Skip Navigation

Human Molecular Genetics 2004 13(Review Issue 2):R187-R194; doi:10.1093/hmg/ddh225
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Frodsham, A. J.
Right arrow Articles by Hill, A. V.S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Frodsham, A. J.
Right arrow Articles by Hill, A. V.S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, Vol. 13, Review Issue 2 © Oxford University Press 2004; all rights reserved

Genetics of infectious diseases

Angela J. Frodsham and Adrian V.S. Hill*

The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK

Received June 22, 2004; Accepted July 19, 2004


   ABSTRACT
TOP
 ABSTRACT
MALARIA
 MYCOBACTERIAL DISEASES
 VIRAL DISEASES
 CONCLUDING REMARKS
 REFERENCES
 
Infectious diseases represent a major health problem worldwide, both in terms of morbidity and mortality. A complex combination of environmental, pathogen and host genetic factors plays a role in determining both susceptibility to particular microbes and the course of infection. Numerous studies have now mapped and identified relevant genes using a variety of both family-based and population-based approaches. Much interest has been focused on susceptibility to malaria, HIV/AIDS and mycobacterial infection, but other bacterial, viral and parasitic diseases are receiving increasing attention. Some major genes have been identified by genome scans of multi-case families, and mouse genetics has contributed to mapping and identification of a few genes. However, the great majority of known susceptibility loci emerged from screening of likely candidate genes. The emerging picture is of highly polygenic diseases, with occasional major genes, along with significant inter-population heterogeneity. This genetic architecture likely reflects the role that evolutionary selection has played in generating and maintaining a diverse repertoire of susceptibility/resistance loci, most with individually small effects. Genome-wide association studies with large sample sizes will be required to define the majority of the relevant polygenes.

Infectious diseases account for a major part of the global health problem, with most of the burden falling in developing countries. Around 14.5 million deaths in the year 2001 were attributable to the effects of infectious diseases. Increasing evidence is becoming available to help defme the role of host genetics in susceptibility to, or outcome of infectious diseases. Owing to the nature of infectious diseases and the complex immune response that ensues after exposure, it is likely that many host genes will play a role in determining differential susceptibility and that only a small fraction of these have been identified thus far.

Haldane's 1949 proposal that genetic variation in globin genes might be driven by providing malaria resistance, and that similar forces from other pathogens could maintain great biochemical diversity, is being increasingly supported (1). This view has now been supported by studies on twins and adoptees (2–7), in addition to considerable data on specific genes and diseases.

Several different, yet complementary approaches to the identification of genetic variation important in the course of infectious disease progression have been taken. By far the most common approach has been to look for association in candidate genes using case–control studies. In general, large sample sets are needed to detect even moderate genetic effects in order to eliminate the possibility of false positive associations. Often, this has not been the case, leading to examples of inconsistent findings in genetic association studies, a problem not specific to the study of infectious diseases (8). However, publication bias may have resulted in many more such findings going unreported. A major problem of this candidate gene approach is in the problem of selection of appropriate candidate genes, but the record of successful guessing in this specific field is reasonably good, perhaps because genes related to infection resistance have higher levels of variation than most. More recently, the use of microarray technology has identified novel candidate genes on the basis of differential expression (9). Finally, clues as to what genes affect response to infection in humans are being found in the analysis of outcome of infection in model organisms such as mice or drosophila (10–12).

More recently, family-based approaches have also become more widely reported. Utilization of large numbers of families to look for linkage to infectious disease has been reported in a relatively small number of infectious diseases thus far (13–19) (Fig. 1). Other linkage studies to identify genes causing rare, monogenic susceptibility phenotypes have been reported, though the causative variation identified are rare mutations rather than polymorphisms and the identified genes rarely, if ever, relevant to common variation in susceptibility (20,21).



View larger version (43K):
[in this window]
[in a new window]
  		Figure 1. Diagrammatic representation of the location of some major infectious disease susceptibility loci identified via genomewide linkage analysis. Text colour represents the disease area: red, schistosomiasis parasite burden; aqua, malaria; blue, leprosy; green, tuberculosis; purple, tuberculosis and leprosy combined; orange, kala azar. Loci: A, Marquet et al. (15); B, Jepson et al. (14); C, Mira et al. (16); D, Siddiqui et al. (17); E, Blackwell et al. (69); F and J, Bellamy et al. (13); G, Miller et al. (70); H, Tosh et al. (18); I, Bucheton et al. (19).

 

   MALARIA
TOP
 ABSTRACT
 MALARIA
MYCOBACTERIAL DISEASES
 VIRAL DISEASES
 CONCLUDING REMARKS
 REFERENCES
 
Approximately 40% of the world's population is at risk from malaria, and around 1 million deaths each year, predominantly in children, can be attributed to this protozoan parasite (22). Probably the greatest number of genes conferring differential susceptibility to any disease has been reported for various manifestations of malaria. The classic example is the selective advantage conferred by the sickle haemoglobin heterozygous genotype (23) which is associated with a 90% reduction in the risk of severe malaria (24). Haemoglobin E is associated with a reduction in disease severity in southeast Asia whereas haemoglobin C, like sickle haemoglobin, is also associated with reduced malaria susceptibility in West Africa, but is clinically less severe (25–27). Additionally, the geographical distribution of the common {alpha}- and ß-thalassaemias, in which globin synthesis is imbalanced, supports a protective effect against Plasmodium falciparum malaria, but the exact mechanism of this remains unclear (28). There are conflicting data on haptoglobin associations with malaria. Ahaptoglobinaemia (i.e. the absence of haptoglobin) is a common phenotype in malaria infected individuals, but this is not entirely dependent on genotype and can be affected by the disease status of the individual (29–31). Although studies of the relative frequencies of the protein isoforms of haptoglobin have shown an association with malaria infection, no evidence of this was seen in a more recent, larger study in West Africa (32–34). By far the strongest effect that a genetic variant has on protection from Plasmodium infection is conferred by the Duffy negative phenotype. A single nuclear polymorphism (SNP) in the promoter of the Duffy antigen/chemokine receptor (DARC) gene alters the binding of the haematopoietic cell specific transcription factor GATA-1, thus inhibiting DARC expression (35). The absence of this receptor from the red blood cell surface results in complete protection from P. vivax malaria infection (36) and this variant has reached fixation in most sub-Saharan Africans.

Extended haplotypes around two genes on the X chromosome have recently been demonstrated to have signatures of positive selection, probably as a result of malaria (37). Both have been associated with differential malaria susceptibility, compellingly in the case of the first, glucose 6-phosphate dehydrogenase (G6PD) (38). The other gene encodes CD40 ligand, which interacts with the key lymphocyte and dendritic cell receptor CD40 (39).

Immunologically important molecules such as cytokines and receptors have been popular candidates for analysis. Variants in tumour necrosis factor alpha (TNFA), CD32 (Fc{gamma}GRIIa) and subunits of the interferon alpha and gamma receptors (IFNARl/IFNGRl) have all been reported to influence susceptibility to clinical malaria (40–45). Previous analyses of the differences in ethnic groups in West Africa revealed that the Fulani are less susceptible to clinical malaria than their neighbours in Burkina Faso (46). Analysis of polymorphisms in the ILA cytokine gene promoter demonstrated an association that could partially explain this difference (47).

The importance of the HLA locus in initiation and regulation of the immune response, together with their well-documented variation, has led to numerous studies of their influence on disease susceptibility and progression. Some of this research is summarized in Table 1. However, because HLA molecules interact with polymorphic parts of the parasite (in turn due to immune selection on these pathogen sequences), and parasite allele frequencies differ geographically (at times very strikingly), it is perhaps not surprising that HLA association with malaria shows interpopulation heterogeneity. Both HLA class I and class II alleles have been found to influence malaria susceptibility in Africa (24,51). HLA has also been observed to influence the parasite strain associated with clinical malaria and the complex interactions between these factors may lead to further variability in HLA allele associations (59,60). A major genetic effect of the HLA region was observed even in studies of a mild malaria phenotype (rather than severe malaria) in a linkage study of Gambian dizygotic twins (14). Other, more thorough, linkage studies have yet to be completed, but could reveal further major as yet unidentified genes that influence the course of malaria infection.


