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Significant associations of HLA-DP alleles with chronic hepatitis B (CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1(*) 05:01 and (*) 09:01, and three protective alleles, DPB1(*) 02:01, (*) 04:01, and (*) 04:02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02:01, *04:01, and *04:02) and the susceptible allele DPB1*05:01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules.

Allele and haplotype frequencies of the human leukocyte antigens (HLA) were studied in the Kinh Vietnamese population. We analyzed 170 unrelated healthy individuals. DNA-based HLA typing was performed using a microsphere-based array genotyping platform with sequence-specific oligonucleotide probes to distinguish HLA-A, -B, -C, -DRB1 and -DQB1 alleles. A total of 21 HLA-A, 37 HLA-B, 18 HLA-C, 25 HLA-DRB1, and 14 HLA-DQB1 alleles were identified. HLA-A*1101, A*2402, A*3303, B*1502, B*4601, Cw*0102, Cw*0702, Cw*0801, DRB1*1202, DQB1*0301, DQB1*0303, and DQB1*0501 were found with frequencies higher than 10%. Two representative haplotypes bearing two to five HLA loci were A*1101-B*1502 and A*3303-B*5801 for HLA-A-B; Cw*0801-B*1502 and Cw*0102-B*4601 for HLA-C-B; B*1502-DRB1*1202 and B*4601-DRB1*0901 for HLA-B-DRB1; DRB1*1202-DQB1*0301 and DRB1*0901-DQB1*0303 for HLA-DRB1-DQB1; A*1101-Cw*0801-B*1502 and A*3303-Cw*0302-B*5801 for HLA-A-C-B; A*1101-B*1502-DRB1*1202 and A*2901-B*0705-DRB1*1001 for HLA-A-B-DRB1, A*1101-Cw*0801-B*1502-DRB1*1202-DQB1*0301 and A*2901-Cw*1505-B*0705-DRB1*1001-DQB1*0501 for HLA-A-C-B-DRB1-DQB1. Allele distribution and haplotype analysis demonstrated that the Vietnamese population shares HLA patterns with southern Chinese, Thai, Javanese and Micronesians, while it also retains unique characteristics.

The frequencies of the human leukocyte antigen alleles HLA-A, HLA-B, and HLA-DRB1 and the A-B-DRB1, A-B, and B-DRB1 haplotypes were studied in Naxi and Yunnan Han populations using polymerase chain reaction (PCR)-sequence-specific amplification for alleles A and B and a PCR-microtiter plate hybridization method for the DRB1 allele. A total of 8 A, 19 B, and 30 DRB1 alleles were found in the Naxi population, and 15 A, 21 B, and 36 DRB1 alleles were found in Yunnan Han population. The common A-B-DRB1 haplotypes in the Naxi population were A*24-B*15-DRB1*1202, A*11-B*15-DRB1*0405, A*11-B*15-DRB1*1202, A*11-B*38-DRB1*08032, and A*11-B*55-DRB1*0405; the common A-B haplotypes were A*11-B*15, A*11-B*38, and A*24-B*15; and the common B-DRB1 haplotypes were B*15-DRB1*1202, B*38-DRB1*08032, and B*48-DRB1*1201. In the Yunnan Han population, the common A-B-DRB1 haplotypes were A*24-B*15-DRB1*1501, A*24-B*46-DRB1*08032, and A*24-B*15-DRB1*1201; the common A-B haplotypes were A*24-B*15, A*24-B*46, and A*34-B*46; and the common B-DRB1 haplotypes were B*15-DRB1*1501, B*46-DRB1*09012, and B*46-DRB1*1401. Phylogenetic tree and principal component analyzes based on HLA-A, HLA-B, and DRB1 allele frequencies suggested that the Naxi ethnic group belongs to the southern Chinese groups, while the Yunnan Han population is a characteristic population located intermediate between northern and southern Chinese groups, although they live in the southwest of China.

