Sasijit Vejbaesya

NRAMP1 and TNF-α polymorphisms and susceptibility to tuberculosis in Thais

Objective and background:  Polymorphisms in the natural resistance‐associated macrophage protein gene 1 (NRAMP1) and tumour necrosis factor (TNF)‐α gene have been found to be associated with susceptibility to tuberculosis in different populations. However, the results are inconsistent. This study aimed to determine whether NRAMP1 and TNF‐α variants are associated with tuberculosis in Thais.

HLA association with hepatitis C virus infection

Hepatitis is one of the most important infectious diseases in Thailand. The knowledge of host factors that influence the course of the disease is still limited. In this study, the HLA class I and class II phenotypes were analyzed in the 2 groups of HCV-infected Thai populations. The first group included 43 individuals with transient HCV infection (HCV antibody positive, HCV RNA PCR negative), and the second included 57 individuals with persistent chronic HCV infection (HCV antibody positive, PCR positive). HLA class I typing was performed by 2-stage microlymphocytotoxicity test, and HLA class II typing, by PCR-SSO. No significant difference in the frequencies of HLA-A and -B antigens was observed between the 2 groups of HCV-infected individuals. The frequency of DRB1*0301 and DQB1*0201 was significantly higher in the persistent-infection group than in the transient-infection group (Pc = 0.03, Pc = 0.04, respectively). In addition, DRB1*0701 and DQA1*0201 were significantly decreased in all the HCV-infected patients compared with levels in the normal controls (Pc = 0.003, Pc = 0.001, respectively). This study demonstrated that DRB1*0301 and DQB1*0201 are associated with persistent HCV infection, whereas DRB1*0701 and DQA*0201 are associated with protection against HCV infection.

TNF and LTA Gene, Allele, and Extended HLA Haplotype Associations with Severe Dengue Virus Infection in Ethnic Thais

Severe dengue virus (DENV) infection is characterized by a cascade of cytokine production, including the production of tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin-alpha (LT-alpha). We have analyzed a variety of polymorphisms in the TNF and LTA genes of 435 ethnic Thais who had subclinical DENV infection, primary or secondary dengue fever (DF), or primary or secondary dengue hemorrhagic fever (DHF). The TNF -238A polymorphism marking the TNF-4,LTA-3 haplotype occurred in a significantly greater number of patients with secondary DHF (20 [15.2%] of 132) than patients with secondary DF (7 [4.1%] of 169) (P < .001; P corrected by use of Bonferroni adjustment, .022; odds ratio, 4.13 [95% confidence interval, 1.59-11.17]). In a subset of patients, the LTA-3 haplotype was associated with in vivo intracellular production of LT-alpha and TNF-alpha during the acute viremic phase of infection. Two extended human major histocompatibility complex (MHC) haplotypes containing TNF-4 and LTA-3, together with HLA-B48, HLA-B57, and HLA-DPB1*0501, were detected only in patients with secondary DHF. These observations indicate that polymorphism in functionally distinct MHC-encoded proteins contributes to the risk of developing severe secondary DENV infection and warrants further investigation.

Report from the killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop: worldwide variation in the KIR loci and further evidence for the co-evolution of KIR and HLA

The killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop (IHIWS) sought to explore worldwide population variation in the KIR loci, and to examine the relationship between KIR genes and their human leukocyte antigen (HLA) ligands. Fifteen laboratories submitted KIR genotype and HLA ligand data in 27 populations from six broad ethnic groups. Data were analyzed for correlations between the frequencies of KIR and their known HLA ligands. In addition, allelic typing was performed for KIR2DL2 and 3DL1 in a subset of populations. Strong and significant correlations were observed between KIR2DL2, 2DL3 genotype frequencies and the frequency of their ligand, HLA-C1. In contrast, only weak associations were seen for 3DL1, 3DS1 and the HLA-Bw4 ligand. Although some aspects of the correlations observed here differ from those reported in other populations, these data provide additional evidence of linked evolutionary histories for some KIR and HLA loci. Investigation of allele-level variation for the B haplotype locus KIR 2DL2 showed that two alleles, *001 and *003, predominate in all populations in this study. Much more allelic variation was observed for the A haplotype locus 3DL1, with several alleles observed at moderate frequencies and extensive variation observed between populations.

Tumor necrosis factor-alpha gene promoter polymorphism is not associated with smoking-related COPD in Thailand.

Objective:  Susceptibility to COPD is, in part, genetically determined. Tumour necrosis factor (TNF)‐α gene promoter polymorphisms have been investigated in different populations with inconsistent results. This study aimed to determine the genetic predisposition in Thai smoking‐related COPD patients.

