Tuberculosis (TB) is one of the most devastating chronic infectious diseases, but the role of host genetics in disease development after infection in this disease remains unidentified. Genome-wide ...association studies (GWASs) in Thais and Japanese were carried out and separately analyzed, attempted replication, then, combined by meta-analysis were not yielding any convincing association evidences; these results suggested that moderate to high effect-size genetic risks are not existed for TB per se. Because of failure in replication attempt of the top 50 single-nucleotide polymorphisms (SNPs) identified form meta-analysis data, we empirically split TB cases into young TB case/control data sets (GWAS-T(young)=137/295 and GWAS-J(young)=60/249) and old TB case/control data sets (GWAS-T(old)=300/295 and GWAS-J(old)=123/685), re-analyzed GWAS based on age-stratified data and replicated the significant findings in two independent replication samples (young TB; Rep-T(young)=155/249, Rep-J(young)=41/462 and old TB; Rep-T(old)=212/187, Rep-J(old)=71/619). GWAS and replication studies conducted in young TB identified at-risk locus in 20q12. Although the locus is located in inter-genic region, the nearest genes (HSPEP1-MAFB) from this locus are promising candidates for TB susceptibility. This locus was also associated with anti-TNF responsiveness, drug with increased susceptibility for TB. Moreover, eight SNPs in an old TB meta-analysis and six SNPs in young TB meta-analysis provided replication evidences but did not survive genome-wide significance.These findings suggest that host genetic risks for TB are affected by age at onset of TB, and this approach may accelerate the identification of the major host factors that affect TB in human populations.
Mannose-binding lectin (MBL) plays a pivotal role in innate immunity; however, its impact on susceptibility to opportunistic infections (OIs) has not yet been examined in a natural history cohort of ...people living with HIV/AIDS.
We used archived samples to analyze the association between MBL expression types and risk of major OIs including Pneumocystis jirovecii pneumonia (PCP), cryptococcosis, talaromycosis, toxoplasmosis, and tuberculosis in a prospective cohort in Northern Thailand conducted from 1 July 2000 to 15 October 2002 before the national antiretroviral treatment programme was launched.
Of 632 patients, PCP was diagnosed in 96 (15.2%) patients, including 45 patients with new episodes during the follow-up period (1006.5 person-years). The total history of PCP was significantly associated with low MBL expression type: high/intermediate (81/587, 13.8%), low (10/33, 30.3%) and deficient (5/12, 41.7%) (p = 0.001), whereas the history of other OIs showed no relation with any MBL expression type. Kaplan-Meier analysis (n = 569; log-rank p = 0.011) and Cox's proportional hazards model revealed that deficient genotype dramatically increased the risk of PCP, which is independent upon sex, age, CD4 count, HIV-1 viral load and hepatitis B and C status (adjusted hazard ratio 7.93, 95% confidence interval 2.19-28.67, p = 0.002).
Deficiency of MBL expression is a strong risk factor determining the incidence of PCP but not other major OIs.
Bacterial translocation has an important role in the pathogenesis of spontaneous bacterial peritonitis in cirrhosis, and the most common pathogens are enterobacteriaceae.1 Previous reports on human ...infections after recent consumption of raw pork products suggested that the gastrointestinal tract is a major route of entry in cases of S suis infections in Thailand and Vietnam.2,3,5 In this region, the occurrence of spontaneous bacterial peritonitis through bacterial translocation of S suis after consumption of raw pork products is possible in patients with liver cirrhosis. A similar case of spontaneous bacterial peritonitis caused by serotype 16 strain of S suis in a patient with alcoholic liver cirrhosis was reported from Vietnam.4 Although the isolation rates for serotypes 5 and 24 are low (2/179 cases; 1.1%), S suisspecific PCR is recommended for identification of streptococcal isolates from sterile sites, and a serious caution against eating raw pork products should be given to patients with liver cirrhosis, especially in southeast Asian countries.
BACKGROUND:Class I HLA molecules contribute to HIV control through antigen presentation to both cytotoxic T lymphocytes (CTLs) and NK cells. Contribution of CTLs to HIV clinical outcome by HLA ...alleles has been well studied. However, reports about the role of NK cells in HIV clinical outcome, particularly, about the effect of HLA-KIR pairs, remain incomplete.