A number of archeological, linguistic, and genetic studies have been carried out on the peopling of the Pacific, while the origin of Polynesians or the Lapita people is still open to debate. The Lapita people are believed to have populated the Bismarck Archipelago more than 3600 years ago. However, their Melanesian descendants still living in the Bismarck Archipelago have not been genetically clarified yet. To address this question, polymorphism of the ABO blood group gene was investigated in the following three populations who are considered to be almost free from recent admixtures: (i) Balopa islanders as Austronesian (AN)-speaking Melanesians living in the northwestern end of the Bismarck Archipelago; (ii) Gidra as non-Austronesian (NAN)-speaking Melanesians in southwestern lowlands of Papua New Guinea; and (iii) Tongan living in Ha'apai island as AN-speaking Polynesians. Interestingly, there were marked differences in allele frequencies of ABO*A101 and ABO*A102 among the three populations. The allele frequencies of ABO*A101 and ABO*A102 were 7.9 and 19.3% in Balopa, 23.2 and 0.0% in Gidra, and 2.9 and 25.0% in Tongan. Both phylogenetic and correspondence analyses suggested that Balopa was more close to Tongan than to Gidra and that Balopa was genetically placed between Tongan and Asian populations. Our results imply that Balopa may be Melanesian descendants of the Lapita people who populated the Bismarck Archipelago.

Cytotoxicity of natural killer (NK) cells is regulated by a balance of signals from two kinds of NK receptors, activating receptors and inhibitory receptors. Natural cytotoxicity receptors (NCR) family, which consists of NKp30, NKp44 and NKp46, is a major human activating NK receptor. NKp30 has been mapped to the HLA class III region near tumor necrosis factor (TNF) family loci. We have analyzed the NKp30 gene of healthy Japanese and found two synonymous substitutions in the coding region, c.111G>A and c.156C>T, and also identified two single-nucleotide polymorphisms (SNPs) in the promotor region, −201G>A and −163G>C. Furthermore, it was confirmed that these polymorphisms of the NKp30 gene show strong linkage disequilibria with each other and with HLA-DRB1 or TNFA polymorphisms. Since susceptibilities to certain diseases were mapped near this region, the NKp30 polymorphisms could be useful genetic markers.

The Minnan and Hakka people groups, the so-called "Taiwanese", are the descendants of early settlers from the southeast coast of China during the last few centuries. Genetically they showed affinities to southern Asian populations, as determined by phylogenetic trees and correspondence analysis calculated from HLA allele frequencies. This corresponds historically with the fact that they are the descendants of the southeast coastal indigenous population (Yueh) of China and should therefore not be considered as descendants of "pure" northern Han Chinese. A33-B58-DRB1*03 (A33-Cw10-B58-DRB1*03-DQB1*02), the most common HLA haplotype among "Taiwanese", with a haplotype frequency of 6.3%, has also been found to be the most common haplotype among Thai-Chinese and Singapore Chinese, two other populations also originating from the southeast coast of China. These observations suggests that this haplotype is the most well-conserved ancient haplotype of the Yueh.

