International Journal of Immunogenetics最新文献

Previous studies of genetic contributions to risk of childhood asthma have implicated common variants with small effect sizes. Some studies using exome sequence data have reported associations with rare coding variants having larger effects on risk, notably an analysis of 145,000 subjects which found association with loss of function (LOF) variants in FLG, the gene coding for filaggrin. Here, we report the results of an analysis of rare nonsynonymous and LOF variants, carried out on the full UK Biobank cohort of 470,000 exome-sequenced participants. The phenotype of childhood asthma was defined as reporting asthma with onset before 18. Regression analysis was applied to gene-wise tests for association of LOF and nonsynonymous variants. Forty-five tests using different pathogenicity predictors were applied to the first cohort of 200,000 participants. Subsequently, the 100 genes showing strongest evidence for association were analysed in the second cohort of 270,000 participants, using only the best-performing predictor for each gene. For FLG, separate analyses were carried out for participants with atopic dermatitis. Three genes achieved statistical significance after correction for testing these 100 genes: FLG, IL33 and PRKCQ. The effects on asthma risk and frequencies of variants in different functional categories were characterised for these genes. Damaging coding variants were associated with increased risk of asthma in FLG and IL33 but reduced risk in PRKCQ. FLG LOF variants were also associated with the risk of atopic dermatitis, and their effect on asthma risk was higher in people who reported a diagnosis of atopic dermatitis. Rare coding variants in a small number of genes have important effects on asthma risk. Further study of individual variant effects might elucidate mechanisms of pathogenesis. This research has been conducted using the UK Biobank Resource.

The present study aimed to determine the association of HLA-DRB1/-DQB1 alleles with response to treatment and anti-citrullinated peptide antibody (ACPA) status in Iranian rheumatoid arthritis (RA) patients. A total of 167 RA patients, including 114 good responders (GRs) and 53 poor responders (PRs) as well as 330 ethnic-matched healthy controls, participated in this study. Disease activity and treatment response were assessed using the Disease Activity Score 28-joint (DAS28) scores during the 9-month post-treatment. HLA-DRB1/-DQB1 alleles were identified using polymerase chain reaction with a sequence-specific primers (PCR-SSP) method and compared between the study groups. Of the patients, 106 (63.5%) were ACPA-positive, 88 (52.7%) human leucocyte antigen (HLA)-shared epitope (SE)-positive, 64 (38.3%) ACPA+SE+ and 37 (22.2%) ACPA−SE−. HLA-SE alleles were significantly more frequent in patients (p = 3.2e − 05), in PR versus GR patients (p = 0.01) and in ACPA+ versus ACPA− patients (p = 0.009). PR patients had a higher prevalence of ACPA+SE+ compared to GR patients (p = 0.02). Higher frequencies of DRB1*04:02 (p_c = 0.03), *04:04 (p_c = 0.007), *04:05 (p_c = 5.0e − 05), *10:01 (p_c = 1.0e − 04), DQB1*03:02 (p_c = 0.002) and *05:01 (p_c = 0.002) alleles, and lower frequencies of DRB1*04:01 (p_c = 0.007), *11:01 (p_c = 0.03), *13:01 (p_c = 0.03) and DQB1*06:03 (p_c = 0.03) alleles were observed in patients compared to healthy controls. These findings suggest a relationship between HLA-SE alleles and ACPA development and a potential link between HLA-SE/non-SE alleles and therapeutic responses in RA patients.

Single antigen bead assays have revolutionised the identification and definition of HLA-specific antibodies and HLA-specific antibody profiles present in patients awaiting transplantation are routinely characterised to inform organ allocation. For highly sensitised patients with a lower likelihood of finding a compatible donor, de-listing of unacceptable antigens is an option to release organ offers. In this study, 164 serum samples from 106 potential renal transplant recipients were tested using HISTO SPOT HLA AB in parallel with testing by LABScreen Single Antigen (One Lambda) and cross-matching by both CDC and flow cytometry. The results were analysed to assess the ability of HISTO SPOT HLA AB to predict a cross-match result and to understand the relative sensitivity of this test compared with other available assays. 136 samples analysed were positive for donor-specific antibodies (DSAs) using HISTO SPOT HLA AB. Of these, 17 (12.5%) were CDC positive, and 82 (60.3%) were positive by flow cytometry. A total of 28 sera which were negative for DSAs using HISTO SPOT HLA AB were negative by CDC and 25 (89.3%) were also flow cytometry cross-match negative. In this early study, HISTO SPOT HLA AB has a 100% negative predictive value for CDC and 89.3% for flow cytometry cross-matching. HISTO SPOT may therefore prove a useful additional tool to inform de-listing strategies and to facilitate transplantation in highly sensitised patients.

