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Calcineurin inhibitors are necessary as immunosuppressants during hematopoietic SCT (HSCT) to prevent alloreactivity, but have unfortunate toxicities. So, we investigated the association of gene polymorphisms with the initial calcineurin inhibitor concentration and the subsequent drug dose from day 1 to day 28 among patients who underwent HSCT at a single institution. We analyzed 58 serial cases of Japanese patients receiving GVHD prophylaxis with CsA (21 cases) or tacrolimus (37 cases). We investigated eight single-nucleotide polymorphisms: rs4244285 ( CYP2C19 ), rs15524, rs4646450, rs3800959, rs776746 ( CYP3A5 ), rs1128503, rs2032582 and rs1045642 ( MDR1 ). The CsA concentration was significantly higher when the genotype of CYP3A5 rs15524 was T/T ( P =0.044) or rs776746 was G/G ( P =0.027). The CYP3A5 rs776746 and rs4646450 genotypes were also associated with tacrolimus concentration ( P =0.013 and P =0.0058, respectively). The dosage of tacrolimus was remarkably reduced from day -1 to day 28 when the patient had the CYP3A5 rs4646450 C/C and/or rs776746 G/G genotype ( P =0.0010 and P =0.0021, respectively). In this study, we show that genetic variation has a predictable effect on the pharmacological responses to calcineurin inhibitors in HSCT patients.

Here we report the first complete sequence and gene map of a human major histocompatibility complex (MHC), a region on chromosome 6 which is essential to the immune system (reviewed in ref. 1 ). When it was discovered over 50 years ago the region was thought to specify histocompatibility genes, but their nature has been resolved only in the last two decades. Although many of the 224 identified gene loci (128 predicted to be expressed) are still of unknown function, we estimate that about 40% of the expressed genes have immune system function. Over 50% of the MHC has been sequenced twice, in different haplotypes, giving insight into the extraordinary polymorphism and evolution of this region. Several genes, particularly of the MHC class II and III regions, can be traced by sequence similarity and synteny to over 700 million years ago, clearly predating the emergence of the adaptive immune system some 400 million years ago. The sequence is expected to be invaluable for the identification of many common disease loci. In the past, the search for these loci has been hampered by the complexity of high gene density and linkage disequilibrium.

The human leukocyte antigen (HLA) super-locus is a genomic region in the chromosomal position 6p21 that encodes the six classical transplantation HLA genes and at least 132 protein coding genes that have important roles in the regulation of the immune system as well as some other fundamental molecular and cellular processes. This small segment of the human genome has been associated with more than 100 different diseases, including common diseases, such as diabetes, rheumatoid arthritis, psoriasis, asthma and various other autoimmune disorders. The first complete and continuous HLA 3.6 Mb genomic sequence was reported in 1999 with the annotation of 224 gene loci, including coding and non-coding genes that were reviewed extensively in 2004. In this review, we present (1) an updated list of all the HLA gene symbols, gene names, expression status, Online Mendelian Inheritance in Man (OMIM) numbers, including new genes, and latest changes to gene names and symbols, (2) a regional analysis of the extended class I, class I, class III, class II and extended class II subregions, (3) a summary of the interspersed repeats (retrotransposons and transposons), (4) examples of the sequence diversity between different HLA haplotypes, (5) intra- and extra-HLA gene interactions and (6) some of the HLA gene expression profiles and HLA genes associated with autoimmune and infectious diseases. Overall, the degrees and types of HLA super-locus coordinated gene expression profiles and gene variations have yet to be fully elucidated, integrated and defined for the processes involved with normal cellular and tissue physiology, inflammatory and immune responses, and autoimmune and infectious diseases.

Purpose  To ascertain and define the position of a potential disease susceptibility gene around D21S0083i prioritized during our previous whole genome case-control association analysis with 27158 microsatellite markers, in Japanese high-myopia patients. Methods  520 high myopic patients and 520 healthy controls were genotyped using 39 SNPs distributed around D21S0083i on chromosome 21q22.3. Results  Only 1 SNP (rs2839471) of 39 SNPs was significant after correction for multiple testing (allele T: P =0.00027, Pc=0.01, OR=1.684). The SNP (rs2839471) did not reside in haplotype blocks constructed by the pair-wise linkage disequilibrium between the SNPs. Conclusions  The SNP (rs2839471) is suggested to be located in the frequent recombinant region within UMODL1. Together this region might play a critical role for susceptibility to high myopia, and warrants further confirming studies and investigations as to the mechanisms by which UMODL1 may contribute to myopia.

[...]it will be essential to identify the antigens associated with the TLR4 sequence variant and subsequent signalling pathways in BD.

To date, almost every chromosome has been implicated in genetic susceptibility to asthma to some degree. When compared with single nucleotide polymorphism, microsatellite markers exhibit high levels of heterozygosity and therefore provide higher statistical power in association. The objective of this study was to perform a genome-wide association study using 23,465 in-house microsatellite markers to detect asthma susceptibility regions in the Busselton population. In this study, three separate pooled DNA screenings yielded 18 markers with significantly different estimated frequencies in the three separate “case and control” pools: each pool consisting of 60 males and 60 females. These markers were evaluated by individual typing in 360 cases and 360 controls. Two markers showed significant differences between cases and controls ( P  = 0.001 and P  = 0.003). Regions surrounding the two markers were subjected to high-density association mapping with a total of 14 additional markers. We were able to confirm and fine map the association in these two regions by typing 14 additional microsatellite markers (1805A09 (D18S0325i), P  = 0.002; 1806D05 (D18S0181i), P  = 0.001). Each region contains a predicted gene that showed strong associations with asthma. Further studies are underway to characterize the novel candidate asthma susceptibility genes identified in this genome-wide study.

