HLA-B Variants Research Articles

The association between HLA-B variants and amoxicillin-induced severe cutaneous adverse reactions in Chinese han population.

Amoxicillin (AMX) is among the most prescribed and the best tolerated antimicrobials worldwide. However, it can occasionally trigger severe cutaneous adverse reactions (SCAR) with a significant morbidity and mortality. The genetic factors that may be relevant to AMX-induced SCAR (AMX-SCAR) remain unclear. Identification of the genetic risk factor may prevent patients from the risk of AMX exposure and resume therapy with other falsely implicated drugs. Four patients with AMX-SCAR, 1,000 population control and 100 AMX-tolerant individuals were enrolled in this study. Both exome-wide and HLA-based association studies were conducted. Molecular docking analysis was employed to simulate the interactions between AMX and risk HLA proteins. Compared with AMX-tolerant controls, a significant association of HLA-B*15:01 with AMX-SCAR was validated [odds ratio (OR) = 22.9, 95% confidence interval (CI): 1.68-1275.67; p = 7.34 × 10-3]. Moreover, 75% carriers of HLA-B*15:01 in four patients with AMX-SCAR, and the carrier frequency of 10.7% in 1,000 control individuals and 11.0% in 100 AMX-tolerant controls, respectively. Within HLA-B protein, the S140 present in all cases and demonstrated the strongest association with AMX-SCAR [OR = 53.5, p = 5.18 × 10-4]. Molecular docking results also confirmed the interaction between AMX and S140 of the HLA-B protein, thus eliminating the false-positive results during in association analysis. Our findings suggest that genetic susceptibility may be involved in the development of AMX-SCAR in Han Chinese. However, whether the HLA-B variants observed in this study can be used as an effective genetic marker of AMX-induced SCAR still needs to be further explored in larger cohort studies and other ethnic populations.

Discovery of the novel HLA-B*39:198 allele, a variant of HLA-B*39:01:01, in a Russian individual.

One nucleotide substitution in codon 336 of HLA-B*39:01:01:01 results in the novel allele, HLA- B*39:198.

Two novel HLA-B variants identified in Russian individuals, HLA-B*37:108 and -B*38:108.

HLA-B*37:108 and -B*38:108, two novel alleles detected in Russian individuals by next generation sequencing.

Nomenclature for factors of the HLA system, update January, February, and March 2023.

Nomenclature for factors of the HLA system, update January, February, and March 2023.

Discovery of the novel HLA-B*38:102 allele, a variant of HLA-B*38:01:01, in a Russian individual.

One nucleotide substitution in codon 1 of HLA-B*38:01:01:01 results in the novel allele, HLA-B*38:102.

Malaria-driven adaptation of MHC class I in wild bonobo populations

The malaria parasite Plasmodium falciparum causes substantial human mortality, primarily in equatorial Africa. Enriched in affected African populations, the B*53 variant of HLA-B, a cell surface protein that presents peptide antigens to cytotoxic lymphocytes, confers protection against severe malaria. Gorilla, chimpanzee, and bonobo are humans’ closest living relatives. These African apes have HLA-B orthologs and are infected by parasites in the same subgenus (Laverania) as P. falciparum, but the consequences of these infections are unclear. Laverania parasites infect bonobos (Pan paniscus) at only one (TL2) of many sites sampled across their range. TL2 spans the Lomami River and has genetically divergent subpopulations of bonobos on each side. Papa-B, the bonobo ortholog of HLA-B, includes variants having a B*53-like (B07) peptide-binding supertype profile. Here we show that B07 Papa-B occur at high frequency in TL2 bonobos and that malaria appears to have independently selected for different B07 alleles in the two subpopulations.

Frequency of class 1 human leukocyte antigen allele subtypes in Egyptian patients with idiopathic uveitis

Bacground Idiopathic uveitis is the most common uveitis type and is viewed as an inconclusive diagnosis for patients as well as physicians. Human leukocyte antigen (HLA) typing helps in understanding the pathogenesis of several diseases. Limited knowledge is known regarding the association of HLA with idiopathic uveitis. Aim This was a cross-sectional observational case–control study evaluating HLA-A and HLA-B allelic and phenotypic frequencies in patients with idiopathic uveitis. Patients and methods HLA-A and HLA-B molecular typing by PCR-sequence-specific oligonucleotide probes and LIRAS interpretation software was performed for 60 patients with idiopathic uveitis and 60 controls recruited from Kasr Al-Ainy Hospitals, Cairo University. Results Anterior uveitis pattern was the most common (55%), followed by pan-uveitis (35%) and posterior uveitis (10%). Overall, 40% of patients had bilateral uveitis, whereas 60% had unilateral uveitis. A total of 23 HLA-A and 43 HLA-B variant alleles were detected. HLA-A*09 and HLA-A*10 allele and phenotype frequencies were significantly higher in the patient group (P=0.023 and 0.034, and P=0.013 and 0.029, respectively). HLA-B*07 allele and phenotype frequencies were significantly higher in the control group (P=0.007 and 0.006, respectively). HLA-B*27 and HLA-B*05 were detected in 8.3 and 26.7%, respectively, with no significant difference. Conclusion HLA-A*09 and HLA-A*10 alleles were statistically significantly higher in patients with idiopathic uveitis. HLA-B*07 might be a protective allele against disease development. Larger cohort needs to be tested to validate these findings. Routine HLA typing and proper follow-up for primarily diagnosed idiopathic uveitis is recommended as it might reveal secondary causes for uveitis, especially in patients with positive HLA-B*27 and HLA-B*05.