View this table:
[in this window]
[in a new window]
  		Table 1. Some of the studies of the genetic effect of HLA loci on susceptibility and resistance to infectious disease
 

   MYCOBACTERIAL DISEASES
TOP
 ABSTRACT
 MALARIA
 MYCOBACTERIAL DISEASES
VIRAL DISEASES
 CONCLUDING REMARKS
 REFERENCES
 
Familial clustering data, twin studies and complex segregation analysis have all suggested a strong genetic component to the human chronic mycobacterial diseases, leprosy and tuberculosis. Early segregation analysis suggested that single or few major genes might be implicated in some populations (3,4,61,62). Several family studies to search for major genes have been undertaken and locations of the loci identified are shown in Figure 1.

There are around 700 000 new cases each year of clinical leprosy which can be divided into two polar types. Lepromatous leprosy is associated with a high bacterial load, a strong type 1 cytokine response and the presence of skin nodules or plaques. Tuberculoid leprosy is associated with the presence of few bacteria (paucibacilliary) and hypopigmented, desensitized skin lesions and often the thickening of local nerves. Host genes that have been identified thus far have been implicated in both types of leprosy or with leprosy per se. Family studies have revealed the presence of three loci that are linked to leprosy. Studies on a South Indian population have revealed that two loci are involved in susceptibility to tuberculoid leprosy on the short arms of both chromosomes 10 and 20 (17,18), and the chromosome 10 gene has recently been identified (Tosh et al., submitted for publication).

Analysis of a cohort of Vietnamese families confirmed the linkage to chromosome 10 and reported a further locus on chromosome 6 (16). Fine mapping of the chromosome 6 locus revealed that a cluster of non-coding polymorphisms within the shared promoter region of two genes; PARK2 and PACRG (63,64). The association within this region was replicated in a large set of Brazilian leprosy cases and controls. Which of these two genes is the most important is, as yet, unknown, as neither represents an obvious candidate for a leprosy susceptibility gene. Both are expressed in the host cells for M. leprae; the Schwann cells and macrophages (63). PARK2, a gene previously associated with juvenile Parkinsonism, is a ubiquitin E3 ligase, whereas PACRG forms part of a molecular chaperone complex (65,66).

Pulmonary tuberculosis (TB) is characterized clinically by fever, cough, weight loss and an abnormal chest X-ray, whereas the symptoms of non-pulmonary TB differ depending on which organ(s) are affected. A study of African families from both West and South Africa found suggestive evidence of susceptibility loci, one on chromosome 15 and the other on chromosome X. Subsequent fine mapping of the linkage on chromosome 15 identified another ubiquitin ligase gene, UBE3A, as a positional candidate in this region (67), indicating again the possible importance of ubiquitin ligases in susceptibility to mycobacterial infection. Further analysis of the chromosome X locus excluded the CD40L gene as the susceptibility gene for this gene (68). Additional studies in Brazilian multi-case families have found some evidence of linkage on both chromosomes 11 and 17, the latter requiring a combined analysis of both leprosy and TB families (69–71).

In addition to family studies, candidate gene studies have been relatively successful in the identification of genes implicated in host susceptibility to leprosy and TB. SLCA11A1 (or NRAMP1) was identified originally after work in a mouse model identified Nramp1 as a susceptibility locus for infection with some strains of Mycobacterium bovis BCG, Leishmania donovani and Salmonella typhimurium (72,73). Studies of the effect of variation in this gene on susceptibility to TB and leprosy have produced conflicting results. The first study of TB susceptibility found that four vaniants in the gene were associated with a higher risk of infection in the Gambia (74). Subsequent studies have replicated this association not only in the initial population, but also in Conakry, Korea, Japan, Cambodia and the USA (75–79). However, not all reports confirm the original findings (Fitness et al., unpublished data), and there are several examples where no association was found, but many of the studies looking at NRAMP1 as a susceptibility gene for TB are small and underpowered for the magnitude of the genetic effect observed (80–82). The findings for leprosy are less clear, one study found evidence of NRAMPI variation affecting susceptibility to leprosy per se, but several other studies have failed to replicate this (83–86).

Another gene that has shown evidence for involvement in mycobacterial disease is the vitamin D receptor (VDR). Vitamin D is an immunomodulatory molecule and via its receptor, can modulate cytokine responses in T cells (87,88). Several small-scale studies have suggested that variants of this receptor may alter both leprosy and TB risk (85,89,90).

Toll-like receptor (TLR) genes were first identified in drosophila gene knockout studies that produced severely immunocompromised flies that are fatally susceptible to fungal infections (91). An extension of this work in mice resulted in the positional cloning of a gene responsible for lipopolysaccharide (LPS) sensitivity in mice. This gene was homologous to the drosophila Toll gene, and was subsequently identified as the murine homologue of the TLR4 gene (92–94). Of the 10 TLR family genes in humans, TLR2 has been most strongly implicated in analysis of mycobacterial ligands (95). Significant association has been published with respect to TB infection, finding that an amino acid substitution causing variant in TLR2 is associated with increased susceptibility to TB in Turkey and Tunisia (96,97). A second amino acid variant is reported to be found only in lepromatous leprosy cases in Korea (98). Whether these changes are themselves affecting TLR2 function or are in linkage disequilibrium with the intronic functional microsatellite is thus far unclear (99). As yet, no evidence has been published linking TLR4 with mycobacterial infection (100,101).

In addition to numerous HLA studies of mycobacterial infection and disease (Table 1) a large number of other immunological candidates have been assessed. Putatively functional variation in genes such as IL8, IFN{gamma} and MBL have been associated with TB susceptibility (102–106), but subsequent analyses of other populations have failed to replicate these associations (106–109). Larger, better designed studies will be required to distinguish real population heterogeneity from chance differences.


   VIRAL DISEASES
TOP
 ABSTRACT
 MALARIA
 MYCOBACTERIAL DISEASES
 VIRAL DISEASES
CONCLUDING REMARKS
 REFERENCES
 
Studies on the host genetics of viral infections are not limited to analyses of susceptibility or severity of infection. In the case of HIV/AIDS, the most frequently studied phenotypes are time to AIDS or death following HIV infection. Studies of persistent hepatitis have been published using multiple phenotypes such as outcome of infection, treatment response and major complications such as hepatocellular carcinoma or fibrosis.

HIV-1 infection is characterized by an extended clinically asymptomatic phase that leads, at a much later stage, to immune deficiency, opportunistic infections, neurological problems and malignancies that characterize AIDS per se. Studies on cohorts of HIV-infected individuals identified a small proportion of a cohort of commercial sex workers in Nairobi who remain HIV seronegative despite repeated exposure (110), though to date, no genetic factors have been identified that can adequately explain this apparent resistance to infection.

Since the discovery of the chemokine receptors as co-receptors with CD4 for viral entry into the host cells, many studies have investigated the role of chemokines and their ligands. The role of variation in the CCR5 gene in resistance to infection and slower disease progression is now well established (111,112). Analysis of the flanking CCR2 gene also showed that an amino acid change in this gene is linked to delayed progression to AIDS, although the mechanism of action of this variant in a rarely used co-receptor is unclear (113). Several studies have looked at the role of the CCR5 ligand RANTES. The presence of an intronic SNP that differentially binds regulatory proteins was associated with increased disease progression to AIDS in both European and African Americans (114), suggesting an evolutionarily important role for this new SNP in immunomodulation, which may be unlinked to HIV-1 disease progression. A second smaller study in the Chinese Han population has replicated this result (115). Another HIV-1 co-receptor ligand in HIV infection, stromal derived factor 1 (SDF1) is also associated with HIV-1 disease progression in some populations (116,117). Many other genes have been identified as HIV-1/AIDS host genetic determinants. These include genes such as IL4, IL10 and NRAMP1 that have been linked with other infectious diseases(118–123).