Background and Aims: Genetic factors, including polymorphisms in the TNFRSF13B gene, which regulates humoral immunity, can influence susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aims to investigate the association between two polymorphisms, rs12603708 and rs3751987, and SARS-CoV-2 susceptibility, disease severity, and humoral immune responses in a Moroccan population.

Materials and Methods: A total of 303 unvaccinated COVID-19 patients (151 severe cases and 152 asymptomatic/moderate cases) and 150 individuals from a SARS-CoV-2-negative group were included in the analysis. Genotyping was performed using TaqMan SNP assays. SARS-CoV-2 antibodies targeting the nucleocapsid protein and IgG antibodies specific to the receptor-binding domain (RBD) were quantified using chemiluminescence microparticles immunoassay. Complete blood counts and C-reactive protein levels were evaluated using an automated platform.

Results: Our analysis revealed that the A/A genotype of rs12603708 significantly increased the risk of SARS-CoV-2 infection in both codominant (p = 0.0055; OR = 3.74; adjusted p value = 0.022) and recessive (p = 0.0049; OR = 3.17; adjusted p value = 0.022) models, as well as the risk of severe disease (p = 0.014; OR = 3.43; adjusted p value = 0.049). For rs3751987, the G/G genotype was linked to higher susceptibility to infection (p = 0.0011; OR = 2.91; adjusted p value = 0.008), while the G/A genotype appeared protective (p = 0.0007; OR = 0.45; adjusted p value = 0.008). No association was found between rs3751987 and disease severity. Analysis of IgG anti-N and anti-RBD levels revealed no significant associations with either polymorphism (p > 0.05).

Conclusion: These findings highlight the role of TNFRSF13B polymorphisms in SARS-CoV-2 susceptibility and severity, while their impact on humoral immune responses appears limited.

Extended RBC antigens typing is very valuable in transfusion immunology since it is highly recommended to ensure better transfusion practices and avoid transfusion-related complications and to establish registries for rare blood donors as recommended by the International Society of Blood Transfusion and World Health Organization.

A group of 236 Tunisian blood donors were genotyped for 19 common blood loci using the Sequence-specific primers polymerase chain reaction (SSP-PCR) method. The statistical analysis was done using the HaploView Software.

The study showed the dominance of the loci: RHCE*e, KEL*02, FY*02 and CO*01; and the absence of the homozygous state of the CO*02 allele. Furthermore, two complete linkage disequilibrium leading to the absence of the two alleles RHCE*C-RHCE*E (C-E) and FY*01N.01 (FY*Anull) were detected. Additionally, it appeared that approximately 91% of these blood donors are positive for the RHD gene; and all subjects who lacked the RHD exon 10 are homozygous for the RHCE*c and RHCE*e variants. The study also revealed that the RH1 negative blood cannot be universal to the Rh system because almost all RH1 negative donated blood is RH:-2,4,-3,5 (ccee), which may constitute a risk in some recipients carrying the anti-RH4 and/or anti-RH5 antibodies.

Considering that some donated RBC units may contain blood with very immunogenic phenotypes, great caution is required when transfusing some subjects, especially in emergency situations because it can be a step towards subsequent complex or multiple alloimmunization.