Unconventional Endo-Lysosomal Assembly of Human Leukocyte Antigen B (HLA-B)

Abstract The immune system surveys the body for foreign or mutated structures with the help of the human leukocyte antigen class I (HLA-I) protein complex, which displays protein fragments called peptides on the cell surface. The genes encoding the HLA-I heavy chain in humans are highly variable, which results in predisposition to or protection from diseases based on individual HLA-I variants. We have observed that sub-optimal assembly conditions for certain HLA-B variants produce peptide-deficient molecules on the cell surface. The monocyte immune cell type overcomes this deficiency in assembly, reversing the previously observed trends. Intracellular HLA-B accumulates in monocytes and monocyte-derived dendritic cells (moDCs) in endo-lysosomal compartments, a predicted location for supplemental peptide assembly. Current findings suggest that certain HLA-B variants are better able to efficiently assemble with intracellular and extracellular antigens in the endolysosomal compartments, conferring a selective advantage in infection conditions where traditional antigen presentation is blocked.

Association of MICA and HLA‐B alleles with leprosy in two endemic populations in Brazil

Leprosy is a prevalent disease in Brazil, which ranks as the country with the second highest number of cases in the world. The disease manifests in a spectrum of forms, and genetic differences in the host can help to elucidate the immunopathogenesis. For a better understanding of MICA association with leprosy, we performed a case-control and a family-based study in two endemic populations in Brazil. MICA and HLA-B alleles were evaluated in 409 leprosy patients and in 419 healthy contacts by PCR-SSOP-Luminex-based technology. In the familial study, analysis of 46 families was completed by direct sequencing of all exons and 3'/5'untranslated regions, using the Ilumina MiSeq platform. All data were collected between 2006 and 2009. Statistical analysis was performed using the Chi-square or Fisher's exact test together with a multivariate analysis. Family-based association was assessed by transmission disequilibrium test (TDT) software FBAT 2.0.4. We found associations between the haplotype MICA*002-HLA-B*35 with leprosy in both the per se and the multibacillary (MB) forms when compared to healthy contacts. The MICA allele *008 was associated with the clinical forms of paucibacillary (PB). Additionally, MICA*029 was associated with the clinical forms of MB. The association of MICA*029 allele (MICA-A4 variant) with the susceptibility to the MB form suggests this variant for the transmembrane domain of the MICA molecule may be a risk factor for leprosy. Two MICA and nine HLA-B variants were found associated with leprosy per se in the Colônia do Prata population. Linkage disequilibrium analysis revealed perfect linkage disequilibrium (LD) between HLA-B markers rs2596498 and rs2507992, and high LD (R2 =.92) between these and the marker rs2442718. This familial study demonstrates that MICA association signals are not independent from those observed for HLA-B. Our findings contribute the knowledge pool of the immunogenetics of Hansen's disease and reveals a new association of the MICA*029 allele.

Multiple low‐frequency and rare HLA‐B allelic variants are associated with reduced risk in 1,105 nasopharyngeal carcinoma patients in Hunan province, southern China

In our study, 1,105 cases of nasopharyngeal carcinoma (NPC) and 1,430 normal controls recruited from Hunan province, southern China were typed for human leukocyte antigen (HLA)-B locus by Sanger sequencing exons 2-4. Besides confirming the NPC association with HLA-B*46:01 allele, HLA-A*02:07-B*46:01 and HLA-A*33:03-B*58:01 haplotypes (all positive), and HLA-B*13 lineage (negative), all of which were relatively common, strong negative associations were observed for five low-frequency and rare alleles or lineages, including HLA-B*07, -B*27:04, -B*39, -B*51:02 and -B*55:02, with odds ratio (OR) ranging from 0.16 to 0.3 (all pcorrected < 0.05). These strong protective associations were independent of linkage disequilibrium (LD) between HLA-A and HLA-B loci. Further analysis indicated a single amino acid change from histidine to tyrosine at residue 171 is probably crucial for the mutant allele, HLA-B*51:02, to mediate resistance to NPC. A subset of NPC cases (n = 821) and normal controls (n = 1,035) were tested for antivirus capsid antigen immunoglobulin A (anti-VCA IgA), which differed drastically between the two groups [67.7% vs. 5.5%, OR (95% confidence interval) = 36 (26.55-48.81), p < 0.0001]. HLA-B allelic variation did not associate with seropositivity for anti-VCA IgA in either group. Results from our study show, more clearly than previously, the existence of a cluster of low-frequency and rare HLA-B variants conferring low, or very low risk to NPC, a phenomenon not observed in other ethnic groups. Our data shed new insights into genetic susceptibility to NPC in southern Chinese populations. Future independent studies are warranted to replicate the findings reported in our study.

