Analysis of the Gene-Dense Major Histocompatibility Complex Class III Region and Its Comparison to Mouse

Xie, Tao; Rowen, Lee; Aguado, Begoña; Ahearn, Mary Ellen; Madan, Anup; Qin, Shizhen; Campbell, R D; Hood, Leroy

doi:10.1101/gr.1736803

Cited by 95 publications

(76 citation statements)

References 67 publications

(65 reference statements)

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“…These are the first HSP genetic associations in childhood ALL, and two separate casecontrol groups yielded comparable findings with combined analysis providing a highly significant result. The HLA complex class III region where the HSP genes reside is the most gene-dense region of the genome (Xie et al 2003), and it is important to exclude confounding by locus due to LD between variants of different loci in the interpretation of the results. We have confirmed the independence of the HSP associations by using HLA-typed reference cell line samples and also statistical tests.…”

Section: Discussionmentioning

confidence: 99%

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

Ucisik-Akkaya

Davis

Gorodezky

et al. 2010

Cell Stress and Chaperones

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Three heat shock protein 70 (HSP70) genes, HSPA1L, HSPA1A, and HSPA1B, are located within the human leukocyte antigen (HLA) class III region. HSPs act as stress signals and regulate natural killer cell response to cancer. HSP70 gene polymorphisms show disease associations partly due to their linkage disequilibrium with HLA alleles. To systematically evaluate their associations with childhood acute lymphoblastic leukemia (ALL), we examined the three functional single nucleotide polymorphisms (SNPs) rs2227956 (T493M) in HSPA1L, rs1043618 in HSPA1A 5′UTR, and rs1061581 (Q351Q) in HSPA1B by TaqMan assays or polymerase chain reaction-restriction fragment length polymorphism in 114 ALL cases and 414 controls from Wales (UK), in 100 Mexican Mestizo ALL cases and 253 controls belonging to the same ethnic group, and in a panel of 82 HLA-typed reference cell line samples. Homozygosity for HSPA1B rs1061581 minor allele G was associated with protection (odds ratio (OR)=0.37, 95% confidence interval (CI)=0.16-0.78; P=0.007) with genedosage effect (additive model) reaching significance (P= 0.0001) in the Welsh case-control group. This association was replicated in the second case-control group from Mexico (OR (recessive model)=0.49, 95% CI=0.24-0.96; P=0.03), and the pooled analysis yielded a strong association (Mantel-Haenszel OR=0.43, 95% CI=0.27-0.69, P= 0.0004). The association was stronger in males in each group and in the pooled analysis. A three-SNP haplotype including the major allele A of rs1061581 showed a highly significant increase in Welsh cases compared with respective controls (6.7% vs 1.8%; P=0.0003) due to the difference between male cases and controls. The protective allele of rs1061581 occurred more frequently on the HLA-DRB3 haplotypes (especially DRB1*03) in the cell line panel, but the HSPA1B association was independent from the HLA-DRB4 association previously detected in the same case-control group from Wales (adjusted P=0.001). Given the cancer promoting roles played by HSPs intracellularly as well as roles in immune surveillance when expressed on the cell surface and the known correlations between expression levels and the HSP polymorphisms, these results are likely to indicate a primary association and warrant detailed assessment in childhood ALL development.

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Section: Discussionmentioning

confidence: 99%

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

Ucisik-Akkaya

Davis

Gorodezky

et al. 2010

Cell Stress and Chaperones

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“…It is a 190-amino acid protein, and has a signal peptide followed by a 120-amino acid extracellular region that forms a V-type Ig-like domain with two N-linked glycosylation sites, a hydrophobic transmembrane region with a positively charged Arg residue, and a 33-amino acid cytoplasmic tail lacking an immunoreceptor tyrosine-based activating motif (ITAM) [4,8]. Analysis of genomic sequences and experimental evidence shows that NKp30 is a pseudogene in mouse but functional in human and rat [9,10].…”

Section: Introductionmentioning

confidence: 99%

Identification and hormonal regulation of a novel form of NKp30 in human endometrial epithelium

Ponnampalam¹,

Gargett²,

Rogers³

2007

Eur J Immunol

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This study reports the discovery and steroid hormonal regulation of a novel glycosylated form of NKp30 in human endometrial epithelium. NKp30 is a member of the immunoglobulin superfamily and one of three existing natural cytotoxicity-triggering receptors. NKp30 is a glycosylated protein and is thought to be selectively expressed in resting and activated natural killer cells. The aims of the present study were to fully characterize NKp30 mRNA and protein in human endometrium during the menstrual cycle, and to investigate the hormonal regulation of NKp30. NKp30 mRNA was significantly up-regulated in fresh tissues during late secretory phase of the menstrual cycle. Interestingly, NKp30 mRNA was also present in clonally derived endometrial epithelial cells (CEE) in comparable amounts to fresh tissue. NKp30 protein was predominantly found in the endometrial glands and luminal epithelia of the secretory phase endometrium. Western blotting and de-glycosylation studies show that a novel glycosylated form of NKp30 is present in endometrial epithelium and that it can dimerize. Further phenotyping of CEE by flow cytometry revealed that they are CK8 + CD49f + NKp30 + CD45 -CD56 -. The data also show that transcription and translation of the novel form of NKp30 can be induced by progesterone treatment after 48 h in endometrial explants in vitro. This is the first report to show the presence of both NKp30 mRNA and a novel glycosylated form of NKp30 protein in endometrial epithelial cells.

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“…Polymorphisms of HLA are connected with many diseases, especially autoimmune disorders (Shiina et al, 2004). The human class III region, spanning approximately 700 kb, contains 61 genes and is the most gene-dense region of the human genome (Xie et al, 2003). It is known for the complement component genes C4 factor B (BF) and C2, which encode subunit proteins for the C3 and C5 convertases, enzymes essential for the complement activation pathways of the humoral immune response (Yu, 1998;Milner and Campbell, 2001).…”

Section: Discussionmentioning

confidence: 99%

Association of MHC class-III gene polymorphisms with ER-positive breast cancer in Chinese Han population

Pan¹,

Ning²,

Chen³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. Polymorphisms of the major histocompatibility complex (MHC) have been linked to many diseases, especially autoimmune disorders. Previous studies have shown that genetic variants in MHC class III are associated with breast cancer. To determine if there is an association between MHC class III and breast cancer risk in the Chinese Han population, we carried out a hospital-based case-control study in Guangdong and Jiangsu Provinces, including 216 histologically confirmed breast cancer patients and 216 healthy controls. Nine SNP markers distributed in the class III-coding region were detected using the Sequenom MassARRAY ® iPLEX System. Deviation from Hardy-Weinberg equilibrium was observed for seven SNPs. There was no significant association between these seven SNP variants and breast cancer in these Chinese women (unconditional logistic regression analysis). However, chr6_31697494 at BAT2, one of the seven SNPs, was found to be significantly associated with both ER-and PR-positive breast cancer. In addition, both chr6_31911109 at C6orf48 and chr6_31975605 at ZBTB12, another two of the seven SNPs, show relevance with ER-positive breast cancer. In conclusion, this is the first evidence that genetic polymorphisms in the MHC class III region are significantly associated with ER-positive breast cancer in the Han Chinese population.

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Analysis of the Gene-Dense Major Histocompatibility Complex Class III Region and Its Comparison to Mouse

Cited by 95 publications

References 67 publications

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

Identification and hormonal regulation of a novel form of NKp30 in human endometrial epithelium

Association of MHC class-III gene polymorphisms with ER-positive breast cancer in Chinese Han population

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