Tumor necrosis factor alpha plays a substantial role in a number of conditions such as inflammation, autoimmunity, insulin resistance and sleep. Three new single nucleotide polymorphisms, -1,031 T/C, -863 C/A and -857 T/C, were recently identified in the upstream 5'-flanking region of TNFA in the Japanese population. In the present study, we developed polymerase chain reaction (PCR)-preferential homoduplex formation assay for the single-step allele typing of TNFA, and determined the genotypes of 271 healthy unrelated Japanese individuals. Four haplotypes, -1,031/-863/-857 TCC, TCT, CAC and CCC, were found to constitute the majority, if not all, of the TNFA alleles of healthy Japanese population. These alleles were designated as TNFA-U01, -U02 -U03 and -U04, respectively, in the order of frequency. Based on HLA-A, -B and -DRB1 genotypes together with TNFA genotypes, multi-locus haplotypes were analyzed. Significant positive associations were observed between TNFA-U01 and A*3303, B*5201, B*4403, B*4601, B*0702, DRB1*1502, DRB1*0101, DRB1*1302, between TNFA-U02 and B*5401, B*3501, DRB1*0405, DRB1*0407, between TNFA-U03 and B*4006, B*4002, DRB1*0803, DRB1*0802, DRB1*0403, DRB1*0901, and between TNFA-U04 and B*4801. Four-locus haplotype estimation revealed that A*3303-B*4403-TNFA-U01-DRB1*1302, A*2402-B*5201-TNFA-U01-DRB1*1502 and A*2402-B*5401-TNFA-U02-DRB1*0405 constitute major extended haplotypes in Japanese. Interestingly, TNFA alleles previously shown to have a higher promoter activity (U02, U03) were found to form haplotypes with certain DRB1 alleles associated with T helper 1 (Th1)-dominant diseases such as rheumatoid arthritis, insulin dependent diabetes mellitus and Crohn's disease in Japanese. In contrast, TNFA allele with a low promoter activity (U01) is in linkage disequilibrium with the DRB1 alleles associated with T helper 2 (Th2)-dominant diseases such as atopic dermatitis and ulcerative colitis. These observations raise the possibility that TNFA upstream promoter region polymorphisms contribute to some of the HLA-disease associations.

Narcolepsy is a sleep disorder in which multiple factors, including environmental and genetic factors, are involved. A genetic factor strongly associated with the disorder has been found in the human leukocyte antigen (HLA) class II region: the haplotype, DRB1*1501–DQB1*0602, predisposes to narcolepsy. No susceptibility genes other than the HLA-haplotype have been found. In this paper, we performed an association study of the tumor necrosis factor-alpha (TNF-α) gene located in the HLA class III region with human narcolepsy, in which we examined the known single-nucleotide polymorphisms (SNPs) in the promoter region in 49 narcoleptic patients, who were all positive for DRB1*1501, and 111 healthy control individuals. The results indicated that the frequency of the genotype at position −857 (−857SNP) was significantly different between the patients and controls, and the allele frequencies of –857SNP revealed that the frequency of –857T was significantly increased in the patients as compared with that in the controls (P=0.0068). In addition, haplotypes presumed from HLA-DRB1, –857SNP and HLA-B loci suggested that –857T was mainly associated with DRB1 alleles other than DRB1*1501: the significant increase in frequency of –857T in the patients was not caused by allelic association with DRB1*1501. Therefore, it is conceivable that the TNF-α with –857T was associated with narcolepsy independently of the strong association of DRB1*1501 with the disorder. Altogether, the data presented here lead us to propose that TNF-α could be a new susceptibility gene in human narcolepsy.

We examined a possible association of three single nucleotide polymorphisms (SNPs) of the tumor necrosis factor alpha (TNF) promoter −1031T>C (rs1799964), −863C>A (rs1800630), and −857C>T (rs1799724) with severe malaria in 466 adult patients having Plasmodium falciparum malaria in northwest Thailand. Four TNF promoter alleles comprising these three SNPs were detected in the studied population. The frequency of the TNF U04 allele designated −1031C, −863C, and −857C was found to be significantly greater in patients with cerebral malaria than in patients with mild malaria (12.6%, cerebral malaria vs 5.6%, mild malaria; odds ratio = 2.5; P= 0.002). The association of U04 with susceptibility to cerebral malaria was not caused by linkage disequilibrium with any specific HLA-B and -DRB1 alleles.