Analysis of HLA association among North Indian HIV positive individuals with and without tuberculosis

BackgroundThe inter-individual variation during HIV infection is influenced by host genetic factors (AIDS restriction genes). Class I human leukocyte antigens, especially the molecules encoded at the B locus (HLAB), are associated with increased susceptibility to acquire HIV infection and further progression to diseases (AIDS). RationaleThe aim of this study was to evaluate which variants of HLA-B are associated with the risk to acquire HIV infection in Indian population. We have recruited HIV-1 infected individuals (n = 240) with or without tuberculosis (TB) co-infection or other opportunistic infections attending the Out Patient Department (OPD) of All India Institute of Medical Sciences (AIIMS), New Delhi, India for this study. We performed HLA-A, HLAB, and HLA-DR genotyping in HIV-infected and Healthy controls. ResultsOur observation showed that the alleles HLA-A*24, B*35, B*51 and HLA DRB1*03 occurred more frequently among HIV-1 positive patients than control subjects suggests that they play a role in susceptibility to HIV-1 infection. Further, higher preponderance of HLA-B*35 (30.2% vs 24%), were also found in HIV+ cohort. An increased frequency of HLA-B*35 in HIV+,TB+ cohort correlates its possible role in the acquisition of tuberculosis infection being 1.7 fold higher in HIV positive studied subjects. ConclusionA comparative high-resolution analysis of B*35Px or B*35Py alleles among healthy controls and HIV+ individuals showed an overrepresentation of HLA-B*35Px alleles in the healthy Indian gene pool (58%) and in the HIV+ cohort (70%). The most common B*35 subtype found among the HIV infected subjects was B*3503/55 (20%; Px group), followed by B*3501 (10%; Py group). Our study concludes that the Indian gene pool possesses higher frequency of B*35Px alleles.

HLA-B*14 allele predicts HIV-1 mother-to-child-transmission, in Salvador, Brazil

BackgroundClass I human leukocyte antigens, especially the molecules encoded at the B locus (HLA-B), are associated with AIDS progression risk. Different groups of HLA-B alleles have been associated to a protective effect or increasing susceptibility to HIV infection and are expressed from the earliest stages of gestation. ObjectiveThe aim of this study was to evaluate which variants of HLA-B are associated with the risk of HIV vertical transmission in infected pregnant women and in their offspring, in a referral center in Salvador Bahia. MethodsWe performed HLA-B genotyping in 52 HIV-infected mothers and their children exposed to HIV-1 during pregnancy (N=65) in Salvador, Brazil. We compared the HLA-B alleles frequency in mothers, uninfected and infected children, according to the use of antiretroviral prophylaxis. ResultsAbsence of antiretroviral antenatal and postnatal prophylaxis was significantly associated with vertical transmission of HIV-1 (p=<0.01, and p=<0.01 respectively). Frequency of HLA-B*14 (29.2%, p=0.002), HLA-B*18 (16.7%, p=0.04) or HLA-B*14:1 (20.8%, p=0.01) alleles subgroups were significantly higher in HIV-1 infected children and persisted (HLA-B*14, p=0.04) even after adjusting for use of antiretroviral prophylaxis. No significant difference in expression of HLA-B alleles was observed among mothers who transmitted the virus compared to those who did not. ConclusionsExpression of HLA-B*14 allele in children exposed to HIV-1 is predictive of vertical transmission and reinforces the important role of genetics in mother-to-child transmission.