The caveolin 1 to caveolin 2 ( CAV1 – CAV2 ) gene region on chromosome 7q31 has been reported to be associated with susceptibility to primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) in previous studies. We investigated whether genetic variants in the CAV1 – CAV2 region are associated with NTG in Japanese patients. Two hundred and ninety-two Japanese patients with NTG and 352 Japanese healthy controls were recruited. We genotyped three single-nucleotide polymorphisms; that is, rs1052990, rs4236601, and rs7795356, in the CAV1 – CAV2 gene region and assessed the allelic diversity among cases and controls. The frequency of the minor allele (G) of rs1052990 was significantly decreased in NTG cases compared with controls ( P =0.014, OR=0.71), whereas NTG or POAG cases had a significantly higher frequency of the allele than controls in previous studies. Conversely, rs7795356 did not show any significant association with NTG cases, and rs4236601 was monomorphic in the Japanese study population. Our findings did not correspond with previous positive results, suggesting that CAV1 – CAV2 variants studied in the present study are not important risk factors for NTG susceptibility in all populations. Further studies are needed to elucidate the possible contribution of the CAV1 – CAV2 region to the development of glaucoma.

Aims:The aim of this study was to investigate the association between normal tension glaucoma and the candidate disease locus glaucoma 1, open angle, B (GLC1B) on chromosome 2. There are many reports describing the results of association or linkage studies for primary open angle glaucoma (POAG), with GLC1B as one of the loci associated with normal or moderately elevated intraocular pressure. However, there are few reports about the association of genes or defined genomic regions with normal tension glaucoma, which is the leading type of glaucoma in Japan. The GLC1B locus is hypothesized to be a causative region for normal tension glaucoma.Methods:Genomic DNA was extracted from whole blood of normal tension glaucoma (n = 143) and healthy controls (n = 103) of Japanese origin.Results:Fifteen microsatellite markers within and/or near to the GLC1B locus were genotyped, and their association with normal tension glaucoma was analysed. Two markers D2S2264 and D2S176 had significant positive associations.Conclusion:The D2S176 marker had the strongest significant association and it is located 24 kb from the nearest gene NCK2, which now becomes an important new candidate gene for future studies of its association with normal tension glaucoma.

CTLA-4 is a negative regulator of activated T cells and the association of CTLA-4 polymorphisms with autoimmune diseases and transplant outcome has been reported. We evaluated the effect of donor CTLA-4 polymorphisms on outcome after allogeneic hematopoietic SCT (HSCT). We analyzed 147 Japanese HLA-matched sibling recipients and their donors who had undergone allogeneic HSCT. Genotyping of three single-nucleotide polymorphisms in CTLA-4 (−318, +49, CT60) was performed using TaqMan-PCR. According to the international HapMap database, only these three CTLA-4 haplotypes, classified as C-G-G, C-A-A and T-A-G, are present in the Japanese population. In this study, percentage expression of the C-G-G, C-A-A and T-A-G haplotypes was 59.5, 30.6 and 9.9%, respectively. Recipients of the C-A-A haplotype donor showed a significantly lower risk of relapse (HR: 0.54, 95% CI: 0.30–0.97, P =0.040) and a trend toward higher OS (HR: 0.61, 95% CI: 0.36–1.0, P =0.054) than did recipients of a donor without the C-A-A haplotype. The presence or absence of the C-A-A haplotype did not affect GVHD or non-relapse mortality. As the presence of the C-A-A haplotype reduced relapse risk and improved survival after allogeneic HSCT, this CTLA-4 haplotype may provide useful information for donor selection.

Effects of polymorphisms in TNFA and TNFR2 on the outcome of 462 cases of unrelated bone marrow transplantation (uBMT) were studied retrospectively. Four alleles of TNFA (U01-U04) distinguished by polymorphism in the upstream region, -1031 (T/C), -863 (C/A) and -857 (C/T), and two alleles of TNFR2 (196M/196R) distinguished by polymorphism at codon 196 were determined. Transplantation involving TNFA-U02- and/or U03-positive donors and/or recipients resulted in a higher incidence of graft-versus-host disease (GVHD) of grade III-IV (P < 0.05 for donor type, P < 0.01 for recipient type) and a lower relapse rate than that involving TNFA-U01 homozygous recipients and/or donors (P < 0.025 for donor type, P < 0.01 for recipient type). These results include the HLA mismatching effect due to linkage disequilibirium of TNFA with HLA loci. However, the effects were also observed in HLA-A, -B and -DRB1 allele-matched transplantation. Transplantation from TNFR2-196R-positive donors exhibited a higher incidence of severe GVHD (P < 0.05) and tendency for a lower relapse rate than that from TNFR2-196M homozygous donors. TNFR2-196R of recipient origin had no effect on GVHD but increased the relapse rate (P < 0.025). These results suggest that TNFA and TNFR2 typings are helpful for predicting uBMT outcome and for preventing severe complications at an early stage.