Genetic epidemiology of glioblastoma multiforme: confirmatory and new findings from analyses of human leukocyte antigen alleles and motifs.
ABSTRACT: Human leukocyte antigen (HLA) class I genes mediate cytotoxic T-lymphocyte responses and natural killer cell function. In a previous study, several HLA-B and HLA-C alleles and haplotypes were positively or negatively associated with the occurrence and prognosis of glioblastoma multiforme (GBM).As an extension of the Upper Midwest Health Study, we have performed HLA genotyping for 149 GBM patients and 149 healthy control subjects from a non-metropolitan population consisting almost exclusively of European Americans. Conditional logistic regression models did not reproduce the association of HLA-B*07 or the B*07-Cw*07 haplotype with GBM. Nonetheless, HLA-A*32, which has previously been shown to predispose GBM patients to a favorable prognosis, was negatively associated with occurrence of GBM (odds ratio=0.41, p=0.04 by univariate analysis). Other alleles (A*29, A*30, A*31 and A*33) within the A19 serology group to which A*32 belongs showed inconsistent trends. Sequencing-based HLA-A genotyping established that A*3201 was the single A*32 allele underlying the observed association. Additional evaluation of HLA-A promoter and exon 1 sequences did not detect any unexpected single nucleotide polymorphisms that could suggest differential allelic expression. Further analyses restricted to female GBM cases and controls revealed a second association with a specific HLA-B sequence motif corresponding to Bw4-80Ile (odds ratio=2.71, p=0.02).HLA-A allelic product encoded by A*3201 is likely to be functionally important to GBM. The novel, sex-specific association will require further confirmation in other representative study populations.
Project description:Here we explore the association between killer cell immunoglobulin-like receptor (KIR)/HLA and human immunodeficiency virus type 1 (HIV-1) acquisition with different viral subtypes circulating in East Africa. In the prospective Cohort Development (CODE) cohort (Mbeya, Tanzania), carriers of KIR3DS1 and its putative ligand (HLA-A or HLA-B Bw4-80Ile alleles) showed increased HIV-1 acquisition risk (odds ratio [OR] = 3.46; 95% confidence interval [CI], 1.12-10.63; P = .04) and a trend for enrichment for subtype A and A-containing recombinants (78% vs. 46%; OR = 4.05; 95% CI, .91-28.30; P = .09) at the expense of subtype C (11% vs. 43%; OR = 0.17; 95% CI, .01-.97; P = .08). In vitro, only natural killer cells from KIR3DS1(+)/HLA-Bw4-80Ile(+) healthy donors showed a 2-fold increased capacity to inhibit replication of subtype C vs subtype A viruses (P = .01). These findings suggest the presence of an innate sieve effect and may inform HIV-1 vaccine development.
Project description:To date, several on-treatment-level virological and serological indices that may predict the response to interferon alpha (IFN-?) have been reported. However, no effective predictors, such as drug-response genes, that can be detected before administration of anti-hepatitis B virus (HBV) therapy with IFN-?, have been found. In the diverse range of chronic viral infection, genes that affect human immunity play important roles in understanding host and viral co-evolution. Killer-cell immunoglobulin-like receptors (KIRs), which are highly polymorphic at the allele and haplotype levels, participate in the antiviral function of natural killer (NK) cells via fine-tuning inhibition and activation of NK-cell responses that occur when the NK cells interact with human leukocyte antigen (HLA) class I molecules on target cells. For each individual, the pairing of KIR and HLA ligand is genetically determined. To investigate whether a particular KIR and HLA repertoire influences the risk of HBV infection and response to IFN-? treatment for chronic hepatitis B (CHB), we genotyped the KIRs and HLA ligands of 119 hepatitis B e antigen (HBeAg)-positive CHB patients. These patients included 43 patients who achieved sustained response (SR) induced by IFN-? treatment for 48?weeks, 76 patients who achieved no response (NR), and 96 healthy subjects as controls. SR was defined as HBeAg loss with HBV DNA?<?2,000?IU/ml and alanine aminotransferase normalization at 24?weeks posttreatment (week 72). In this study, we showed that activating KIR genes were less prevalent in Han Chinese, especially in Han Chinese with CHB, than in Caucasians. Furthermore, the KIR3DS1 gene, in combination with HLA-B Bw4-80Ile, strongly influenced the therapeutic outcomes for CHB patients who were treated with IFN-?. The frequency of the combination of genes encoding KIR3DS1 and HLA-B Bw4-80Ile was higher in patients who had a sustained treatment response than in patients who had NR [35.3 versus 1.3%; odds ratio (OR)?=?19.85; P?=?0.0008]. Activating KIR3DS1 and HLA-B Bw4-80Ile synergistically predicted SR to IFN-? for HBeAg-positive CHB patients. Genotyping for the KIR3DS1 gene and the HLA-B Bw4-80Ile allele might help physicians choose the optimal candidates for anti-HBV treatment with IFN-?.