Infection with either the hepatitis B or hepatitis C virus results in either an acute, self-limited disease or, in a minority, in persistent infection. Persistent carriage rates, which confer an increased risk of liver complications, failure or end stage carcinoma, are ~10–20% in hepatitis B when compared with ~80–90% of hepatitis C infections. Studies of the host genetic factors implicated in disease chronicity have found that non-HLA genes that were mentioned earlier in this review, such as TNFA, MBL and VDR, are all associated with persistence of hepatitis B infection (89,124,125). The unusual immunological dichotomy of the outcome of disease makes HBV viral persistence an ideal candidate for family linkage-based studies enabling the identification of novel major genes that determine this fate. Recently a genomewide scan in Gambian families has mapped a major susceptibility locus to chromosome 21 and two neighbouring genes appear to be involved (Frodsham et al., submitted for publication).

In HCV viral persistence, the high numbers that are treated (with either interferon alpha alone or in combination with anti-retroviral therapy) allow for the analysis of genetic influence on treatment response and complications of infection in addition to the outcome of infection. The role of the CCR5 receptor, already acknowledged to be important in viral infection, has been investigated with respect to HCV infection. An initial study among haemophiliacs suggested that CCR5 may play a role in determining HCV persistence (126) but this has been disputed (127–129), though a recent paper suggests that CCR5 may be important in the risk of liver complications such as portal inflammation and risk of fibrosis (130) but not to the outcome of infection. Studies of the interferon induced genes such as MxA and PKR show that variation in these genes is a factor in the hosts' response to therapy (131). The picture for IL10 however, is not so clear, with contradictory results from different studies (132–134). Even though persistence rates are higher in HCV than in HBV, the lower prevalence makes family identification difficult, therefore limiting the possibility of family studies the genetics of HCV persistence.


   CONCLUDING REMARKS
TOP
 ABSTRACT
 MALARIA
 MYCOBACTERIAL DISEASES
 VIRAL DISEASES
 CONCLUDING REMARKS
REFERENCES
 
Available information supports the view that for the majority of infectious diseases host susceptibility is likely to be highly polygenic. Indeed, the relatively few major genes that have been identified in several genomewide linkage scans for bacterial, parasitic and viral infectious diseases support the view that the genetic susceptibility in these diseases is widely distributed among numerous polygenes.

The International HapMap project (135), an entire human genome sequence and increasing amounts of resequencing data for chromosomal segments, means that there are now millions of SNPs available for association studies (136). With high throughput technologies it is now feasible, but still very expensive, to perform a genomewide association screen to identify novel genes involved in response to infection, even in the diseases such as HIV and HCV persistence, where family studies have thus far, been impossible. Such data should provide far greater insights into disease pathogenesis than has been possible with the few dozen candidate genes that have been evaluated to date. The impact of these new insights on the control of these major global diseases could be considerable in identifying targets for new therapies, in improved vaccination strategies and eventually in disease elimination. In time, it should also be possible to define each individual a personalized risk profile that could predict their own unique susceptibility to various infectious organisms. It is likely that many of the SNPs contained in such a screen will be relevant to multiple infectious pathogens, as there is already considerable evidence that the immunomodulatory role of certain polymorphisms extends across disease boundaries. Extension of this approach into pharmacogenetics should result in individually tailored immunotherapy according on the host's genetic profile.


   ACKNOWLEDGEMENTS
 
The authors would like to thank Graham Cooke and Andrew Walley for their help in compiling this paper. A.J.F. is a Wellcome Trust Research Training Fellow and A.V.S.H. is a Wellcome Trust Principal Research Fellow.


   FOOTNOTES
 
* To whom correspondence should be addressed. Tel: +44 1865287759; Fax: +44 1865287686; Email: adrian.hill{at}well.ox.ac.uk


   REFERENCES
TOP
 ABSTRACT
 MALARIA
 MYCOBACTERIAL DISEASES
 VIRAL DISEASES
 CONCLUDING REMARKS
 REFERENCES
 

  1. Haldane, J.B.S. (1949) Disease and evolution. Ricercha Sci. 19 (suppl.), 68–76.

  2. Sorensen, T.I., Nielsen, G.G., Andersen, P.K. and Teasdale, T.W. (1988) Genetic and environmental influences on premature death in adult adoptees. N. Engl. J. Med., 318, 727–732.[Abstract]

  3. Chakravarti, M.R. and Vogel, F. (1973) A twin study in leprosy. Top. Hum. Genet., 1, 1–123.

  4. Comstock, G.W. (1978) Tuberculosis in twins: a re-analysis of the Prophit survey. Am. Rev. Respir. Dis., 117, 621–624.[Web of Science][Medline]

  5. Jepson, A.P., Banya, W.A., Sisay-Joof, F., Hassan-King, M., Bennett, S. and Whittle, H.C. (1995) Genetic regulation of fever in Plasmodium falciparum malaria in Gambian twin children. J. Infect. Dis., 172, 316–319.[Web of Science][Medline]

  6. Lin, T.M., Chen, C.J., Wu, M.M., Yang, C.S., Chen, J.S., Lin, C.C., Kwang, T.Y., Hsu, S.T., Lin, S.Y. and Hsu, L.C. (1989) Hepatitis B virus markers in Chinese twins. Anticancer Res., 9, 737–742.[Web of Science][Medline]

  7. Herndon, C.N. and Jennings, R.G. (1951) A twin-family study of susceptibility to poliomyelitis. Am. J. Hum. Genet., 3, 17–46.[Web of Science][Medline]

  8. Colhoun, H.M., McKeigue, P.M. and Davey Smith, G. (2003) Problems of reporting genetic associations with complex outcomes. Lancet, 361, 865–872.[CrossRef][Web of Science][Medline]

  9. Bryant, P.A., Venter, D., Robins-Brovcrne, R. and Curtis, N. (2004) Chips with everything: DNA microarrays in infectious diseases. Lancet Infect. Dis., 4, 100–111.[CrossRef][Web of Science][Medline]

  10. Reiling, N., Holscher, C., Fehrenbach, A., Kroger, S., Kirschning, C.J., Goyert, S. and Ehlers, S. (2002) Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J. Immunol., 169, 3480–3484.[Abstract/Free Full Text]

  11. Lazzaro, B.P., Sceurman, B.K. and Clark, A.G. (2004) Genetic basis of natural variation in D. melanogaster antibacterial immunity. Science, 303, 1873–1876.[Abstract/Free Full Text]

  12. Wasserman, S.A. (2004) Nature's fortress against infection. Nat. Immunol., 5, 474–475.[CrossRef][Web of Science][Medline]

  13. Bellamy, R., Beyers, N., McAdam, KP., Ruwende, C., Gie, R., Samaai, P., Bester, D., Meyer, M., Corrah, T., Collin, M. et al. (2000) Genetic susceptibility to tuberculosis in Africans: a genome-wide scan. Proc. Natl Acad. Sci. USA, 97, 8005–8009.[Abstract/Free Full Text]

  14. Jepson, A., Sisay-Joof, F., Banya, W., Hassan-King, M., Frodsham, A., Bennett, S., Hill, A.V. and Whittle, H. (1997) Genetic linkage of mild malaria to the major histocompatibility complex in Gambian children: study of affected sibling pairs. Br. Med. J., 315, 96–97.[Free Full Text]

