A haplotype in the CCR5 gene promoter was associated with the susceptibility to HIV-1 infection in a northern Chinese population

It has been reported that single nucleotide polymorphisms (SNPs) in the promoter of the CCR5 gene are associated with the risk for HIV-1 infection and AIDS progression. Using resequencing, we performed a systematic survey of 78 HIV-1 seropositive individuals and 70 population-matched healthy control individuals from northern China to investigate SNPs of the CCR5 gene promoter and evaluated their effects on HIV-1 infection and the progression of AIDS. Linkage disequilibrium (LD) plots and haplotypes were generated using Haploview software. The association analyses were statistically compared using the Chi-square test with SPSS13.0 software for Windows. Seven SNPs (58755A>G, 58791C>T, 58934G>T, 59029A>G, 59353C>T, 59402A>G and 59653C>T) in the region of the CCR5 gene promoter were evaluated in this study. Among the seven SNPs, the minor allele frequencies of 58755G and 58791T were less than 2%. The differences in frequencies of the other five SNPs were not significant between case and control cohorts (P > 0.05). In the case cohort, the association between these SNPs and clinical features (CD4⁺ T-lymphocyte counts and clinical categories) was not significant (P > 0.05); however, there was a significant association between the haplotype GGTAC and susceptibility to HIV-1 infection (P < 0.05), which is not consistent with other reports studied in different populations. The results suggest that the haplotype GGTAC may have a role in the process of HIV-1 infection in the northern Chinese population.     

Genetic association of the antiviral restriction factor TRIM5alpha with human immunodeficiency virus type 1 infection

The innate antiviral factor TRIM5alpha restricts the replication of some retroviruses through its interaction with the viral capsid protein, leading to abortive infection. While overexpression of human TRIM5alpha results in modest restriction of human immunodeficiency virus type 1 (HIV-1), this inhibition is insufficient to block productive infection of human cells. We hypothesized that polymorphisms within TRIM5 may result in increased restriction of HIV-1 infection. We sequenced the TRIM5 gene (excluding exon 5) and the 4.8-kb 5' putative regulatory region in genomic DNA from 110 HIV-1-infected subjects and 96 exposed seronegative persons, along with targeted gene sequencing in a further 30 HIV-1-infected individuals. Forty-eight single nucleotide polymorphisms (SNPs), including 20 with allele frequencies of >1.0%, were identified. Among these were two synonymous and eight nonsynonymous coding polymorphisms. We observed no association between TRIM5 polymorphism in HIV-1-infected subjects and their set-point viral load after acute infection, although one TRIM5 haplotype was weakly associated with more rapid CD4(+) T-cell loss. Importantly, a TRIM5 haplotype containing the nonsynonymous SNP R136Q showed increased frequency among HIV-1-infected subjects relative to exposed seronegative persons, with an odds ratio of 5.49 (95% confidence interval = 1.83 to 16.45; P = 0.002). Nonetheless, we observed no effect of individual TRIM5alpha nonsynonymous mutations on the in vitro HIV-1 susceptibility of CD4(+) T cells. Therefore, any effect of TRIM5alpha polymorphism on HIV-1 infection in primary lymphocytes may depend on combinations of SNPs or on DNA sequences in linkage disequilibrium with the TRIM5alpha coding sequence.     

Single-nucleotide polymorphisms in the interleukin-10 gene: differences in frequencies,linkage disequilibrium patterns,and haplotypes in three United States ethnic groups

Interleukin-10 (IL-10) is a cytokine that seems to function as a downregulator of the innate (nonadaptive) immune system. Approximately three-quarters of interindividual variability in human IL-10 levels has been attributed to genetic variation, and there is evidence suggesting a potential role for IL-10 in a range of human diseases. To provide a basis for haplotype analysis and future disease association studies, we characterized genetic variation in IL10 by sequencing all exons, and 2.5 kb of the 5'- and the 3'-flanking region in a panel of DNA samples from 24 African Americans, 23 European Americans, and 24 Hispanic Americans. The region sequenced was found to contain 28 single-nucleotide polymorphisms (SNPs), 16 with frequency >2% and 14 with frequency >5%. All SNPs with frequency >5% were present in subjects from all three populations. No SNP caused amino acid changes. Differences in pairwise linkage-disequilibrium (LD) patterns and in SNP and haplotype frequency distributions among the three populations may be of potential importance for disease association studies.     