Project description:BACKGROUND:Persistent cervical high-risk human papillomavirus (hrHPV) infection is a necessary cause of cervical cancer. However, the host genetic factors underlying its risk are not well understood. We hypothesized that immunogenetic variation plays a role in hrHPV infection and persistence. Therefore, we conducted a study of classical HLA alleles and their association with hrHPV infection and persistence among women. METHODS:We characterized HPV infection using SPF10/LiPA25in Nigerian women at baseline and at 6?months follow-up visits in 2014. hrHPV infection was prevalent if at least one carcinogenic HPV genotype was detected at the baseline visit and persistent if at least one carcinogenic HPV genotype was detected at the baseline and follow-up visits. Classical HLA alleles were imputed from genotypes in the MHC region using the HLA genotype imputation with attribute bagging (HIBAG) algorithm. HLA association tests were conducted under additive genetic models. RESULTS:The mean (±SD) age of the 517 study participants was 38 (±8) years, 48% were HIV negative, 24% were hrHPV positive at baseline and 10% had persistent hrHPV infections. In multivariate regression models adjusted for age, HIV status and the first principal component, DQA1*01:02 and DQA1*02:01 were positively associated with prevalent but not persistent hrHPV infections, while DQA1*05:01 was negatively associated with prevalent hrHPV but positively associated with persistent cervical hrHPV infections. Four haplotypes (A*30:01-DQA1*05:01, B*07:02-C*07:02, B*07:02-DQA1*05:01 and C*07:02-DQA1*05:01) were significantly associated with prevalent cervical hrHPV infections and several haplotypes that included the DQA1*05:01 allelic variant were significantly associated with persistent cervical hrHPV infections. Six amino acid positions on DQ?1 were associated with prevalent but not persistent cervical hrHPV infections. CONCLUSIONS:In this first study to investigate the association between HLA alleles and persistent hrHPV in African women, we identified important risk alleles that merit further investigation. Our findings provide new insights into risk factors for hrHPV infection in African ancestry women.
Project description:Stevens Johnson syndrome (SJS) is part of a spectrum of adverse drug reactions resulting in the destruction of skin, mucous membranes, and the ocular surface. A similar, more severe form of the disorder included in this spectrum is toxic epidermal necrolysis (TEN). Approximately 35% of patients suffer chronic sequelae such as vascularization, corneal scarring, conjunctival inversion to the cornea, keratinization, symblepharon, scarring of the palpebral conjunctiva, trichiasis, and severe dry eye. We focused on 80 Indian patients with SJS/TEN with severe ocular complications (SOC) and investigated the association of alleles at HLA -A, HLA-B and HLA-C loci; the controls were 50 healthy Indian volunteers. Genotyping at HLA-A, HLA-B, and HLA-C loci showed a significant positive association with HLA-A*33:03, HLA-B*44:03, and HLA-C*07:01 alleles, and a significant negative association with HLA-B*57:01 and HLA-C*06:02. This indicates that HLA-A*33:03, HLA-B*44:03 and HLA-C*07:01 are risk alleles, and HLA-B*57:01 and HLA-C*06:02 are protective alleles in this population. We also found that the haplotypes consisting of HLA-B*44:03 and HLA-C*07:01 were strongly associated with SJS/TEN with SOC in our Indian population (p?=?1.1?×?10-7, odds ratio?=?11.0). Describing the association of the haplotype could facilitate the understanding of increased risk factors for developing SJS/TEN with SOC.