  15. Marquet, S., Abel, L., Hillaire, D. and Dessein, A. (1999) Full results of the genome-wide scan which localises a locus controlling the intensity of infection by Schistosoma mansoni on chromosome Sq31–q33. Eur. J. Hum. Genet., 7, 88–97.[CrossRef][Web of Science][Medline]

  16. Mira, M.T., Alcais, A., Van Thuc, N., Thai, V.H., Huong, N.T., Ba, N.N., Verner, A., Hudson, T.J., Abel, L. and Schurr, E. (2003) Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat. Genet., 33, 412–415.[CrossRef][Web of Science][Medline]

  17. Siddiqui, M.R., Meisner, S., Tosh, K., Balakrishnan, K., Ghei, S., Fisher, S.E., Golding, M., Shanker Narayan, N.P., Sitaraman, T., Sengupta, U. et al. (2001) A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat. Genet., 27, 439–441.[CrossRef][Web of Science][Medline]

  18. Tosh, K., Meisner, S., Siddiqui, M.R., Balakrishnan, K., Ghei, S., Golding, M., Sengupta, U., Pitchappan, R.M. and Hill, A.V. (2002) A region of chromosome 20 is linked to leprosy susceptibility in a South Indian population. J. Infect. Dis., 186, 1190–1193.[CrossRef][Web of Science][Medline]

  19. Bucheton, B., Abel, L., El-Safi, S., Kheir, M.M., Pavek, S., Lemainque, A. and Dessein, A.J. (2003) A major susceptibility locus on chromosome 22q12 plays a critical role in the control of kala-azar. Am. J. Hum. Genet., 73, 1052–1060.[CrossRef][Web of Science][Medline]

  20. Newport, M.J., Huxley, C.M., Huston, S., Hawrylowicz, C.M., Oostra, B.A., Williamson, R. and Levin, M. (1996) A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N. Engl. J. Med., 335, 1941–1949.[Abstract/Free Full Text]

  21. Levin, M., Newport, M.J., D'Souza, S., Kalabalikis, P., Brown, LN., Lenicker, H.M., Agius, P.V., Davies, E.G., Thrasher, A., Klein, N. et al. (1995) Familial disseminated atypical mycobacterial infection in childhood: a human mycobacterial susceptibility gene? Lancet, 345, 79–83.[CrossRef][Web of Science][Medline]

  22. Butler, D., Maurice, J. and O'Brien, C. (1997) Time to put malaria control on the global agenda. Nature, 386, 535–536.[CrossRef][Medline]

  23. Allison, A.C. (1954) Protection afforded by sickle-cell trait against subtertian malareal infection. Br. Med. J., 4857, 290–294.

  24. Hill, A.V., Allsopp, C.E., Kwiatkowski, D., Anstey, N.M., Twumasi, P., Rowe, P.A., Bennett, S., Brewster, D., McMichael, A.J. and Greenwood, B.M. (1991) Common west African HLA antigens are associated with protection from severe malaria. Nature, 352, 595–600.[CrossRef][Medline]

  25. Hutagalung, R., Wilairatana, P., Looareesuwan, S., Brittenham, G.M., Aikawa, M. and Gordeuk, V.R. (1999) Influence of hemoglobin E trait on the severity of Falciparum malaria. J. Infect. Dis., 179, 283–286.[CrossRef][Web of Science][Medline]

  26. Chotivanich, K., Udomsangpetch, R., Pattanapanyasat, K., Chierakul, W., Simpson, J., Looareesuwan, S. and White, N. (2002) Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P. falciparum malaria. Blood, 100, 1172–1176.[Abstract/Free Full Text]

  27. Modiano, D., Luoni, G., Sirima, B.S., Simpore, J., Verra, F., Konate, A., Rastrelli, E., Olivieri, A., Calissano, C., Paganotti, G.M. et al. (2001) Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature, 414, 305–308.[CrossRef][Medline]

  28. Flint, J., Hill, A.V., Bowden, D.K., Oppenheimer, S.J., Sill, P.R., Serjeantson, S.W., Bana-Koiri, J., Bhatia, K., Alpers, M.P., Boyce, A.J. et al. (1986) High frequencies of alpha-thalassaemia are the result of natural selection by malaria. Nature, 321, 744–750.[CrossRef][Medline]

  29. Rougemont, A., Quilici, M., Delmont, J. and Ardissone, J.P. (1980) Is the HpO phenomenon in tropical populations really genetic? Hum. Hered., 30, 201–203.[CrossRef][Web of Science][Medline]

  30. Hill, A.V., Whitehouse, D.B., Bowden, D.K., Hopkinson, D.A., Draper, C.C., Peto, T.E., Clegg, J.B. and Weatherall, D.J. (1987) Ahaptoglobinaemia in Melanesia: DNA and malarial antibody studies. Trans. R. Soc. Trop. Med. Hyg., 81, 573–577.[CrossRef][Web of Science][Medline]

  31. Boreham, P.F., Lenahan, J.K., Port, G.R. and McGregor, LA. (1981) Haptoglobin polymorphism and its relationship to malaria infections in The Gambia. Trans. R. Soc. Top. Med. Hyg., 75, 193–200.[CrossRef]

  32. Elagib, A.A., Kider, A.O., Akerstrom, B. and Elbashir, M.I. (1998) Association of the haptoglobin phenotype (1-1) with falciparum malaria in Sudan. Trans. R. Soc. Trop. Med. Hyg., 92, 309–311.[CrossRef][Web of Science][Medline]

  33. Quaye, I.K., Ekuban, F.A., Goka, B.Q., Adabayeri, V., Kurtzhals, J.A., Gyan, B., Ankrah, N.A., Hviid, L. and Akanmori, B.D. (2000) Haptoglobin 1-1 is associated with susceptibility to severe Plasmodium falciparum malaria. Trans. R. Soc. Trop. Med. Hyg., 94, 216–219.[CrossRef][Web of Science][Medline]

  34. Aucan, C., Walley, A.J., Greenwood, B.M. and Hill, A.V. (2002) Haptoglobin genotypes are not associated with resistance to severe malaria in The Gambia. Trans. R. Soc. Trop. Med. Hyg., 96, 327–328.[CrossRef][Web of Science][Medline]

  35. Tournamille, C., Colin, Y., Cartron, J.P. and Le Van Kim, C. (1995) Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat. Genet., 10, 224–228.[CrossRef][Web of Science][Medline]

  36. Miller, L.H., Mason, S.J., Dvorak, J.A., McGinniss, M.H. and Rothman, LK. (1975) Erythrocyte receptors for (Plasmodium knowlesi) malaria: Duffy blood group determinants. Science, 189, 561–563.[Abstract/Free Full Text]

  37. Sabeti, P.C., Reich, D.E., Higgins, J.M., Levine, H.Z., Richter, D.J., Schaffner, S.F., Gabriel, S.B., Platko, J.V., Patterson, N.J., McDonald, G.J. et al. (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature, 419, 832–837.[CrossRef][Medline]

  38. Ruwende, C., Khoo, S.C., Snow, R.W., Yates, S.N., Kwiatkowski, D., Gupta, S., Warn, P., Allsopp, C.E., Gilbert, S.C., Peschu, N. et al. (1995) Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature, 376, 246–249.[CrossRef][Medline]

  39. Sabeti, P., Usen, S., Farhadian, S., Jallow, M., Doherty, T., Newport, M., Pinder, M., Ward, R. and Kwiatkowski, D. (2002) CD40L association with protection from severe malaria. Genes Immun., 3, 286–291.[CrossRef][Web of Science][Medline]