Molecular screening and association study of IL15 gene polymorphisms in rheumatoid arthritis

Interleukin 15 (IL-15) is a pleiotropic pro-inflammatory cytokine known to play a relevant role in rheumatoid arthritis (RA) pathogenesis. In this study we aimed to investigate for the first time the contribution of IL15 gene to RA susceptibility. We screened 13 single nucleotide polymorphisms (SNPs) localised within IL15 regulatory regions (promoter, 5' UTR region and 3' UTR region) in a total of 420 individuals, who were genotyped by direct sequencing of PCR products. In addition, an association study of these IL15 SNPs was conducted in three independent case-control cohorts of Spanish Caucasian origin, including a total of 645 RA patients and 656 healthy controls. The presence of the 13 selected IL15 SNPs in our population was confirmed and no new genetic variants were found. The distribution of the IL15 selected SNPs in RA patients and controls showed no statistically significant deviation in any of the populations studied. Additionally, we performed a haplotype analysis that revealed three IL15 haplotype blocks. None of the haplotype blocks was associated with RA susceptibility or severity in the three cohorts analysed. Our results suggest that the IL15 gene polymorphisms do not appear to play a major role in RA genetic predisposition in our population.     

The impact of missing and erroneous genotypes on tagging SNP selection and power of subsequent association tests

OBJECTIVE: Single nucleotide polymorphisms (SNPs) serve as effective markers for localizing disease susceptibility genes, but current genotyping technologies are inadequate for genotyping all available SNP markers in a typical linkage/association study. Much attention has recently been paid to methods for selecting the minimal informative subset of SNPs in identifying haplotypes, but there has been little investigation of the effect of missing or erroneous genotypes on the performance of these SNP selection algorithms and subsequent association tests using the selected tagging SNPs. The purpose of this study is to explore the effect of missing genotype or genotyping error on tagging SNP selection and subsequent single marker and haplotype association tests using the selected tagging SNPs. METHODS: Through two sets of simulations, we evaluated the performance of three tagging SNP selection programs in the presence of missing or erroneous genotypes: Clayton's diversity based program htstep, Carlson's linkage disequilibrium (LD) based program ldSelect, and Stram's coefficient of determination based program tagsnp.exe. RESULTS: When randomly selected known loci were relabeled as 'missing', we found that the average number of tagging SNPs selected by all three algorithms changed very little and the power of subsequent single marker and haplotype association tests using the selected tagging SNPs remained close to the power of these tests in the absence of missing genotype. When random genotyping errors were introduced, we found that the average number of tagging SNPs selected by all three algorithms increased. In data sets simulated according to the haplotype frequecies in the CYP19 region, Stram's program had larger increase than Carlson's and Clayton's programs. In data sets simulated under the coalescent model, Carlson's program had the largest increase and Clayton's program had the smallest increase. In both sets of simulations, with the presence of genotyping errors, the power of the haplotype tests from all three programs decreased quickly, but there was not much reduction in power of the single marker tests. CONCLUSIONS: Missing genotypes do not seem to have much impact on tagging SNP selection and subsequent single marker and haplotype association tests. In contrast, genotyping errors could have severe impact on tagging SNP selection and haplotype tests, but not on single marker tests.     