HIV peptidome-wide association study reveals patient-specific epitope repertoires associated with HIV control

Genetic variation in the peptide-binding groove of the highly polymorphic HLA class I molecules has repeatedly been associated with HIV-1 control and progression to AIDS, accounting for up to 12% of the variation in HIV-1 set point viral load (spVL). This suggests a key role in disease control for HLA presentation of HIV-1 epitopes to cytotoxic T cells. However, a comprehensive understanding of the relevant HLA-bound HIV epitopes is still elusive. Here we describe a peptidome-wide association study (PepWAS) approach that integrates HLA genotypes and spVL data from 6,311 HIV-infected patients to interrogate the entire HIV-1 proteome (3,252 unique peptides) for disease-relevant peptides. This PepWAS approach predicts a core set of epitopes associated with spVL, including known epitopes but also several previously uncharacterized disease-relevant peptides. More important, each patient presents only a small subset of these predicted core epitopes through their individual HLA-A and HLA-B variants. Eventually, the individual differences in these patient-specific epitope repertoires account for the variation in spVL that was previously associated with HLA genetic variation. PepWAS thus enables a comprehensive functional interpretation of the robust but little-understood association between HLA and HIV-1 control, prioritizing a short list of disease-associated epitopes for the development of targeted therapy.

A novel HLA-B variant, HLA-B*14:02:16, discovered by amplicon-based next-generation sequencing.

HLA-B*14:02:16 differs from B*14:02:01:01 by a synonymous nucleotide substitution in codon 141.

RNA processing and protein expression of HLA-B*07:44N.

The assignment of human leukocyte antigen (HLA) null alleles is clinically relevant in the setting of stem cell transplantation. Cell surface expression profiling and mRNA processing analysis of the HLA-B allele previously designated as B*07:44, have been performed. Cell surface expression of HLA-B*07:44 was determined using flow cytometry. Genomic full-length and HLA-B*07-specific cDNA sequencing were carried out by Sanger procedure. Flow cytometric analysis confirmed previous serologic results and demonstrated a lack of cell membrane expression of the HLA-B protein. The mRNA processing, studied using direct HLA-B*07-specific cDNA sequencing, revealed the presence of a unique, aberrantly spliced mRNA, with a deletion of the last 43 bp on the 5'-end of exon 4. The substitution from T to G at genomic position 1799 compared to B*07:02:01 introduced a new and stronger splice donor site at exon 4. This alternative splicing produced an mRNA containing a premature stop codon at position 280, explaining the absence of mature HLA-B7 protein on the cell surface. These findings led us to consider this HLA-B variant as a HLA null allele. The World Health Organization (WHO) Nomenclature Committee has since renamed this variant B*07:44N .

Transporter associated with antigen processing (TAP) dependencies and cell surface peptide occupancies of HLA-B allotypes

Abstract Human leukocyte antigens (HLA) class I molecules comprise a highly polymorphic heavy chain complexed to beta2-microglobulin (β2m). The heterodimers bind and display short peptides on the cell surface for intracellular surveillance by cytotoxic T cells. Peptides that assemble with HLA class I molecules are typically derived from the cytosol of cells, whereas the assembly of HLA class I occurs within the ER lumen. The transporter associated with antigen processing (TAP) is essential for peptide transport from the cytosol into the ER. In this study we showed that frequently occurring HLA-B variants display distinct patterns of TAP dependencies. Some HLA-B allotypes are detectable at significant levels in TAP-deficient and TAP-inhibited cells. Such allotypes are predominantly peptide-occupied in TAP-sufficient cells, but display higher percentages of empty protein in cells with inhibited or dysfunctional forms of TAP. TAP activity is known to be blocked by many viral proteins and in some cancers. Our findings indicate TAP dependency-influenced variations in cell surface expression and peptide occupancies of HLA-B allotypes under pathoglocical conditions.

HLA-B polymorphisms and intracellular assembly modes.

Human leukocyte antigen (HLA) class I molecules are ligands for antigen receptors of cytotoxic T cells (CTL) and inhibitory receptors of natural killer (NK) cells. The high degree of HLA class I polymorphism allows for the selection of distinct and diverse sets of antigenic peptide ligands for presentation to CTL. The extensive polymorphisms of the HLA class I genes also result in large variations in their intracellular folding and assembly characteristics. Recent findings indicate that North American HLA-B variants differ significantly in the stabilities of their peptide-deficient forms and in the requirements for the endoplasmic reticulum (ER)-resident factor tapasin for proper assembly. In HIV-infected individuals, the presence of tapasin-independent HLA-B allotypes links to more rapid progression to death. Further studies are important to better understand how the intrinsic structural characteristics of HLA class I folding intermediates affect immune responses mediated by CTL and NK cells.

Chimps, Humans, and the Hominid Struggle against Viruses.

Chimps, Humans, and the Hominid Struggle against Viruses.

HLA-B*15:327, a novel variant of HLA-B*15, discovered in a Taiwanese unrelated hematopoietic stem cell donor.

One nucleotide substitution at residue 86 of HLA-B*15:27:01 results in a new allele, HLA-B*15:327.

HLA-B*46:60, a novel variant of HLA-B*46:01:01, detected in a Taiwanese unrelated hematopoietic stem cell donor by sequence-based typing.

One nucleotide replacement at residue 89 of HLA-B*46:01:01 results in a novel allele, HLA-B*46:60.