  40. McGuire, W., Hill, A.V., Allsopp, C.E., Greenwood, B.M. and Kwiatkowski, D. (1994) Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature, 371, 508–510.[CrossRef][Medline]

  41. McGuire, W., Knight, J.C., Hill, A.V., Allsopp, C.E., Greenwood, B.M. and Kwiatkowski, D. (1999) Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles. J. Infect. Dis., 179, 287–290.[CrossRef][Web of Science][Medline]

  42. Knight, J.C., Udalova, I., Hill, A.V., Greenwood, B.M., Peshu, N., Marsh, K. and Kwiatkowski, D. (1999) A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet., 22, 145–150.[CrossRef][Web of Science][Medline]

  43. Cooke, G.S., Aucan, C., Walley, A.J., Segal, S., Greenwood, B.M., Kwiatkowski, D.P. and Hill, A.V. (2003) Association of Fcgamma receptor IIa (CD32) polymorphism with severe malaria in West Africa. Am. J. Trop. Med. Hyg., 69, 565–568.[Abstract/Free Full Text]

  44. Aucan, C., Walley, A.J., Hennig, B.J., Fitness, J., Frodsham, A., Zhang, L., Kwiatkowski, D. and Hill, A.V. (2003) Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in The Gambia. Genes Immun., 4, 275–282.[CrossRef][Web of Science][Medline]

  45. Koch, O., Awomoyi, A., Usen, S., Jallow, M., Richardson, A., Hull, J., Pinder, M., Newport, M. and Kwiatkowski, D. (2002) IFNGR1 gene promoter polymorphisms and susceptibility to cerebral malaria. J. Infect. Dis., 185, 1684–1687.[CrossRef][Web of Science][Medline]

  46. Modiano, D., Petrarca, V., Sirima, B.S., Nebie, L., Diallo, D., Esposito, F. and Coluzzi, M. (1996) Different response to Plasmodium falciparum malaria in west African sympatric ethnic groups. Proc. Natl Acad. Sci. USA, 93, 13206–13211.[Abstract/Free Full Text]

  47. Luoni, G., Verra, F., Arca, B., Sirima, B.S., Troye-Blomberg, M., Coluzzi, M., Kwiatkowski, D. and Modiano, D. (2001) Antimalarial antibody levels and ILA polymorphism in the Fulani of West Africa. Genes Immun., 2, 411–414.[CrossRef][Web of Science][Medline]

  48. Carrington, M., Nelson, G.W., Martin, M.P., Kissner, T., Vlahov, D., Goedert, J.J., Kaslow, R., Buchbinder, S., Hoots, K. and O'Brien, S.J. (1999) HLA and HIV-1: heterozygote advantage and B*35–Cw*04 disadvantage. Science, 283, 1748–1752.[Abstract/Free Full Text]

  49. McNeil, A.J., Yap, P.L., Gore, S.M., Brettle, R.P., McColl, M., Wyld, R., Davidson, S., Weightman, R., Richardson, A.M. and Robertson, J.R. (1996) Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease. Quad. J. Med., 89, 177–185.

  50. Migueles, S.A., Sabbaghian, M.S., Shupert, W.L., Bettinotti, M.P., Marincola, F.M., Martino, L., Hallahan, C.W., Selig, S.M., Schwartz, D., Sullivan, J. et al. (2000) HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc. Natl Acad. Sci. USA, 97, 2709–2714.[Abstract/Free Full Text]

  51. Hill, A.V., Yates, S.N., Allsopp, C.E., Gupta, S., Gilbert, S.C., Lalvani, A., Aidoo, M., Davenport, M. and Plebanski, M. (1994) Human leukocyte antigens and natural selection by malaria. Philos. Trans. R. Soc. Lond. B. Biol. Sci., 346, 379–385.[CrossRef][Web of Science][Medline]

  52. Ravikumar, M., Dheenadhayalan, V., Rajaram, K., Lakshmi, S.S., Kumaran, P.P., Paramasivan, C.N., Balakrishnan, K. and Pitchappan, R.M. (1999) Associations of HLA-DRBl, DQB1 and DPB1 alleles with pulmonary tuberculosis in South India. Tuber. Lung. Dis., 79, 309–317.[CrossRef][Medline]

  53. Shaw, M.A., Donaldson, L.J., Collins, A., Peacock, C.S., Lins-Lainson, Z., Shaw, J.J., Ramos, F., Silveira, F. and Blackwell, J.M. (2001) Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes. Genes Immun., 2, 196–204.[CrossRef][Web of Science][Medline]

  54. Singh, S.P., Mehra, N.K., Dingley, H.B., Pande, J.N. and Vaidya, M.C. (1983) HLA-DR associated genetic control of pulmonary tuberculosis in north lndia. Indian J. Chest Dis. Allied Sci., 25, 252–258.[Medline]

  55. de Vries, R.R., Fat, R.F., Nijenhuis, L.E. and van Rood, J.J. (1976) HLA-linked genetic control of host response to Mycobacterium leprae. Lancet, 2, 1328–1330.[Web of Science][Medline]

  56. Thursz, M.R., Kwiatkowski, D., Allsopp, C.E., Greenwood, B.M., Thomas, H.C. and Hill, A.V. (1995) Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N. Engl. J. Med., 332, 1065–1069.[Abstract/Free Full Text]

  57. Almarri, A. and Batchelor, J.R. (1994) HLA and hepatitis B infection (see comments). Lancet, 344, 1194–1195.[CrossRef][Web of Science][Medline]

  58. Zavaglia, C., Bortolon, C., Ferrioli, G., Rho, A., Mondazzi, L., Bottelli, R., Ghessi, A., Gelosa, F., Iamoni, G. and Ideo, G. (1996) HLA typing in chronic type B, D and C hepatitis. J. Hepatol., 24, 658–665.[CrossRef][Web of Science][Medline]

  59. Gilbert, S.C., Plebanski, M., Gupta, S., Morris, J., Cox, M., Aidoo, M., Kwiatkowski, D., Greenwood, B.M., Whittle, H.C. and Hill, A.V. (1998) Association of malaria parasite population structure, HLA, and immunological antagonism. Science, 279, 1173–1177.[Abstract/Free Full Text]

  60. Young, K., Frodsham, A., Doumbo, O.K., Gupta, S., Dolo, A., Hu, J., Robson, K.J.H., Crisanti, A., Gilbert, S.C. and Hill, A.V. (2004) Inverse associations of HLA and malaria parasite type in two West African populations. Infect. Immun., in press.

  61. Fine, P.E. (1981) Immunogenetics of susceptibility to leprosy, tuberculosis, and leishmaniasis. An epidemiological perspective. Int. J. Lepr. Other Mycobact. Dis., 49, 437–454.[Web of Science][Medline]

  62. Abel, L. and Demenais, F. (1988) Detection of major genes for susceptibility to leprosy and its subtypes in a Caribbean Island: Desirade island. Am. J. Hum. Genet., 42, 256–266.[Web of Science][Medline]

  63. Mira, M.T., Alcais, A., Nguyen, V.T., Moraes, M.O., Di Flumeri, C., Vu, H.T., Mai, C.P., Nguyen, T.H., Nguyen, N.B., Pham, X.K. et al. (2004) Susceptibility to leprosy is associated with PARK2 and PACRG. Nature, 427, 636–640.[CrossRef][Medline]

  64. West, A.B., Lockhart, P.J., O'Farell, C. and Farrer, M.J. (2003) Identification of a novel gene linked to parkin via a bi-directional promoter. J. Mol. Biol., 326, 11–19.[CrossRef][Web of Science][Medline]

  65. West, A., Periquet, M., Lincoln, S., Lucking, C.B., Nicholl, D., Bonifati, V., Rawal, N., Gasser, T., Lohmann, E., Deleuze, J.F. et al. (2002) Complex relationship between Parkin mutations and Parkinson disease. Am. J. Med. Genet., 114, 584–591.[CrossRef][Web of Science][Medline]