Production of interleukin-10 by peripheral blood mononuclear cells from residents of a marshland area in China endemic for Schistosoma japonicum

Interleukin-10 (IL-10) cytokine production was assessed using peripheral blood mononuclear cells (PBMC) from 67 individuals living in an area endemic for schistosomiasis japonica in China (Dongting Lake, Hunan Province), and 11 control subjects from a non-endemic part of the same Province. Production of IL-10 was measured following in vitro stimulation of PBMC using whole parasite extract (SWAP) or a panel of recombinant Schistosoma japonicum antigens (22-kDa tegumental membrane-associated antigen, glyceraldehyde-3-phosphate dehydrogenase, paramyosin, 14-kDa fatty acid-binding protein and 28-kDa glutathione S-transferase) which are of recognized interest in the development of protective immunity to schistosomiasis. Significantly, PBMC isolated from the exposed population compared with the non-exposed population produced higher levels of IL-10. There was a trend towards higher mean levels of IL-10 release in putatively resistant (insusceptible) (consistently egg negative but highly exposed) individuals compared with susceptible (egg-positive) subjects from the exposed population. Analysis of individual exposure (the duration of water contact and the percent body surface area in contact with water, expressed as m2 h/day) vs. IL-10 production indicated a weak but consistent and statistically significant inverse correlation, with lower levels of exposure being associated with higher levels of IL-10. These results suggest an association between IL-10 production and resistance to S. japonicum in subjects from this Chinese population exposed to infection.     

Analysis of Interleukin-8 Gene Variants Reveals Their Relative Importance as Genetic Susceptibility Factors for Chronic Periodontitis in the Han Population

Interleukin (IL)-8, an important chemokine that regulates the inflammatory response, plays an important role in periodontitis. Previous studies indicate that certain IL-8 gene polymorphisms are associated with periodontitis susceptibility in some populations. However, the literature is somewhat contradictory, and not all IL-8 polymorphisms have been examined, particularly in Han Chinese individuals. The aim of this study was to investigate the association of every IL-8 SNP with chronic periodontitis in Han Chinese individuals. We analyzed 23 SNPs with minor allele frequency (MAF)≥0.01, which were selected from 219 SNPs in the NCBI dbSNP and preliminary HapMap data analyses from a cohort of 400 cases and 750 controls from genetically independent Han Chinese individuals. Single SNP, haplotype and gender-specific associations were performed. We found that rs4073 and rs2227307 were significantly associated with chronic periodontitis. Further haplotype analysis indicated that a haplotype block (rs4073-rs2227307-rs2227306) that spans the promoter and exon1 of IL-8 was highly associated with chronic periodontitis. Additionally, the ATC haplotype in this block was increased 1.5-fold in these cases. However, when analyzing the samples by gender, no significant gender-specific associations in IL-8 were observed, similar to the results of haplotype association analyses in female and male subgroups. Our results provide further evidence that IL-8 is associated with chronic periodontitis in Han Chinese individuals. Furthermore, our results confirm previous reports suggesting the intriguing possibilities that IL-8 plays a role in the pathogenesis of chronic periodontitis and that this gene may be involved in the etiology of this condition.     

Schistosoma mansoni,S. haematobium,and S. japonicum: early events associated with penetration and migration of schistosomula through human skin

Migratory pattern of schistosomula of Schistosoma mansoni, S. haematobium, and S. japonicum through human skin were analyzed in skin organ cultures. These studies showed that the schistosomula of S. mansoni and S. haematobium has similar migratory patterns through human skin. During the first 24h after infection nearly 90% of S. mansoni and S. haematobium schistosomula were present only in the epidermis. Majority of the schistosomula were found in the dermis only after 48h and they appear to reach the dermal vessels around 72h after infection. Migratory pattern of S. japonicum on the other hand was significantly different from the other two species in that over 90% of the parasites had already reached the dermis within the first 24h and schistosomula were present in the dermal vessels within 2h after infection. Analysis of the cytokine pattern at 8h after infection by a macro gene array and RT-PCR analysis showed that out of 24 different cytokines analyzed only IL-1ra, IL-10, and TNF-alpha were increased in the human skin following infections with S. mansoni and S. haematobium, whereas, after infection with S. japonicum there was significant increases in IL-1beta, IL-1ra, IL-2, IL-6, IL-8, IL-10, IL-15, IL-18, and TNF-alpha. Immunohistochemical analysis of epidermal sheets showed focal accumulation of HLA-DR(+) cells in areas where schistosomula of S. mansoni had entered the human skin.     

