori, which are
transmitted by different species of mosquito vectors. Although
a proportion of exposed subjects can remain free of parasites,
most will be asymptomatically infected (microfilariae or
parasite antigens are detected in blood), and in some cases
they develop pathology, which can be chronic (lymphoedema,
hydrocele, and elephantiasis), acute (adenolymphangitis), or
systemic (tropical pulmonary eosinophilia).
The host genetics of susceptibility to lymphatic filariasis
have been investigated solely by candidate gene association
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studies [10]. These have shown significant results at CHIT1
[90], MBL2 [90,91], TGFB1 [92], TLR2 [93] and CTLA4 [94] for
susceptibility to infection, at VEGFA for progression to
hydrocele [95], and at TNFR2 and ET1 for progression to
elephantiasis as opposed to hydrocele [96].
The most interesting results regard MBL2, encoding mannose-binding lectin, a liver-derived collagen-like plasma protein
that binds to sugars on the surfaces of pathogens and initiates
the innate immune response by activating complement. Indeed,
significant associations with W. bancrofti infection of gene
polymorphisms with a known effect on plasma protein levels
were observed in two different populations from India and
Tanzania. A role for MBL2 deficiency in lymphatic filariasis is
1
2
p34.3
p22.3
p32.3
p21
p16.3
p31.3
q25.3
q31.1
q31.3
q32.1
q41
q43
q44
q12.1
q12.3
q13.2
q13.3
q14.1
q11.2
IL1A-IL1B
• AmT, Pf, VL
• AS, RA
q14.1
q15
q32.1
q32.3
q33.1
q34
q35
IL10
• AfT, As, CL, Pf, Tr
• AA, IBD, SLE
q23.1
q23.2
q23.3
q31.1
q31.2
q31.3
q32
q33.3
IL18RA, SLC11A1
• CL, VL
q36.3
q37.1
q37.3
12
q34
q35.1
q35.2
q35.3
15
p15.3
p15.1
p13.33
p14
p13.31
p13.2
q23.31
p11.22
p11.21
q13.11
q13.12
q13.13
q14.1
p12.2
q22.1
q21.13
CTGF
• CL, Sj, Sm
q22.33
q23.2
q23.3
q24.1
q21.31
q21.32
q21.33
q22.3
IFNGR1
• Sm, Pf, VL
q31.1
q22.31
q22.32
q22.33
q31.31
q31.1
q31.33
q31.2
q31.3
q32
q33.1
q33.2
q33.3
q34.11
q33
q24.3
q25.1
q34
q35
q25.3
q26
q27
q36.1
q34.3
q36.3
19
p13
q21.31
q23.1
q24.11
q24.21
q24.23
q24.31
q24.32
q24.33
p13.2
p11.2
p11.2
p13.12
q11.2
NOS2A
• Pf
• AA
p13.11
p12
q11.21
q12
q11.2
q21.2
q21.31
q12.1
q22.2
q22.31
q23
SMAD3
• CL
• AA
q21.32
q22.2
q25.2
q12.1
MIF
• AmT, CL
q12.2
q13.2
HP
• AmT, Pf
q23.2
q23.3
q24.1
q24.2
q23.1
q24.3
q26.1
q23.2
q23.3
q25.1
q26.3
q11.23
q13.11
q13.12
q25.3
q26.2
q11.22
q12
q22
q21
q24.1
q25.1
CCL2
• AmT, CL
q21.33
q12.2
q22.1
q23.3
p13.3
p12
IL4R
• AmT
• AA
p11.2
q21.3
IFNG
• AmT, As, CL,
Sm, Pf
FCN2
• AmT, CL
22
q15.1
q21.1
TLR4
• Pf, VL
• AA, IBD
p13.1
q21.2
q21.1
q21.2
p12.1
q14
STAT6
• As, Sh
• AA
q14.3
q15
q24.2
q26.13
q26.2
q26.3
q21.3
q21
17
q13.3
q12
MBL2
• LF, Pf, VL
• SLE
q21.33
q22
q25.2
q25.3
q26.11
q16.3
q13
q21.11
p12.3
q11.2
q12
q13.1
q23.33
q25.1
q21.13
p13.2