  66. Imai, Y., Soda, M., Murakami, T., Shoji, M., Abe, K. and Takahashi, R. (2003) A product of the human gene adjacent to parkin is a component of Lewy bodies and suppresses Pael receptor-induced cell death. J. Biol. Chem., 278, 51901–51910.[Abstract/Free Full Text]

  67. Cervino, A.C., Lakiss, S., Sow, O., Bellamy, R., Beyers, N., Hoal-van Helden, E., van Helden, P., McAdam, K.P. and Hill, A.V. (2002) Fine mapping of a putative-taberculosis-susceptibility locus on chromosome 15q11–13 in African families. Hum. Mol. Genet., 11, 1599–1603.[Abstract/Free Full Text]

  68. Campbell, S.J., Sabeti, P., Fielding, K., Sillah, J., Bah, B., Gustafson, P., Manneh, K., Lisse, L, Sirugo, G., Bellamy, R. et al. (2003) Variants of the CD40 ligand gene are not associated with increased susceptibility to tuberculosis in West Africa. Immunogenetics, 55, 502–507.[CrossRef][Web of Science][Medline]

  69. Blackwell, J.M., Black, G.F., Peacock, C.S., Miller, E.N., Sibthorpe, D., Gnananandha, D., Shaw, J.J., Silveira, F., Lins-Lainson, Z., Ramos, F. et al. (1997) Immunogenetics of leishmanial and mycobacterial infections: the Belem family study. Philos. Trans. R. Soc. Lond. B. Biol. Sci., 352, 1331–1345.[Abstract/Free Full Text]

  70. Miller, E.N., Jamieson, S.E., Joberty, C., Fakiola, M., Hudson, D., Peacock, C.S., Cordell, H.J., Shaw, M.A., Lins-Lainson, Z., Shaw, J.J. et al. (2004) Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes Immun., 5, 63–67.[CrossRef][Web of Science][Medline]

  71. Jamieson, S.E., Miller, E.N., Black, G.F., Peacock, C.S., Cordell, H.J., Howson, J.M., Shaw, M.A., Burgner, D., Xu, W., Lins-Lainson, Z. et al. (2004) Evidence for a cluster of genes on chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians. Genes Immun., 5, 46–57.[CrossRef][Web of Science][Medline]

  72. Vidal, S.M., Malo, D., Vogan, K., Skamene, E. and Gros, P. (1993) Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell, 73, 469–485.

  73. Malo, D., Vogan, K., Vidal, S., Hu, J., Cellier, M., Schurr, E., Fuks, A., Bumstead, N., Morgan, K. and Gros, P. (1994) Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites. Genomics, 23, 51–61.[CrossRef][Web of Science][Medline]

  74. Bellamy, R. (1999) The natural resistance-associated macrophage protein and susceptibility to intracellular pathogens. Microbes Infect., 1, 23–27.[CrossRef][Web of Science][Medline]

  75. Awomoyi, A.A., Marchant, A., Howson, J.M., McAdam, K.P., Blackwell, J.M. and Newport, M.J. (2002) Interleukin-10, polymorphism in SLC11A1 (formerly NRAMPI), and susceptibility to tuberculosis. J. Infect. Dis., 186, 1808–1814.[CrossRef][Web of Science][Medline]

  76. Cervino, A.C., Lakiss, S., Sow, O. and Hill, A.V. (2000) Allelic association between the NRAMP1 gene and susceptibility to tuberculosis in Guinea-Conakry. Ann. Hum. Genet., 64, 507–512.[CrossRef][Web of Science][Medline]

  77. Ryu, S., Park, Y.K., Bai, G.H., Kim, S.J., Park, S.N. and Kang, S. (2000) 3'UTR polymorphisms in the NRAMP1 gene are associated with susceptibility to tuberculosis in Koreans. Int. J. Tuberc. Lung. Dis., 4, 577–580.[Web of Science][Medline]

  78. Gao, P.S., Fujishima, S., Mao, X.Q., Remus, N., Kanda, M., Enomoto, T., Dake, Y., Bottini, N., Tabuchi, M., Hasegawa, N. et al. (2000) Genetic variants of NRAMP1 and active tuberculosis in Japanese populations. International Tuberculosis Genetics Team. Clin. Genet., 58, 74–76.[CrossRef][Web of Science][Medline]

  79. Ma, X., Dou, S., Wright, J.A., Reich, R.A., Teeter, L.D., El Sahly, H.M., Awe, R.J., Musser, J.M. and Graviss, E.A. (2002) 5' dinucleotide repeat polymorphism of NRAMP1 and susceptibility to tuberculosis among Caucasian patients in Houston. Texas. Int. J. Tuberc. Lung. Dis., 6, 818–823.

  80. Liaw, Y.S., Tsai-Wu, J.J., Wu, C.H., Hung, C.C., Lee, C.N., Yang, P.C., Luh, K.T. and Kuo, S.H. (2002) Variations in the NRAMP1 gene and susceptibility of tuberculosis in Taiwanese. Int. J. Tuberc. Lung. Dis., 6, 454–460.[Web of Science][Medline]

  81. Soborg, G., Andersen, A.B., Madsen, H.O., Kok-Jensen, A., Skinhoj, P. and Garred, P. (2002) Natural resistance-associated macrophage protein 1 polymorphisms are associated with microscopy-positive tuberculosis. J. Infect. Dis., 186, 517–521.[CrossRef][Web of Science][Medline]

  82. El Baghdadi, J., Remus, N., Benslimane, A., El Annaz, H., Chentoufi, M., Abel, L. and Schurr, E. (2003) Vaniants of the human NRAMP1 gene and susceptibility to tuberculosis in Morocco. Int. J. Tuberc. Lung. Dis., 7, 599–602.[Web of Science][Medline]

  83. Abel, L., Vu, D.L., Oberti, J., Nguyen, V.T., Van, V.C., Guilloud-Bataille, M., Schurr, E. and Lagrange, P.H. (1995) Complex segregation analysis of leprosy in southern Vietnam. Genet. Epidemiol., 12, 63–82.[CrossRef][Web of Science][Medline]

  84. Shaw, M.A., Atkinson, S., Dockrell, H., Hussain, R., Lins-Lainson, Z., Shaw, J., Ramos, F., Silveira, F., Mehdi, S.Q., Kaukab, F. et al. (1993) An RFLP map for 2q33–q37 from multicase mycobacterial and leishmanial disease families: no evidence for an Lsh/Ity/Bcg gene homologue influencing susceptibility to leprosy. Ann. Hum. Genet., 57 (Pt 4), 251–271.[Web of Science][Medline]

  85. Roy, S., Frodsham, A., Saha, B., Hazra, S.K., Mascie-Taylor, C.G. and Hill, A.V. (1999) Association of vitamin D receptor genotype with leprosy type. J. Infect. Dis., 179, 187–191.[CrossRef][Web of Science][Medline]

  86. Meisner, S.J., Mucklow, S., Warner, G., Sow, S.O., Lienhardt, C. and Hill, A.V. (2001) Association of NRAMP1 polymorphism with leprosy type but not susceptibility to leprosy per se in west Africans. Am. J. Trop. Med. Hyg., 65, 733–735.[Abstract]

  87. D'Ambrosio, D., Cippitelli, M., Cocciolo, M.G., Mazzeo, D., Di Lucia, P., Lang, R., Sinigaglia, F. and Panina-Bordignon, P. (1998) Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J. Clin. Invest., 101, 252–262.[Web of Science][Medline]

  88. Cippitelli, M. and Santoni, A. (1998) Vitamin D3: a transcriptional modulator of the interferon-gamma gene. Eur. J. Immunol., 28, 3017–3030.[CrossRef][Web of Science][Medline]

  89. Bellamy, R., Ruwende, C., Corrah, T., McAdam, K.P., Thursz, M., Whittle, H.C. and Hill, A.V. (1999) Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J. Infect. Dis., 179, 721–724.[CrossRef][Web of Science][Medline]

  90. Bornman, L., Campbell, S.J., Fielding, K., Bah, B., Sillah, J., Gustafson, P., Manneh, K., Lisse, L, Allen, A., Sirugo, G. et al. (2004) Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control and family study. J. Infect. Dis., in press.