High degree of variability in human leukocyte antigens (HLAs) system restricts availability of histocompatible HLA-matched-related donors, thus increasing reliance on worldwide bone marrow registries network. Nevertheless, due to limited coverage/accessibility/affordability of some ethnicities in these registries, haploidentical haematopoietic stem cell transplantation (HSCT) emerged as an alternative option, though with allorecognition-mediated graft versus host disease (GvHD) (>40% cases). A dimorphism [−21 methionine (M) or threonine (T)] in HLA-B leader peptide (exon 1) which differentially influences its HLA-E binding, plausibly regulates natural killer cell functionality, affecting GvHD vulnerability and clinically in practice for donor selection. Here, we analysed population-specific influence of this functionally relevant dimorphism on post HSCT GvHD occurrence and clinical utility (if any) towards defining donor permissibility. High resolution HLA-B genotyping data were analysed in 178 study participants, including 89 HSCT patient–donor pairs, for the frequency distribution of −21 leader dimorphism. Distribution of HLA-Bw4/Bw6 was deduced with killer cell immunoglobulin receptor ligand calculator tool in IPD-IMGT/HLA database. Though −21T (∼85%) was over represented in the study participants, no significant influence is observed for this variant between HLA-identical v/s haplo HSCT either with or without GvHD, at allelic and genotypic levels as well as in BLEAT (HLA-B Leader Assessment Tool)-based donor–recipient matching. Stratified analysis of −21 M/T into Bw4/Bw6 groups revealed a higher frequency of −21T + Bw4 in GvHD (+) group compared to GvHD (−) (p < 0.05), plausibly linking this haplotype with occurrence of GvHD post HSCT and importance of HLA class I-mediated NK cell functionality in GvHD.

Recently, it has been realized that immune processes participate in the pathogenesis of human cancers. A large number of genetic polymorphisms in immune-related genes have been extensively examined for their roles in the susceptibility of gastric cancer (GC) and colorectal cancer (CRC), including IL4 gene rs2070874, IL4RA gene rs1801275, IL18 gene rs187238, IL18RAP gene rs917997, IL17A gene rs8193036, IL23R gene rs1884444 and IL23R gene rs10889677. However, there is no consistent conclusion, which calls for further research. In this case–control study, these 7 genetic polymorphisms were genotyped by Sanger sequencing in a total of 1247 patients with cancer (GC/CRC: 460/787) and 800 healthy individuals. A total of 31 previous studies and our present study were included in this meta-analysis. The case–control study revealed that in Hubei Chinese population, rs2070874, rs187238 and rs10889677 were significantly associated with CRC risk, whereas only rs917997 was significantly associated with GC risk. The meta-analysis showed that rs2070874, rs917997, rs8193036 and rs1884444 were significantly associated with GC risk in Chinese population, whereas rs2070874 in total population, rs1801275 in Asian population and rs187238 in Chinese population were significantly associated with CRC risk. IL4 gene rs2070874, IL18RAP gene rs917997, IL17A gene rs8193036 and IL23R gene rs1884444 may serve as the susceptible factors for GC carcinogenesis in Chinese population. IL4 gene rs2070874 in total population, IL4RA gene rs1801275 in Asian population and IL18 gene rs187238 in Chinese population may be genetic biomarkers for CRC susceptibility.

The association between heterozygous C4 deficiency and systemic lupus erythematosus (SLE) is unclear. There is a lack of data in South Asian Indians on any possible association of C4A and C4B null alleles with lupus. We aimed to study the prevalence of C4A and C4B null alleles in a cohort of SLE patients with persistently low C4 levels compared to healthy controls (HC). Patients with SLE and HC were recruited for this prospective observational study. C4 (C4AQ and C4BQ) polymorphisms were tested using a touch-down polymerase chain reaction protocol. One hundred and three SLE patients and 103 HC were included in the study. Persistently low C4 levels were observed in 25 (23.6%) of SLE. The frequency of C4A and C4B null alleles was similarly distributed across SLE and HC (4% and 3.8%, respectively). Univariate analysis showed a low age, higher proportion of elevated dsDNA, and higher positive anti-SSA (Sjogren's syndrome-related antigen A) antibodies at presentation were associated in SLE patients with the null allele group on comparison without the null allele group. However, these associations did not persist in the multivariate analysis. In conclusion, C4 null allele frequency was similar in SLE and HC. No characteristic associations were observed in SLE with C4 null alleles was observed. Therefore, C4 null allele is an unlikely explanation for persistently low C4 in South Indian Asian patients with lupus.