p12.1
p11.22
p11.21
q23.1
q21.11
q16.1
p13.2
p13.13
p13.12
p13.11
p11.2
p12.1
q22.1
q22.2
q22.3
q11.23
p13.3
p12.31
q21.3
q12
q11.22
q14.3
q15
16
p13.1
p12
p11.2
q11.21
q14.1
q22.31
IL12B
• Pf
• CeD, IBD, Ps
p21.1
p13.3
p12.1
p11.2
q22.1
ADRB2
• As, Pf
• AA
p21.3
p12.3
p13.3
p12.3
q21.2
IL4
• CL, Pf, Sm, VL
• AA, Ps
p23
p14.1
q13
IL13
• As, On, Pf, Sh, Sm
• AA
p24.1
IL6
• AfT, CL
p14.3
q12
p13
p13
q21.1
p21.1
p15.3
p12.1
5q31-q33
• Pf, Sm, VL
• AA, IBD
q21.3
CTLA4
• CL, LF
• AA, AIT, CeD, RA,
SLE, T1D
q24.3
q31.1
CR1
• Pf
• SLE
q14.3
q21.1
q22.1
q22.3
q23.3
q24.1
FCGR2A, FCGR2B
• Pf
• SLE
10
q11.21
q11.22
q11.23
p21.31
p21.2
p21.1
9
p21.3
TNF, LTA
• AfT, AmT, CL, Pf, VL
• AA, AIT, CeD, IBD, MS,
RA, Ps, SLE
p22.1
q11.2
q14.3
q23.3
p22.3
p12.3
p12
1p21-q23
• Sm, VL
• AA
7
EDN1
• AmT, LF
p24.3
p14.1
p13.3
p13.2
p13.1
p12
q12
q21.3
6
p15.31
p15.2
p15.1
p14.3
p11.2
p21.1
p13.3
Onchocerciasis, or river blindness, is caused by the
filarid nematode Onchocerca volvulus, transmitted by Simulium
p14
p31.1
p21.3
Onchocerciasis
p15.33
p16.1
1271
also supported by experiments on B. malayi infection in
knockout mice showing longer survival of knockout microfilariae than of the wild type [97]. It is noteworthy that functional
genetic variants of MBL2 or MBL deficiency have shown
associations with a range of infectious and non-communicable
diseases, although the exact nature of the associations is
controversial and might be context-dependent [98,99].
On the other hand, there is little and contrasting evidence
for a role of HLA alleles in either infection or pathology [7].
5
p25.3
p25.1
p24.3
p24.1
Host genetics and parasitic infections
q24.1
q24.3
q13.31
TGFB1
• AmT, LF, VL
• AA
q12.3
q13.1
IL2RB
• VL
• AA
q13.32
q13.33
q13.41
q13.2
q13.31
q13.42
q25.3
q13.32
q13.43
q13.33
FIG. 1. Loci showing associations or linkages with parasitic and immunological disorders. Loci involved in susceptibility to parasitic diseases are
those discussed in the sections dedicated to individual parasites. Additional loci were identified for malaria from previous reviews [1,2,100]. For
immunological disorders, the Huge Navigator [101] database was searched for loci showing associations in genome-wide association studies or
meta-analysis. AA, asthma–allergy; AfT, African trypanosomiasis; AIT, autoimmune thyroid disease; AmT, American trypanosomiasis; As, ascariasis;
AS, ankylosing spondylitis; CeD, coeliac disease; CL, cutaneous leishmaniasis; LF, lymphatic filariasis; IBD, inflammatory bowel disease; MS, multiple
sclerosis; On; Onchocerca volvulus; Pf, Plasmodium falciparum; Ps, psoriasis; RA, rheumatoid arthritis; Sh, Schistosoma haematobium; Sj; Schistosoma
japonicum; SLE, systemic lupus erythematosus; Sm, Schistosoma mansoni; T1D, type 1 diabetes; Tr; Trichuris trichiura; VL, visceral leishmaniasis.