  91. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.M. and Hoffinann, J.A. (1996) The dorsoventral regulatory gene cassette spatzle/Tol/cactus controls the potent antifungal response in Drosophila adults. Cell, 86, 973–983.[CrossRef][Web of Science][Medline]

  92. Poltorak, A., Smirnova, L, He, X., Liu, M.Y., Van Huffel, C., McNally, O., Birdwell, D., Alejos, E., Silva, M., Du, X. et al. (1998) Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol. Dis., 24, 340–355.[CrossRef][Web of Science][Medline]

  93. Poltorak, A., He, X., Smirnova, I, Liu, M.Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C. et al. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science, 282, 2085–2088.[Abstract/Free Full Text]

  94. Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K. and Akira, S. (1999) Cutting edge: To11-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol., 162, 3749–3752.[Abstract/Free Full Text]

  95. Heldwein, K.A. and Fenton, M.J. (2002) The role of Toll-like receptors in immunity against mycobacterial infection. Microbes Infect., 4, 937–944.[CrossRef][Web of Science][Medline]

  96. Ogus, A.C., Yoldas, B., Ozdemir, T., Uguz, A., Olcen, S., Keser, I., Coskun, M., Cilli, A. and Yegin, O. (2004) The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur. Respir. J., 23, 219–223.[Abstract/Free Full Text]

  97. Ben-Ali, M., Barbouche, M.R., Bousnina, S., Chabbou, A. and Dellagi, K. (2004) Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin. Diagn. Lab. Immunol., 11, 625–626.[Abstract/Free Full Text]

  98. Kang, T.J. and Chae, G.T. (2001) Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol. Med. Microbiol., 31, 53–58.[CrossRef][Web of Science][Medline]

  99. Yim, J.J., Ding, L., Schaffer, A.A., Park, G.Y., Shim, Y.S. and Holland, S.M. (2004) A microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene: functional implications and racial differences. FEMS Immunol. Med. Microbiol., 40, 163–169.[CrossRef][Web of Science][Medline]

  100. Cooke, G.S., Segal, S. and Hill, A.V. (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med., 347, 1978–1980; author reply 1978–1980.[Free Full Text]

  101. Shim, T.S., Turner, O.C. and Orme, LM. (2003) Toll-like receptor 4 plays no role in susceptibility of mice to Mycobacterium tuberculosis infection. Tuberculosis (Edinb.), 83, 367–371.

  102. Ma, X., Reich, R.A., Wright, J.A., Tooker, H.R., Teeter, L.D., Musser, J.M. and Graviss, E.A. (2003) Association between interleukin-8 gene alleles and human susceptibility to tuberculosis disease. J. Infect. Dis., 188, 349–355.[CrossRef][Web of Science][Medline]

  103. Rossouw, M., Nel, H.J., Cooke, G.S., van Helden, P.D. and Hoal, E.G. (2003) Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet, 361, 1871–1872.[CrossRef][Web of Science][Medline]

  104. Garred, P., Madsen, H.O., Balslev, U., Hofmann, B., Pedersen, C., Gerstoft, J. and Svejgaard, A. (1997) Susceptibility to HIV infection and progression of AIDS in relation to variant alleles of mannose-binding lectin. Lancet, 349, 236–240.[CrossRef][Web of Science][Medline]

  105. Hoal-Van Helden, E.G., Epstein, J., Victor, T.C., Hon, D., Lewis, L.A., Beyers, N., Zurakowski, D., Ezekowitz, A.B. and Van Helden, P.D. (1999) Mannose-binding protein B allele confers protection against tuberculous meningitis. Pediatr. Res., 45, 459–464.[Web of Science][Medline]

  106. Soborg, C., Madsen, H.O., Andersen, A.B., Lillebaek, T., Kok-Jensen, A. and Garred, P. (2003) Mannose-binding lectin polymorphisms in clinical tuberculosis. J. Infect. Dis., 188, 777–782.[CrossRef][Web of Science][Medline]

  107. Cooke, G.S., Campbell, S.J., Fielding, K., Sillah, J., Manneh, K., Sirugo, G., Bennett, S., McAdam, K.P., Lienhardt, C. and Hill, A.V. (2004) Interleukin-8 polymorphism is not associated with pulmonary tuberculosis in the gambia. J. Infect. Dis., 189, 1545–1546; author reply 1546.[CrossRef][Web of Science][Medline]

  108. Bellamy, R., Ruwende, C., McAdam, K.P., Thursz, M., Sumiya, M., Summerfield, J., Gilbert, S.C., Corrah, T., Kwiatkowski, D., Whittle, H.C. et al. (1998) Mannose-binding protein deficiency is not associated with malaria, hepatitis B carriage nor tuberculosis in Africans. Quat. J. Med., 91, 13–18.

  109. Lio, D., Marino, V., Serauto, A., Gioia, V., Scola, L., Crivello, A., Forte, G.L, Colonna-Romano, G., Candore, G. and Caruso, C. (2002) Genotype frequencies of the +874T->A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis. Eur. J. Immunogenet., 29, 371–374.[CrossRef][Web of Science][Medline]

  110. Fowke, K.R., Nagelkerke, N.J., Kimani, J., Simonsen, J.N., Anzala, A.O., Bwayo, J.J., MacDonald, K.S., Ngugi, E.N. and Plummer, F.A. (1996) Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet, 348, 1347–1351.[CrossRef][Web of Science][Medline]

  111. Dean, M., Carrington, M., Winkler, C., Huttley, G.A., Smith, M.W., Allikmets, R., Goedert, J.J., Buchbinder, S.P., Vittinghoff, E., Gomperts, E. et al. (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science, 273, 1856–1862.[Abstract/Free Full Text]

  112. Huang, Y., Paxton, W.A., Wolinsky, S.M., Neumann, A.U., Zhang, L., He, T., Kang, S., Ceradini, D., Jin, Z., Yazdanbakhsh, K. et al. (1996) The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat. Med., 2, 1240–1243.[CrossRef][Web of Science][Medline]

  113. Smith, M.W., Carrington, M., Winkler, C., Lomb, D., Dean, M., Huttley, G. and O'Brien, S.J. (1997) CCR2 chemokine receptor and AIDS progression. Nat. Med., 3, 1052–1053.[Web of Science][Medline]

  114. An, P., Nelson, G.W., Wang, L., Donfield, S., Goedert, J.J., Phair, J., Vlahov, D., Buchbinder, S., Farrar, W.L., Modi, W. et al. (2002) Modulating influence on HIV/AIDS by interacting RANTES gene variants. Proc. Natl Acad. Sci. USA, 99, 10002–10007.[Abstract/Free Full Text]

  115. Liu, X.L., Wang, F.S., Jin, L., Liu, M.X. and Xu, D.Z. (2003) Preliminary study on the association of chemokine RANTES gene polymorphisms with HIV-1 infection in Chinese Han population. Zhonghua Liu Xing Bing Xue Za Zhi, 24, 971–975.[Medline]

  116. Mummidi, S., Ahuja, S.S., Gonzalez, E., Anderson, S.A., Santiago, E.N., Stephan, K.T., Craig, F.E., O'Connell, P., Tryon, V., Clark, R.A. et al. (1998) Genealogy of the CCRS locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Nat. Med., 4, 786–793.[CrossRef][Web of Science][Medline]