METHODS:The effects of HLA allele-KIR pairs on HIV clinical outcome were statistically analyzed in a Thai cohort of treatment-naïve chronically infected (n=209).
RESULTS:Five HLA allele-KIR pairs scored significantly in viral load (VL) differences. Among them, opposing effects on VL were identified among subjects expressing KIR2DL2 ligands within HLA-C1 grouphigher VL in individuals expressing HLA-B*46:01+KIR2DL2+ compared to individuals without KIR (HLA-B*46:01+KIR2DL2-) (5.0 vs 4.6 log10 copies/ml, p=0.02), in HLA-C*01:02+KIR2DL2+ (5.0 vs 4.6 log10 copies/ml; p=0.02), and lower VL in HLA-C*12:03+KIR2DL2+ (4.3 vs 5.6 log10 copies/ml; p=0.01). In the longitudinal analysis of ten-year follow-up, HLA-B*46:01+KIR2DL2+ve subjects also had a higher mortality rate compared to the subjects without that pair, independent of variables including anti-retroviral treatment, as well as CD4+ T cell count, sex, and age (aHR 5.9, p=0.02).
CONCLUSION:We identified several HLA allele-KIR pairs associated with clinical outcome differences including opposing effects on VL within one HLA group with the same KIR. Among them, HLA-B*46:01 emerged in Southeast Asia about 50,000 years ago, and is now the most prevalent HLA-B allele in that area. These findings highlight that each endemic area has unique features of anti-HIV innate immunity that impact clinical outcome.
Tuberculosis (TB) is known to be affected by host genetic factors. We reported a specific genetic risk factor through a genome-wide association study (GWAS) that focused on young age onset TB. In ...this study, we further focused on the heterogeneity of Mycobacterium tuberculosis (M. tb) lineages and assessed its possible interaction with age at onset on host genetic factors. We identified the pathogen lineage in 686 Thai TB cases and GWAS stratified by both infected pathogen lineage information and age at onset revealed a genome-wide significant association of one single-nucleotide polymorphism (SNP) on chromosome 1p13, which was specifically associated with non-Beijing lineage-infected old age onset cases (P=2.54E-08, OR=1.74 (95% CI=1.43-2.12)), when we compared them to the population-matched healthy controls. This SNP locates near the CD53 gene, which encodes a leukocyte surface glycoprotein. Interestingly, the expression of CD53 was also correlated with the patients' active TB status. This is the first report of a pathogen lineage-based genome-wide association study. The results suggested that host genetic risk in TB is depended upon the pathogen genetic background and demonstrate the importance of analyzing the interaction between host and pathogen genomes in TB.
Background. We sought to determine whether infections with human coronaviruses (HCoVs) 229E, OC43, HKU1, and NL63 are associated with pneumonia and to define the epidemiology of HCoV infection in ...rural Thailand. Methods. We developed a real-time reverse-transcription polymerase chain reaction (RT-PCR) assay panel for the recognized HCoV types and compared HCoV infections in patients hospitalized with pneumonia, outpatients with influenza-like illness, and asymptomatic control patients between September 2003 and August 2005. Results. During study year 1, 43 (5.9%) of 734 patients with pneumonia had HCoV infections; 72.1% of the infections were with OC43. During study year 2, when control patients were available, 21 (1.8%) of 1156 patients with pneumonia, 12 (2.3%) of 513 outpatients, and 6 (2.1%) of 281 control patients had HCoV infections. Compared with infection in control patients, infection with any HCoV type or with all types combined was not associated with pneumonia (adjusted odds ratio for all HCoV types, 0.67 95% confidence interval, 0.26–1.75; P= .40 ). HCoV infections were detected throughout both study years; 93.6% of OC43 infections in the first year occurred from January through March. Conclusions. HCoV infections were infrequently detected in rural Thailand by use of sensitive real-time RTPCR assays. We found no association between HCoV infection and illness. However, we noted year-to-year variation in the prevalence of HCoV strains, which likely influenced our results.