A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes

We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3'-untranslated-region SNP (rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio [OR](common) 0.64, combined P [Pcomb]=7.85x10(-10)). A Monte Carlo simulation to address multiple testing suggests that this association is not a type I error. The coding regions of IL12B were resequenced in 96 individuals with psoriasis, and 30 additional IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (rs6887695) located approximately 60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227. Together, these two SNPs mark a common IL12B risk haplotype (OR(common) 1.40, Pcomb=8.11x10(-9)) and a less frequent protective haplotype (OR(common) 0.58, Pcomb=5.65x10(-12)), which were statistically significant in all three studies. Since IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines (IL12A and IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (OR(common) 1.44, Pcomb=3.13x10(-6)). Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (OR(common) 1.66, Pcomb=1.33x10(-8)). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.     

Association of single-nucleotide polymorphisms in the suppressor of cytokine signaling 2 (SOCS2) gene with type 2 diabetes in the Japanese

Several previous linkage scans in type 2 diabetes (T2D) families indicated a putative susceptibility locus on chromosome 12q15-q22, while the underlying gene for T2D has not yet been identified. We performed a region-wide association analysis on 12q15-q22, using a dense set of >500 single-nucleotide polymorphisms (SNPs), in 1492 unrelated Japanese individuals enrolled in this study. We identified an association between T2D and a haplotype block spanning 13.6 kb of genomic DNA that includes the entire SOCS2 gene. Evolutionary-based haplotype analysis of haplotype-tagging SNPs followed by a "sliding window" haplotypic analysis indicated SNPs that mapped to the 5' region of the SOCS2gene to be associated with T2D with high statistical significance. The SOCS2 gene was expressed ubiquitously in human and murine tissues, including pancreatic beta-cell lines. Adenovirus-mediated expression of the SOCS2 gene in MIN6 cells or isolated rat islets significantly suppressed glucose-stimulated insulin secretion. Our data indicate that SOCS2 may play a role in susceptibility to T2D in the Japanese.     

Host genetic risk factors for West Nile virus infection and disease progression

West Nile virus (WNV), a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p?=?0.035) and MX1, (OR 0.19, p?=?0.014) were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p?=?0.003) was associated with increased risk for West Nile encephalitis and paralysis (WNE/P). Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression.     

Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population

Background

Susceptibility to tuberculosis is not only determined by Mycobacterium tuberculosis infection, but also by the genetic component of the host. Macrophage receptor with a collagenous structure (MARCO) is essential components required for toll like receptor-signaling in macrophage response to Mycobacterium tuberculosis, which may contribute to tuberculosis risk.

Principal Findings

To specifically investigated whether single nucleotide polymorphisms (SNPs) in MARCO gene are associated with pulmonary tuberculosis in Chinese Han population. By selecting tagging SNPs in MARCO gene, 17 tag SNPs were identified and genotyped in 923 pulmonary tuberculosis patients and 1033 healthy control subjects using a hospital based case-control association study. Single-point and haplotype analysis revealed an association in intron and exon region of MARCO gene. One SNP (rs17009726) was associated with susceptibility to pulmonary tuberculosis, where the carriers of the G allele had a 1.65 fold (95% CI = 1.32–2.05, p _corrected = 9.27E–5) increased risk of pulmonary tuberculosis. Haplotype analysis revealed that haplotype GC containing G allele of 17009726 and haplotype TGCC (rs17795618T/A, rs1371562G/T, rs6761637T/C, rs2011839C/T) were also associated with susceptibility to pulmonary tuberculosis (p _corrected = 0.0001 and 0.029, respectively).

Conclusions

Our study suggested that genetic variants in MARCO gene were associated with pulmonary tuberculosis susceptibility in Chinese Han population, and the findings emphasize the importance of MARCO mediated immune responses in the pathogenesis of tuberculosis.     