  117. Winkler, C., Modi, W., Smith, M.W., Nelson, G.W., Wu, X., Carrington, M., Dean, M., Honjo, T., Tashiro, K., Yabe, D. et al. (1998) Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE study, hemophilia growth and development study (HGDS), multicenter AIDS cohort study (MACS), multicenter hemophilia cohort study (MHCS), San Francisco city cohort (SFCC). Science, 279, 389–393.[Abstract/Free Full Text]

  118. Nakayama, E.E., Hoshino, Y., Xin, X., Liu, H., Goto, M., Watanabe, N., Taguchi, H., Hitani, A., Kawana-Tachikawa, A., Fukushima, M. et al. (2000) Polymorphism in the interleukin-4 promoter affects acquisition of human immunodeficiency virus type 1 syncytium-inducing phenotype. J. Virol., 74, 5452–5459.[Abstract/Free Full Text]

  119. Shin, H.D., Winkler, C., Stephens, J.C., Bream, J., Young, H., Goedert, J.J., O'Brien, T.R., Vlahov, D., Buch binder, S., Giorgi, J. et al. (2000) Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10. Proc. Natl Acad. Sci. USA, 97, 14467–14472.[Abstract/Free Full Text]

  120. Smolnikova, M.V. and Konenkov, V.I. (2002) Association of IL2, TNFA, IL4 and IL10 promoter gene polymorphisms with the rate of progression of the HIV infection. Russ. J. Immunol., 7, 349–356.[Medline]

  121. Marquet, S., Sanchez, F.O., Arias, M., Rodriguez, J., Paris, S.C., Skamene, E., Schurr, E. and Garcia, L.F. (1999) Variants of the human NRAMP1 gene and altered human immunodeficiency virus infection susceptibility. J. Infect. Dis., 180, 1521–1525.[CrossRef][Web of Science][Medline]

  122. Donninger, H., Cashmore, T.J., Scriba, T., Petersen, D.C., Janse van Rensburg, E. and Hayes, V.M. (2004) Functional analysis of novel SLC11 A1 (NRAMPI) promoter variants in susceptibility to HIV-1. J. Med. Genet., 41, e49.[Free Full Text]

  123. Bafica, A., Scanga, C.A., Schito, M., Chaussabel, D. and Sher, A. (2004) Influence of coinfecting pathogens on HIV expression: evidence for a role of Toll-like receptors. J. Immunol., 172, 7229–7234.[Abstract/Free Full Text]

  124. Hohler, T., Kruger, A., Gerken, G., Schneider, P.M., Meyer zum Buschenefelde, K.H. and Rittner, C. (1998) A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection. Clin. Exp. Immunol., 111, 579–582.[CrossRef][Web of Science][Medline]

  125. Thomas, H.C., Foster, G.R., Sumiya, M., McIntosh, D., Jack, D.L., Turner, M.W. and Summerfield, J.A. (1996) Mutation of gene of mannose-binding protein associated with chronic hepatitis B viral infection (see comments). Lancet, 348, 1417–1419.[CrossRef][Web of Science][Medline]

  126. Woitas, R.P., Ahlenstiel, G., Iwan, A., Rockstroh, J.K., Brackmann, H.H., Kupfer, B., Matz, B., Offergeld, R., Sauerbruch, T. and Spengler, U. (2002) Frequency of the HIV-protective CC chemokine receptor 5-Delta32/Delta32 genotype is increased in hepatitis C. Gastroenterology, 122, 1721–1728.[CrossRef][Web of Science][Medline]

  127. Promrat, K., McDermott, D.H., Gonzalez, C.M., Kleiner, D.E., Koziol, D.E., Lessie, M., Merrell, M., Soza, A., Heller, T., Ghany, M. et al. (2003) Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C. Gastroenterology, 124, 352–360.[CrossRef][Web of Science][Medline]

  128. Mangia, A., Santoro, R., D'Agruma, L. and Andriulli, A. (2003) HCV chronic infection and CCRS-delta32/delta32. Gastroenterology, 124, 868–869; author reply 869–870.[CrossRef][Web of Science][Medline]

  129. Mascheretti, S., Hinrichsen, H., Ross, S., Buggisch, P., Hampe, J., Foelsch, U.R. and Schreiber, S. (2004) Genetic variants in the CCR gene cluster and spontaneous viral elimination in hepatitis C-infected patients. Clin. Exp. Immunol., 136, 328–333.[CrossRef][Web of Science][Medline]

  130. Hellier, S., Frodsham, A.J., Hennig, B.J., Klenerman, P., Knapp, S., Ramaley, P., Satsangi, J., Wright, M., Zhang, L., Thomas, H.C. et al. (2003) Association of genetic variants of the chemokine receptor CCRS and its ligands, RANTES and MCP-2, with outcome of HCV infection. Hepatology, 38, 1468–1476.[Web of Science][Medline]

  131. Knapp, S., Yee, L.J., Frodsham, A.J., Hennig, B.J., Hellier, S., Zhang, L., Wright, M., Chiaramonte, M., Graves, M., Thomas, H.C. et al. (2003) Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Genes Immun., 4, 411–419.[CrossRef][Web of Science][Medline]

  132. Edwards-Smith, C.J., Jonsson, J.R., Purdie, D.M., Bansal, A., Shorthouse, C. and Powell, E.E. (1999) Interleukin-10-promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology, 30, 526–530.[CrossRef][Web of Science][Medline]

  133. Yee, L.J., Tang, J., Gibson, A.W., Kimberly, R., Van Leeuwen, D.J. and Kaslow, R.A. (2001) Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection. Hepatology, 33, 708–712.[CrossRef][Web of Science][Medline]

  134. Knapp, S., Hennig, B.J., Frodsham, A.J., Zhang, L., Hellier, S., Wright, M., Goldin, R., Hill, A.V., Thomas, H.C. and Thursz, M.R. (2003) Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection. Immunogenetics, 55, 362–369.[CrossRef][Web of Science][Medline]

  135. The International HapMap Project. (2003) Nature, 426, 789–796.[CrossRef][Medline]

  136. Bentley, D.R. (2000) The human genome project—an overview. Med. Res. Rev., 20, 189–196.[CrossRef][Web of Science][Medline]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Clin. Microbiol. Rev.Home page
J. M. Blackwell, S. E. Jamieson, and D. Burgner
HLA and Infectious Diseases
Clin. Microbiol. Rev., April 1, 2009; 22(2): 370 - 385.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
M.-F. Roy, N. Riendeau, C. Bedard, P. Helie, G. Min-Oo, K. Turcotte, P. Gros, F. Canonne-Hergaux, and D. Malo
Pyruvate kinase deficiency confers susceptibility to Salmonella typhimurium infection in mice
J. Exp. Med., November 26, 2007; 204(12): 2949 - 2961.
[Abstract] [Full Text] [PDF]

Home page
 Arch Gen PsychiatryHome page
H. Juvonen, A. Reunanen, J. Haukka, M. Muhonen, J. Suvisaari, R. Arajarvi, T. Partonen, and J. Lonnqvist
Incidence of Schizophrenia in a Nationwide Cohort of Patients With Type 1 Diabetes Mellitus
Arch Gen Psychiatry, August 1, 2007; 64(8): 894 - 899.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
F. J. Sheedy and L. A. J. O'Neill
The Troll in Toll: Mal and Tram as bridges for TLR2 and TLR4 signaling
J. Leukoc. Biol., August 1, 2007; 82(2): 196 - 203.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Frodsham, A. J.
Right arrow Articles by Hill, A. V.S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Frodsham, A. J.
Right arrow Articles by Hill, A. V.S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?