To estimate the species-specific mutation rates at the DRB1 locus in humans and chimpanzee, we analyzed the nucleotide sequence of a 37.6-kb chimpanzee chromosomal segment containing the entire Patr-DRB1*0701 allele and the flanking nongenic region and we compared it with two corresponding human sequences containing the HLA-DRB1*070101 allele using the sequence of HLA-DRB1*04011 as an outgroup. Because the allelic pair of HLA-DRB1*070101 and Patr-DRB1*0701 shows the lowest number of substitutions between the two species, it appears that these sequences diverged close to the time of the humans-chimpanzee divergence (6 million years ago). Alignment of the nucleotide sequences for HLA-DRB1*070101 and Patr-DRB1*0701 alleles showed that they share a high degree of similarity, suggesting that the stusdied chromosomal segments with these sequences have not been subjected to recombination since the humans-chimpanzee divergence. Comparison of the flanking 10.6 kb of nongenic sequences revealed an average of 41.5 and 83 single nucleotide substitutions in humans and chimpanzee, respectively. Thus, the species-specific nucleotide substitution rates in the flanking nongenic region were estimated to be 6.53 x 10 -10 and 1.31 x 10 -9 per site per year in humans and chimpanzee, respectively. Unexpectedly, the estimated rate in humans was twofold lower than in chimpanzee (P < 10 -3 , Tajima's relative rate test) and lower than the average substitution rate in the human genome. Because the nucleotide substitution rate in nongenic regions free from selection is expected to be equal to the mutation rate, the estimated substitution rate should correspond to the species-specific mutation rate at the DRB1 locus. Our results strongly suggest that the mutation rate at DRB1 locus differs among species.

Graft-vs-host disease (GVHD) is an adverse effect of allogenic bone marrow transplantation. Although a major cause of GVHD following bone marrow transplantation is incompatibility of major histocompatibility antigen (human leukocyte antigen, HLA) in donor-recipient pairs, the incompatibility of minor histocompatibility antigen (mHa) is known as another cause, especially in HLA-matched donor-recipient pairs. In 1998, Lunetta and Rogus proposed the use of discordant sib-pair (DSP) linkage analysis for detecting mHa and calculated the statistical power using the GVHD model, assuming single mHa locus with multiple alleles. Recently, we proposed a different GVHD model, assuming multiple mHa loci with two alleles (biallelic), considering the single-nucleotide polymorphisms. When the effect of each mHa locus on the occurrence of GVHD is independent, the possible triangle for DSP proposed by Lunetta and Rogus is not optimum, but a new possible triangle, named here as GVHD region, is needed. We evaluated, based on Monte Carlo simulation, the test criteria [log of odds (lod) score cutoffs] and power of DSP using the GVHD region for various parameter sets. The GVHD region showed a higher power than the DSP and entire regions in plausible situations. Our results suggest that the application of GVHD region to DSP is effective for the screening of mHa loci.

The association of Fcgamma receptor (FcgammaR) polymorphisms with systemic lupus erythematosus (SLE) has been demonstrated in various populations; however, the results have been inconsistent. We recently identified a single-nucleotide polymorphism encoding a non-synonymous substitution, Ile232Thr (I232T), of FCGR2B and its association with SLE in Japanese and in Thais. Multiple functional FcgammaR genes with polymorphisms (FCGR2A, FCGR2B, FCGR3A, and FCGR3B) cluster in 1q23, and some of them are in linkage disequilibrium (LD). To differentiate contributions from multiple-linked loci, comparison of different populations may provide useful information. In this study, we analyzed the above four FCGR polymorphisms of the Chinese patients and controls for the association with SLE. FCGR2A-H131R, FCGR2B-I232T, FCGR3A-F176V, and FCGR3B genotypes were determined in 167 Chinese patients with SLE and 129 healthy controls. Association was examined using case-control analysis. Allele frequencies of FCGR2B-232T and FCGR3A-176F were significantly increased in SLE [odds ratio (OR) = 1.67 and OR = 1.41, respectively]. Interestingly, while these alleles had a tendency of positive LD in the controls, FCGR2B-232T was in positive association with FCGR3A-176V in SLE, suggesting that these two alleles were associated with SLE in an independent manner. Comparison between SLE with and without nephritis indicated significant association of FCGR2B-232T with nephritis (OR = 2.65). When the present results were combined with our previous data on the Japanese and the Thais using meta-analytic methods, highly significant and independent association was observed for FCGR2B and FCGR3A genotypes. These results strongly suggested that FCGR2B is a common susceptibility factor to SLE in the Asians.