HLA-DR and -DQ associations with melioidosis

Melioidosis is an important infectious disease of southeast Asia caused by an intracellular bacterium, Burkholderia pseudomallei. Cellular immunity is postulated to play important roles in immunity to melioidosis that may influence the severity and clinical outcome of the disease. The present study was undertaken to investigate possible associations of melioidosis with HLA class II alleles. HLA typing of HLA-DRB1, -DQA1, and -DQB1 was performed using polymerase chain reaction and sequence-specific oligonucleotide hybridization (PCR-SSO). Seventy-nine melioidosis patients and 105 healthy, ethnically and geographically matched controls were studied. Among 24 DRB1 alleles, 7 DQA1 alleles, and 13 DQB1 alleles identified in this population, an association with melioidosis was observed with DRB1*1602 which was increased in melioidosis patients (10.1%) compared to normal controls (4.8%), p = 0.047 (odds ratio (OR) = 2.25). In addition, significant increase of DRB1*1602 allele frequency and decrease of DQA1*03 were also observed in septicemic melioidosis patients, the most severe form of the disease (p = 0.01, OR = 3.10; and p = 0.047, respectively). Furthermore, a trend of association of DRB1*0701, DQA1*0201, and DQB1*0201 with relapse cases of melioidosis was also noted. In contrast, no HLA association was observed in localized melioidosis or melioidosis with diabetes mellitus. These findings provide the suggestive evidence of an immunogenetic basis of certain aspects of melioidosis.

Analysis of TAP and HLA-DM polymorphism in Thai rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disease with a strong association with DR4 in many populations. In the Thai population, rheumatoid arthritis is associated with DRB1*0405. To evaluate the role of polymorphism in TAP and HLA-DM genes, which are important in antigen processing and presentation in predisposition to rheumatoid arthritis, 82 Thai patients with rheumatoid arthritis and 100 unrelated normal controls were studied. TAP and HLA-DM typing was performed by ARMS-PCR and PCR-SSO method, respectively. There was no difference in the distribution of TAP1, TAP2, DMA, and DMB genes between the patients and controls. This study suggested that TAP and HLA-DM genes do not confer susceptibility to rheumatoid arthritis.

HLA class I supertype associations with clinical outcome of secondary dengue virus infections in ethnic Thais

BACKGROUND Human leukocyte antigen (HLA) supertypes are groups of functionally related alleles that present structurally similar antigens to the immune system. OBJECTIVES To analyze HLA class I supertype associations with clinical outcome in hospitalized Thai children with acute dengue illness. METHODS Seven hundred sixty-two patients and population-matched controls recruited predominantly in Bangkok were HLA-A and -B typed. HLA supertype frequencies were compared and tested for significant dengue disease associations using logistic regression analyses. Multivariable models were built by conducting forward stepwise selection procedures. RESULTS In the final logistic regression model, the HLA-B44 supertype was protective against dengue hemorrhagic fever (DHF) in secondary infections (odds ratio [OR] = 0.46, 95% confidence interval [CI], .30-.72), while the HLA-A02 supertype (OR = 1.92, 95% CI, 1.30-2.83) and the HLA-A01/03 supertype (OR = 3.01, 95% CI, 1.01-8.92) were associated with susceptibility to secondary dengue fever. The B07 supertype was associated with susceptibility to secondary DHF in the univariate analysis (OR = 1.60, 95% CI, 1.05-2.46), whereas that was not retained in the final model. CONCLUSIONS As the HLA-B44 supertype is predicted to target conserved epitopes in dengue, our results suggest that B44 supertype-restricted immune responses to highly conserved regions of the dengue proteome may protect against secondary DHF.

Killer cell immunoglobulin-like receptors in Thai patients with leukemia and diffuse large B-cell lymphoma.

Natural killer (NK) cells are key components of the innate immune system that have been implicated in the immune response against tumor cells. Killer cell immunoglobulin-like receptors (KIR) regulate NK cell activity by interaction with specific human leukocyte antigen (HLA) class I. In this study, KIR gene polymorphisms and their HLA ligands were investigated in Thai patients with chronic myelogenous leukemia (CML) (n=60), acute myelogenous leukemia (AML) (n=60), acute lymphoblastic leukemia (ALL) (n=55), and diffuse large B-cell lymphoma (DLBCL) (n=60) compared with 150 healthy controls. The frequency of KIR3DL1 with HLA-Bw4 was significantly lower in DLBCL patients than in controls (P=0.0006, Pc=0.02), whereas no significant differences were seen in KIR gene frequencies and their ligands between leukemia patients and controls. This study suggest a role of inhibitory KIR with its ligand in the protection against DLBCL.

The Effect of Peak and Current Serum Panel-Reactive Antibody on Graft Survival

BACKGROUND Preformed antibodies against HLA antigens are known risk factors for early graft loss. Pretransplantation panel-reactive antibody (PRA) is often used to estimate the degree of sensitization. This study was conducted to determine the risk of early graft loss among subjects with a PRA cutoff value of 10%. OBJECTIVES To evaluate the influence on 1-year graft survival of pretransplant recipient sensitization using 10% peak and current PRA cutoff values. METHODS From January 1988 to July 2007, T-cell and B-cell PRA data were available for 247 (41%) and 241 (40%) patients, respectively. Medical records were reviewed for graft survival, current PRA value, and peak PRA value (both T and B cell). Complement-dependent cytotoxicity (CDC) is the only method of PRA identification in this study. We analyzed the correlation between PRA level and graft survival. RESULTS Current T-cell PRA > 10% was significantly associated with poorer 1-year graft survival when compared with those with PRA < or = 10% in kidney transplantation from both donor sources: 48.6% versus 86.3% (P = .007) for living donor 94.7% versus 70.0% (P = .029) for deceased donor. Most of the graft losses in recipients with a high PRA occurred within the first 3 months posttransplantation. CONCLUSION In our experience, current serum T-cell CDC PRA value > 10% was significantly associated with a decreased 1-year graft survival; interventions will be required to preserved graft function in these high-risk individuals.