Dataset Information

Genome-wide analysis of genetic risk factors for rheumatic heart disease in Aboriginal Australians provides support for pathogenic molecular mimicry

ABSTRACT: Background. Rheumatic heart disease (RHD) following Group A Streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers pro-inflammatory cardiac valve-reactive T-cells. Methods. Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single nucleotide polymorphisms (SNPs) were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. Results. The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P=1.86x10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (OR 1.44, 95%CI 1.09-1.90, P=9.56x10-3) and HLA-DQA1*0103_DQB1*0601 (OR 1.27, 95%CI 1.07-1.52, P=7.15x10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P=2.36x10-3) was protective. Human myosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the two risk haplotypes than the protective haplotype. Conclusions. Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis.

PROVIDER: EGAS00001002678 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Similar Datasets

Project description:Afamitresgene autoleucel, an HLA-restricted autologous specific peptide enhanced affinity receptor (SPEAR) T-cell therapy targeting MAGE-A4, was developed to treat HLA-A*02 positive patients with MAGE-A4 expressing solid tumors. A multicenter, dose-escalation, Phase 1 trial (NCT03132922) was conducted evaluating afamitresgene autoleucel in patients with relapsed or refractory (≥1 prior line of therapy) metastatic solid tumors. The primary endpoint was safety. The secondary endpoint was anti-tumor activity including overall response rate, best overall response, time to response, duration of response, duration of stable disease, progression-free survival and overall survival. Thirty-eight patients were treated with afamitresgene autoleucel across 9 tumor types, including 16 with synovial sarcoma (SS). Overall, afamitresgene autoleucel was well tolerated. The most common adverse events were cytopenias. Cytokine release syndrome occurred in 55% of all patients with severity grade ≤2 in 90% of reported cases. Overall response rate (ORR) was 24% and disease control rate (DCR) was 74% with objective responses in 7 patients with SS, 1 patient with non-small cell lung cancer, and 1 patient with head and neck squamous cell carcinoma. ORR in patients with SS, all prior treated with ifosfamide chemotherapy, was 44%, and DCR was 94%. Median progression-free survival and overall survival were 20.4 weeks (95% CI: 10.0, 52.1) and 58.1 weeks (95% CI: 36.3,-), respectively, for patients with SS and 12.3 weeks (95% CI: 10.857, 19.1) and 42.9 weeks (95% CI: 20.7, -), respectively, for the overall population. Translational findings demonstrated that afamitresgene autoleucel infiltrates into tumors, has an IFNγ-driven mechanism-of-action, and triggers adaptive immune responses. Overall, afamitresgene autoleucel has an acceptable safety profile with early and durable responses in HLA-A*02 positive patients with MAGE-A4 expressing solid tumors, especially in patients with metastatic SS. The recommended treatment regimen for Phase 2 evaluation involves lymphodepleting chemotherapy consisting of cyclophosphamide 600 mg/m2 x 3 days and fludarabine 30 mg/m2 x 4 days followed by afamitresgene autoleucel at a dose range of 1 to 10 billion transduced T-cells.

Project description:Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in-silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analysed in-vitro and in-vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterised three cis-regulatory SNPs located at the promoter and two intronic regulatory elements, which affect the binding of the transcription factors C/EBPα, HMGA1, DBP and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele HR=0.85, 95%CI=0.72-1.00, P-trend=0.048). Conclusion: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2, which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele. Total gene expression of normal breast sample from healthy controls. This submission represents transcriptome component of study.

Project description:Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in-silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analysed in-vitro and in-vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterised three cis-regulatory SNPs located at the promoter and two intronic regulatory elements, which affect the binding of the transcription factors C/EBPα, HMGA1, DBP and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele HR=0.85, 95%CI=0.72-1.00, P-trend=0.048). Conclusion: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2, which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele. Genotype of normal breast sample from healthy controls.

Dataset Information

Genome-wide analysis of genetic risk factors for rheumatic heart disease in Aboriginal Australians provides support for pathogenic molecular mimicry

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets