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Identifying the HLA DRB1-DQB1 molecules and predicting epitopes associated with high-risk HPV infection clearance and redetection.

ABSTRACT: Several determining factors are involved in HPV infection outcomes; human leukocyte antigen (HLA) polymorphisms have been described as related factors. This study has ascertained the effect of genetic variation on HLA-DRB1 and DQB1 genes on HPV-16/-18/-31/-33/-45 and -58 clearance and redetection in Colombian women. PCR and qPCR were used for viral identification and the Illumina MiSeq system was used for HLA-typing of cervical samples (n?=?276). Survival models were adjusted for identifying alleles/haplotypes related to HPV clearance/redetection; L1/L2 protein-epitope binding to MHC-II molecules was also predicted. Significant associations suggested effects favouring or hampering clearance/redetection events depending on the viral type involved in infection, e.g. just DRB1*12:01:01G favoured HPV-16 (coeff: 4.8) and HPV-45 clearance (coeff: 12.65) whilst HPV-18 (coeff: 2E-15), HPV-31 (coeff: 8E-17) and HPV-58 hindered elimination (coeff: 1E-14). An effect was only observed for some alelles when configured as haplotypes, e.g. DRB1*04:07:01G (having the greatest frequency in the target population) was associated with DQB1*02:01:1G or *03:02:03. Epitope prediction identified 23 clearance-related peptides and 29 were redetection-related; eight might have been related to HPV-16/-18 and -58 persistence and one to HPV-18 elimination. HLA allele/haplotype relationship with the course of HPV infection (clearance/redetection) depended on the infecting HPV type, in line with the specific viral epitopes displayed.

SUBMITTER: Del Rio-Ospina L

PROVIDER: S-EPMC7190668 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Identifying the HLA DRB1-DQB1 molecules and predicting epitopes associated with high-risk HPV infection clearance and redetection.

Del Río-Ospina Luisa L Camargo Milena M Soto-De León Sara C SC Sánchez Ricardo R Moreno-Pérez Darwin A DA Patarroyo Manuel E ME Patarroyo Manuel A MA

Scientific reports 20200429 1

Several determining factors are involved in HPV infection outcomes; human leukocyte antigen (HLA) polymorphisms have been described as related factors. This study has ascertained the effect of genetic variation on HLA-DRB1 and DQB1 genes on HPV-16/-18/-31/-33/-45 and -58 clearance and redetection in Colombian women. PCR and qPCR were used for viral identification and the Illumina MiSeq system was used for HLA-typing of cervical samples (n = 276). Survival models were adjusted for identifying all ...[more]

PMID: 32350356

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Project description:Potential correlation of human papillomavirus (HPV) 16 E6 variants and human leukocyte antigen (HLA) class II polymorphisms has been suggested in patients with cervical cancer, so far little information is available about the possible interaction between E6 variants and HLA class II variability during the obviously accelerated progression to cervical cancer in young women. In this study, we aimed to explore the association between the HPV16 E6 variants and HLA-DRB1, DQB1 alleles in a Chinese young cervical cancer population. The HLA-DRB1, HLA-DQB1 polymophisms were genotyped by low-resolution polymerase chain reaction (PCR) with sequence-specific primer. HPV16 E6 DNA was tested by Sanger fluorescent dye dideoxy-termination technique. The difference of DRB1, DQB1 polymorphisms between young cervical cancer patients (≤35ys, n=61) and older ones (>35ys, n=85) and the association with E6 variants were analyzed. Results showed that the distribution pattern of HLA-DRB1, DQB1 alleles was different between young cervical cancer patients and older ones. The allele frequency of DQB1*0501 in young patients was significantly lower than older ones (6.6% vs. 23.5%, p<0.05). The HPV16 E6 A4 lineage was the exclusive type observed in young patients, and its prevalence was significantly higher than that of older cases (82.86% vs.41.94%, p<0.05). DRB1*03 was not found in young patients positive for the HPV16 E6 A4 lineage, whereas it was observed in 19.2 % older patients with A4 positive(Pc<0.05). In conclusion, specific association between certain HPV16 E6 variant and genetic polymorphisms of HLA may play a role during the progression of early onset cervical cancer in young patients. Certain HLA-DRB1 and HLA-DQB1 alleles may be related to the A4 lineage among young cervical cancer patients, which was the unique HPV16 E6 variant found in Chinese young patients. Our finding may provide an insight into the pathogenic factors that associated with cervical cancer in young women.

Project description:Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.

Project description:ObjectiveSystemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile-onset SSc.MethodsDRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenile-onset SSc (n = 76) to healthy Caucasian controls (n = 581).ResultsInitial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P = 0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P = 0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P = 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P = 0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P = 0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P = 0.01) and in those with antibodies to topoisomerase (OR 0.14, P = 0.024).ConclusionAssociations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.

Project description:INTRODUCTION: Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients' genotypic risk of developing MS. METHODS AND RESULTS: A transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6×10(-3)), *04:05-*03:01 (OR = 2.4, P = 4.4×10(-6)) and *03:01-*02:01 (OR = 2.1, P = 1.0×10(-15)) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4×10(-11)) and the *15:02-*06:01 (OR = 0.3, P = 1.5×10(-3)) haplotypes exhibited a lower than expected transmission rate (under-transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient's risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01-*02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05:02, *06:01 alleles. CONCLUSIONS: These findings show that the association of specific, independent DRB1*-DQB1* haplotypes confers susceptibility or resistance to MS in the MS-prone Sardinian population. The data also supports a functional role for specific residues of the DRB1 and DQB1 proteins in predisposing patients to MS.

Dataset Information

Identifying the HLA DRB1-DQB1 molecules and predicting epitopes associated with high-risk HPV infection clearance and redetection.

Publications

Identifying the HLA DRB1-DQB1 molecules and predicting epitopes associated with high-risk HPV infection clearance and redetection.

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