Project description:A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D) mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis ("HH") and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD) with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry.
Project description:BACKGROUND:Immune dysregulation has been widely observed in those with posttraumatic stress disorder (PTSD). An individual's immune response is shaped, in part, by the highly polymorphic Human Leukocyte Antigen (HLA) locus that is associated with major psychiatric disorders such as schizophrenia, major depression and bipolar disorder. The aim of the current study was to investigate the association between common HLA alleles and PTSD. METHODS:Genome-wide association data was used to predict alleles of 7 classical polymorphic HLA genes (A, B, C, DRB1, DQA1, DQB1, DPB1) in 403 lifetime PTSD cases and 369 trauma exposed controls of African ancestry. Association of HLA allelic variations with lifetime PTSD was analyzed using logistic regression, controlling for ancestry, sex and multiple comparisons. The effect of HLA alleles on gene expression was assessed by weighted correlation network analysis (WGCNA), using 353 subjects with available expression data. Enrichment analysis was performed using anRichment to identify associated pathways of each module. RESULTS:HLA-B*58:01 (p?=?0.035), HLA-C*07:01 (p?=?0.035), HLA-DQA1*01:01 (p?=?0.003), HLA-DQB1*05:01 (p?=?0.009) and HLA-DPB1*17:01 (p?=?0.017) were more common in PTSD cases, while HLA-A*02:01 (p?=?0.026), HLA-DQA1*05:05 (p?=?0.011) and HLA-DRB1*11:01 (p?<?0.001) were more frequent in controls. WGCNA was used to explore expression patterns of the PTSD related alleles. Gene expression modules of PTSD-related HLA alleles were enriched in various pathways, including pathways related to immune and neural activity. CONCLUSIONS:To the best of our knowledge, this is the first study to report an association of HLA alleles with PTSD. Altogether, our results support the link between the immune system, brain and PTSD.
Project description:Human leukocyte antigen (HLA) alleles have been implicated as risk factors for immune-mediated adverse drug reactions. The authors recently reported a strong association between HLA-A*32:01 and vancomycin-induced drug reaction with eosinophilia and systemic symptoms. Identification of individuals with the risk allele before or shortly after the initiation of vancomycin therapy is of great clinical importance to prevent morbidity and mortality, and improve drug safety and antibiotic treatment options. A prerequisite to the success of pharmacogenetic screening tests is the development of simple, robust, cost-effective single HLA allele test that can be implemented in routine diagnostic laboratories. In this study, the authors developed a simple, real-time allele-specific PCR for typing the HLA-A*32:01 allele. Four-hundred and fifty-eight DNA samples including 30 HLA-A*32:01-positive samples were typed by allele-specific PCR. Compared with American Society for Histocompatibility and Immunogenetics-accredited, sequence-based, high-resolution, full-allelic HLA typing, this assay demonstrates 100% accuracy, 100% sensitivity (95% CI, 88.43% to 100%), and 100% specificity (95% CI, 99.14% to 100%). The lowest limit of detection of this assay using PowerUp SYBR Green is 10 ng of template DNA. The assay demonstrates a sensitivity and specificity to differentiate the HLA-A*32:01 allele from closely related non-HLA-A*32 alleles and may be used in clinical settings to identify individuals with the risk allele before or during the course of vancomycin therapy.