Chromosome maps from Ensembl.org. The MHC class I and II regions are not shown.
ª2014 The Authors
Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1265–1275
1272
Clinical Microbiology and Infection, Volume 20 Number 12, December 2014
blackflies. Adult filariae develop and reside in nodules of
subcutaneous tissue, causing a range of clinical conditions,
including pruritus, dermatitis and, most severely, ocular
lesions that can lead to blindness, and inflammatory skin
disease (sowda).
An autosome-wide genome linkage scan of O. volvulus
infection intensity, as measured by the number of microfilariae
in skin nodules, was performed in Ghana, and showed a QTL,
termed Ov1, in the 2p21–p14 region [102]. The authors
reviewed the literature to compare Ov1 with the body of
linkage and association data obtained for atopic diseases:
linkage has been shown at regions proximal to Ov1 for asthma,
IgE levels, and bronchial hyper-reactivity [103–105]. However,
the loci/polymorphisms underlying the linkage signals, both for
Onchocerca infection and for asthma, have not been identified,
and it therefore remains to be determined whether they result
from a common genetic basis. Interestingly, a previous case–
control study had shown association of alleles at KM, located in
the 2p21–p14 region and encoding immunoglobulin j light
chain, with susceptibility to Onchocerca infection in Ecuadorians
of African but not Amerindian ancestry [106].
A second candidate gene association study was conducted
in Ghana and Guinea, and showed association of IL13
polymorphisms with the sowda phenotype, providing further
evidence for the important role of this cytokine in immunity to
helminths [107].
Significant and consistent associations of HLA class II alleles
(DRQA1*0501–DQB1*0301) with immunity to either localized or generalized disease have been reported in Liberia,
Nigeria, and Cameroon [7], suggesting a role in the recognition
of a specific Onchocerca antigen.
CMI
which the burden of these disorders could be, at least in part, the
result of the selective pressure imposed by parasitic and other
infections on the human genome [108]. It is therefore foreseeable that much knowledge, on the biology of both parasitic and
immunological diseases, can still be gained by the performance of
large, multicentre and genome-wide (i.e. hypothesis-free) association studies, which have so far been pioneered with some
important success in the malaria field, and, to a lesser extent, for
visceral leishmaniasis and Chagas disease. Also, next-generation
sequencing technologies, applied both at the genome level and at
the transcriptome level, could be able to overcome some of the
limitations of GWASs and to provide insights into the genetic
regulation of gene expression, shortening the gap between
genotype and phenotype.
A further promising line of research that is of vital
importance for the successful implementation of control
measures is represented by genetic epidemiology studies aimed
at uncovering the mechanisms involved in the host response to
antiparasitic drugs [109] and in parasite transmission [110].
Acknowledgements
V. D. Mangano was funded by EVIMalaR (European Community’s Seventh Framework Programme, FP7/2007-2013, grant
agreement No. 242095).
Transparency Declaration
The authors have no conflicts of interest.
Conclusions
Supporting Information
Fig. 1 shows loci that have been reported to be associated or
linked with susceptibility to multiple parasitic diseases or to
both parasitic and immunological disorders. As discussed in the
above paragraphs, the identification of these loci is probably
biased by the hypothesis-driven selection of candidate genes.
Nonetheless, it is noteworthy that common genetic regulation
of susceptibility to different parasites may exist. This could
possibly be because susceptibility to one infection affects
susceptibility to concomitant or subsequent infections with
different pathogens. It can be therefore hypothesized that a
genetic factor which has been selected because of a survival
advantage against one parasitic disease could be protective
against other diseases as well. It is similarly noteworthy that
some loci are also involved in susceptibility to allergy or
autoimmune diseases, outlining an evolutionary scenario in
Additional Supporting Information may be found in the online
version of this article:
Table S1 Erythrocyte-related loci showing association with
severe P. falciparum malaria
Table S2 Loci showing association or linkage with
cutaneous and visceral leishmaniasis
Table S3 Loci showing association or linkage with
American trypanosomiasis
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