Increased human IgE induced by killing Schistosoma mansoni in vivo is associated with pretreatment Th2 cytokine responsiveness to worm antigens

In schistosomiasis endemic areas, children are very susceptible to postchemotherapy reinfection, whereas adults are relatively resistant. Different studies have reported that schistosome-specific IL-4 and IL-5 responses, or posttreatment worm-IgE levels, correlate with subsequent low reinfection. Chemotherapy kills i.v. worms providing an in vivo Ag challenge. We measured anti-worm (soluble worm Ag (SWA) and recombinant tegumental Ag (rSm22.6)) and anti-egg (soluble egg Ag) Ab levels in 177 Ugandans (aged 7-50) in a high Schistosoma mansoni transmission area, both before and 7 wk posttreatment, and analyzed these data in relation to whole blood in vitro cytokine responses at the same time points. Soluble egg Ag-Ig levels were unaffected by treatment but worm-IgG1 and -IgG4 increased, whereas worm-IgE increased in many but not all individuals. An increase in worm-IgE was mainly seen in >15-year-olds and, unlike in children, was inversely correlated to pretreatment infection intensities, suggesting this response was associated both with resistance to pretreatment infection, as well as posttreatment reinfection. The increases in SWA-IgE and rSm22.6-IgE positively correlated with pretreatment Th2 cytokines, but not IFN-gamma, induced by SWA. These relationships remained significant after allowing for the confounding effects of pretreatment infection intensity, age, and pretreatment IgE levels, indicating a link between SWA-specific Th2 cytokine responsiveness and subsequent increases in worm-IgE. An exceptionally strong relationship between IL-5 and posttreatment worm-IgE levels in < 15-year-olds suggested that the failure of younger children to respond to in vivo Ag stimulation with increased levels of IgE, is related to their lack of pretreatment SWA Th2 cytokine responsiveness.     

An iminosugar N-pentafluorobenzyl-1-deoxynojirimycin as a novel potential immunosuppressant for the treatment of Th2-related diseases

Increased levels of Th2 cytokine interleukin-4 (IL-4) have been reported to be involved in the pathogenesis of the parasite Schistosoma japonicum (S. japonicum) infection or detected in the serum of the causative agent of acquired immunodeficiency syndrome (AIDS) patients. This correlates with a worsened outcome of AIDS. The inhibition of a Th2 type response might aid in the treatment of these Th2-related diseases. Previously, we found that N-pentafluorobenzyl-1-deoxynojirimycin (5F-DNM), a new derivative of 1-deoxynojirimycin (DNM) (an inhibitor of the glycoprotein processing enzymes, glucosidase I and II), had specific inhibition effects on human CD4(+) T cells. In this study, we further found that 5F-DNM not only markedly inhibited in vitro IL-4 production from human PBMCs, CD4(+) T cells and mouse splenocytes but also strongly inhibited the production of IL-4 in splenocytes from a mouse model of S. japonicum infection. The numbers of S. japonicum worms were significantly decreased in vivo upon the treatment of mice with 5F-DNM. We demonstrated the mechanism of 5F-DNM effects on CD4(+) T cells acts via the inhibition of the IL-4/JAK1/STAT6 signaling pathway. Moreover, 5F-DNM was found to induce CD4 internalization (transfer from the cellular surface to the cytoplasm) in CD4(+) T cells and had no significant effects on the overall expression levels of CD4. These findings indicate that 5F-DNM might be used as a potential candidate for the treatment of S. japonicum parasitic infection, AIDS and other Th2-related diseases.     