Influenza A (H5N1) is endemic in poultry across much of Southeast Asia, but limited information exists on the distinctive features of the few human cases. In Thailand, we instituted nationwide ...surveillance and tested respiratory specimens by polymerase chain reaction and viral isolation. From January 1 to March 31, 2004, we reviewed 610 reports and identified 12 confirmed and 21 suspected cases. All 12 confirmed case-patients resided in villages that experienced abnormal chicken deaths, 9 lived in households whose backyard chickens died, and 8 reported direct contact with dead chickens. Seven were children <14 years of age. Fever preceded dyspnea by a median of 5 days, and lymphopenia significantly predicted acute respiratory distress syndrome development and death. Among hundreds of thousands of potential human cases of influenza A (H5N1) in Asia, a history of direct contact with sick poultry, young age, pneumonia and lymphopenia, and progression to acute respiratory distress syndrome should prompt specific laboratory testing for H5 influenza.
The rapid advancement of genome technologies holds great promise for improving the quality and speed of clinical and public health laboratory investigations and for decreasing their cost. The latest ...generation of genome DNA sequencers can provide highly detailed and robust information on disease-causing microbes, and in the near future these technologies will be suitable for routine use in national, regional, and global public health laboratories. With additional improvements in instrumentation, these next- or third-generation sequencers are likely to replace conventional culture-based and molecular typing methods to provide point-of-care clinical diagnosis and other essential information for quicker and better treatment of patients. Provided there is free-sharing of information by all clinical and public health laboratories, these genomic tools could spawn a global system of linked databases of pathogen genomes that would ensure more efficient detection, prevention, and control of endemic, emerging, and other infectious disease outbreaks worldwide.
To examine associations between clinical features of Streptococcus suis serotype 2 infections in humans in Thailand and genotypic profiles of isolates, we conducted a retrospective study during ...2006-2008. Of 165 patients for whom bacterial cultures of blood, cerebrospinal fluid, or both were positive for S. suis serotype 2, the major multilocus sequence types (STs) found were ST1 (62.4%) and ST104 (25.5%); the latter is unique to Thailand. Clinical features were examined for 158 patients. Infections were sporadic; case-fatality rate for adults was 9.5%, primarily in northern Thailand. Disease incidence peaked during the rainy season. Disease was classified as meningitis (58.9%) or nonmeningitis (41.1%, and included sepsis 35.4% and others 5.7%). Although ST1 strains were significantly associated with the meningitis category (p<0.0001), ST104 strains were significantly associated with the nonmeningitis category (p<0.0001). The ST1 and ST104 strains are capable of causing sepsis, but only the ST1 strains commonly cause meningitis.
Class I human leukocyte antigen (HLA) alleles interact with both cytotoxic T lymphocytes through their T-cell receptors, and natural killer cells through their killer immunoglobulin-like receptors ...(KIRs). Compared with the reported protective effect of KIR3DL1/S1-HLA-Bw4 interactions in HIV-infected patients, the effect of KIR2D-HLA-C combinations on HIV control remains unclear. Here, we investigate the effect of KIR2D-HLA-C combinations on HIV disease progression.
We performed a cross-sectional and longitudinal analysis of a Thai HIV cohort.
Two hundred and nine HIV-1 CRF01_AE-infected, treatment-naive Thai patients (CD4 T-cell counts of >200/μl) and 104 exposed seronegatives were studied. The effect of KIR-HLA receptor-ligand combinations on viral transmission and survival rate was statistically analyzed.
We found the following results: higher frequency of patients expressing both KIR2DL3 and HLA-C1 among infected patients compared with exposed seronegative (odds ratio 4.8, P = 0.004), higher viral load in patients expressing HLA-C1 with KIR2DL3 compared with those without this receptor-ligand combination (median 4.8 vs. 4.2 log copies/ml, P = 0.033), higher numbers of KIR2DL3-HLA-C1 interactions was associated with a higher viral load (β = 0.13, P = 0.039 by linear regression model), and higher mortality rate in carriers of the KIR2DL3-HLA-C1 combination (adjusted hazard ratio 1.9, P = 0.012 by Cox hazard model).
We have identified a deleterious effect of the KIR2DL3-HLA-C1 receptor-ligand combination on HIV clinical outcomes in a Thai cohort. Further investigation into mechanisms underlying this susceptibility may aid the understanding of the role of natural killer cells in HIV disease control and pathogenesis.
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