Project description:Human leukocyte antigen- (HLA-) A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele and haplotype frequencies were studied in a subset of 237 volunteer bone marrow donors registered at the South African Bone Marrow Registry (SABMR). Hapl-o-Mat software was used to compute allele and haplotype frequencies from individuals typed at various resolutions, with some alleles in multiple allele code (MAC) format. Four hundred and thirty-eight HLA-A, 235 HLA-B, 234 HLA-DRB1, 41 HLA-DQB1, and 29 HLA-C alleles are reported. The most frequent alleles were A?02:02g (0.096), B?07:02g (0.082), C?07:02g (0.180), DQB1?06:02 (0.157), and DRB1?15:01 (0.072). The most common haplotype was A?03:01g~B?07:02g~C?07:02g~DQB1?06:02~DRB1?15:01 (0.067), which has also been reported in other populations. Deviations from Hardy-Weinberg equilibrium were observed in A, B, and DRB1 loci, with C~DQB1 being the only locus pair in linkage disequilibrium. This study describes allele and haplotype frequencies from a subset of donors registered at SABMR, the only active bone marrow donor registry in Africa. Although the sample size was small, our results form a key resource for future population studies, disease association studies, and donor recruitment strategies.
Project description:Prediction of HLA epitopes is important for the development of cancer immunotherapies and vaccines. However, current prediction algorithms have limited predictive power, in part because they were not trained on high-quality epitope datasets covering a broad range of HLA alleles. To enable prediction of endogenous HLA class I-associated peptides across a large fraction of the human population, we used mass spectrometry to profile >185,000 peptides eluted from 95 HLA-A, -B, -C and -G mono-allelic cell lines. We identified canonical peptide motifs per HLA allele, unique and shared binding submotifs across alleles and distinct motifs associated with different peptide lengths. By integrating these data with transcript abundance and peptide processing, we developed HLAthena, providing allele-and-length-specific and pan-allele-pan-length prediction models for endogenous peptide presentation. These models predicted endogenous HLA class I-associated ligands with 1.5-fold improvement in positive predictive value compared with existing tools and correctly identified >75% of HLA-bound peptides that were observed experimentally in 11 patient-derived tumor cell lines. Overall design: RNA transcript expression was quantified for mono-allelic HLA-C cell lines (HLA-C*04:01 and HLA-C*07:01, 4 replicates each) in order to assess its contribution to Class I peptide prediction and compare it against HLA-A and HLA-B.
Project description:We previously demonstrated in the Chinese macaque model that an oral vaccine made of inactivated SIV and Lactobacillus plantarum induced CD8(+) regulatory T-cells, which suppressed the activation of SIV(+)CD4(+) T-cells, prevented SIV replication, and protected macaques from SIV challenges. Here, we sought whether a similar population of CD8(+) T-regs would induce the suppression of HIV replication in elite controllers (ECs), a small population (3‰) of HIV-infected patients with undetectable HIV replication. For that purpose, we investigated the in vitro antiviral activity of fresh CD8(+) T-cells on HIV-infected CD4(+) T-cells taken from 10 ECs. The 10 ECs had a classical genomic profile: all of them carried the KIR3DL1 gene and 9 carried at least 1 allele of HLA-B:Bw4-80Ile (i.e., with an isoleucine residue at position 80). In the nine HLA-B:Bw4-80Ile-positive patients, we demonstrated a strong viral suppression by KIR3DL1-expressing CD8(+) T-cells that required cell-to-cell contact to switch off the activation signals in infected CD4(+) T-cells. KIR3DL1-expressing CD8(+) T-cells withdrawal and KIR3DL1 neutralization by a specific anti-killer cell immunoglobulin-like receptor (KIR) antibody inhibited the suppression of viral replication. Our findings provide the first evidence for an instrumental role of KIR-expressing CD8(+) regulatory T-cells in the natural control of HIV-1 infection.