Recent Advances in the Characterization of Genetic Factors Involved in Human Susceptibility to Infection by Schistosomiasis

Human resistance to infection by schistosomes is associated to a strong Th2 immune. However a persistent Th2 response can cause severe kidney and liver disease in human. In this review, we mainly focused on the control of infection levels caused by schistosomes. Several experimental models allowed us to better understand the immunological mechanisms of the host against schistosome infection. High IgE and eosinophil levels are associated with resistance to infection by schistosomes and this effect is counterbalanced by IgG4. IgE and eosinophils are highly dependent on IL-4, IL-13, and Il-5, which are three main Th2 cytokines. We also examined the genetic factors involved in human susceptibility to infection by schistosomiasis. Infection levels are mainly regulated by a major locus SM1, in 5q31-q33 region, which contains the genes encoding for the IL-4, IL-13, and Il-5 cytokines. An association between an IL13 polymorphism, rs1800925, and infection levels has been shown. This polymorphism synergistically acts with another polymorphism (rs324013) in the STAT6 gene, encoding for the signal transducer of the IL13 pathway. This pathway has also been involved in atopic disorders. As helminthiasis, atopy is the result of aberrant Th2 cytokine response to allergens, with an increased production of IL-4, IL-13, Il-9 and Il-5, with high amounts of allergen-specific and total IgE and eosinophilia. However, the Th2 immune response is protective in helminthiasis but aggravating in atopic disorders. Several studies reported interplay between helminthic infections and allergic reactions. The different results are discussed here.     

Schistosoma japonicum eggs modulate the activity of CD4+ CD25+ Tregs and prevent development of colitis in mice

Crohn's disease (CD) is considered to be caused by a disorder of the immune system and helminth infections may interact with development of the disease. We induced colitis in mice by trinitrobenzenesulfonic acid (TNBS) and observed the effects of intraperitoneally injected eggs of Schistosoma japonicum on the course of the disease. The inflammation in the colon was reduced in egg-treated mice and secretion of IFN-gamma (a Th1 cytokine) by cultured spleen cells in vitro was greatly suppressed, and of IL-4, IL-5 and IL-10 (Th2 cytokines) significantly elevated after egg injection. Also, the percentage of regulatory T-cells (Tregs) was increased in the spleens of egg-exposed mice with TNBS-induced colitis compared to non-egg exposed animals. The data suggest that Tregs may be activated by S. japonicum eggs and play a role in restoring immune disorders in TNBS-induced colitis of mice.     

Tagging SNPs in the kallikrein genes 3 and 2 on 19q13 and their associations with prostate cancer in men of European origin

Two of the classical kallikrein genes KLK3 and KLK2 on 19q13.4 are plausible candidates in prostate cancer susceptibility. They are expressed almost exclusively in prostate tissue. We have performed a comprehensive analysis of association of variants in these two genes with prostate cancer among men of European descent using a tagging SNP approach. Thirteen SNPs selected from the HapMap database were analyzed in a sample of 596 histologically verified prostate cancer cases and 567 ethnically matched controls. Five SNPs showed significant association at single marker level. Linkage disequilibrium (LD) analysis revealed four LD blocks. We performed a haplotype analysis within each LD block. A major haplotype in block 1 that contains the first two significantly associated SNPs was significantly underrepresented in the prostate cancer cases; a second haplotype in block 3 also showed significant frequency differences between cases and controls. Four of the studied SNPs show positive associations with serum PSA levels. A structure analysis revealed no population stratification in our samples that could have confounded the association results. These findings suggest a plausible role of kallikrein gene variants in the etiology of prostate cancer among men of European ancestry.     

A TNF region haplotype offers protection from typhoid fever in Vietnamese patients

The genomic region surrounding the TNF locus on human chromosome 6 has previously been associated with typhoid fever in Vietnam (Dunstan et al. in J Infect Dis 183:261–268, 2001). We used a haplotypic approach to understand this association further. Eighty single nucleotide polymorphisms (SNPs) spanning a 150 kb region were genotyped in 95 Vietnamese individuals (typhoid case/mother/father trios). A subset of data from 33 SNPs with a minor allele frequency of >4.3% was used to construct haplotypes. Fifteen SNPs, which tagged the 42 constructed haplotypes were selected. The haplotype tagging SNPs (T1–T15) were genotyped in 380 confirmed typhoid cases and 380 Vietnamese ethnically matched controls. Allelic frequencies of seven SNPs (T1, T2, T3, T5, T6, T7, T8) were significantly different between typhoid cases and controls. Logistic regression results support the hypothesis that there is just one signal associated with disease at this locus. Haplotype-based analysis of the tag SNPs provided positive evidence of association with typhoid (posterior probability 0.821). The analysis highlighted a low-risk cluster of haplotypes that each carry the minor allele of T1 or T7, but not both, and otherwise carry the combination of alleles *12122*1111 at T1–T11, further supporting the one associated signal hypothesis. Finally, individuals that carry the typhoid fever protective haplotype *12122*1111 also produce a relatively low TNF-α response to LPS.     

Familial aggregation of human susceptibility to co- and multiple helminth infections in a population from the Poyang Lake region, China

Human helminthiases are common in China, especially in rural areas where sanitation conditions are poor. Co- and multiple infections with helminths are strikingly frequent. A cross-sectional parasitological and questionnaire survey was carried out in a population of 3205 individuals belonging to 498 families from five villages in the Poyang Lake region, Jiangxi Province, China, to assess their helminth infection status and to collect information on risk factors for infection. The prevalences for Ascaris lumbricoides, Schistosoma japonicum and Trichuris trichiura were 30.9%, 15.7% and 47%, respectively. Hookworm infection prevalence was low (0.7%). A significant association was observed between A. lumbricoides and T. trichiura infection, and also between S. japonicum and T. trichiura infection. Variance components analysis was undertaken to investigate the aggregation of S. japonicum and the soil-transmitted helminths, A. lumbricoides and T. trichiura. While A. lumbricoides was found to aggregate only at a household level, T. trichiura was shown to cluster predominantly in families. Both genetic and household effects were found to be important in determining the risk of infection with S. japonicum. Variance components analysis for A. lumbricoides/T. trichiura co-infections indicated a significant domestic environmental effect, attributable for 32.7% of the co-infection risk. Aggregation of S. japonicum/T. trichiura co-infection was also observed at a household level. The risk of infection with multiple helminth species, although mainly environmentally influenced, was also shown to have significant involvement of genetic and household components. The results of this study indicate that a shared household is a major contributing risk factor for helminth co-infections and emphasises the need for increased standards of sanitation and hygiene to prevent parasite transmission. Further, the results suggest that susceptibility to one helminth infection is not completely independent of another, and that there exist common genetic factors underlying infection with multiple helminth species.     

Evidence for the segregation of a major gene in human susceptibility/resistance to infection by Schistosoma mansoni.

Severe clinical disease caused by the major human parasite Schistosoma mansoni is the consequence of high and prolonged infections. Epidemiological studies indicate that, for individuals having frequent contacts with cercaria-infested waters, both infection intensities and reinfection after treatment depend, in large part, on their intrinsic susceptibility/resistance to infection, suggesting the role of genetic factors in human resistance to S. mansoni. To investigate whether a major gene controls human susceptibility/resistance to infection by S. mansoni, segregation analysis of infection intensities, adjusted for the factors relevant in schistosomiasis (water contact, age, sex), was performed on 20 Brazilian pedigrees (269 individuals), using both the unified mixed model and the regressive model of analysis. The results are consistent with the hypothesis that there is a codominant major gene controlling human susceptibility/resistance to infection by S. mansoni. Parameter estimates indicate a frequency of .20-.25 for the deleterious allele; thus, about 5% of the population is predisposed to high infections, 60% is resistant, and 35% has an intermediate, although fairly good, level of resistance. These findings provide a genetic basis for earlier observations on the lower resistance and the predisposition to reinfection of certain individuals. In addition to the detection of a major gene effect, the data suggest that immunity to S. mansoni develops progressively during childhood to reach a maximum around the age of puberty. The implications of these results for the strategy to be used in endemic areas to reduce morbidity and to control parasite transmission are discussed.