Association between human leukocyte antigen class I and II alleles and hepatitis C virus infection in high-risk hemodialysis patients awaiting kidney transplantation

Recent evidences have shown that several host genetic factors influence susceptibility or protection to hepatitis C virus (HCV) infection. There are controversial data regarding the associations of human leukocyte antigens (HLA) and the clearance or progression of HCV. The aim of this study was to investigate whether particular HLA molecules were associated with HCV infection in recipients awaiting kidney transplantation considered at high-risk to infection due to protracted hemodialysis treatment. To this purpose, 301 kidney recipients with HCV infection and 1103 uninfected recipients were examined for HLA class I and II molecules. In our case-control study, HLA-A^*26 is positively associated with HCV infection while HLA-A^*29, -B^*40 and -DRB1^*01 are negatively associated with HCV infection. Multiple logistic regression analysis demonstrated that age (OR = 1.02; 95% CI = 1.01–1.04; p < 0.00), HLA-A^*26, -A^*29, -B^*40 and -DRB1^*01 [(OR = 1.54; 95% CI = 1.03–2.30; p = 0.03); (OR = 0.50; 95% CI = 0.26–0.99; p = 0.05); (OR = 0.42; 95% CI = 0.23-0, 7; p = 0.01); (OR = 0.62; 95% CI = 0.41-0, 94; p = 0.03); respectively] are independent predictors of HCV infection. Our results suggest that particular HLA molecules, as host genetic factors, may have a relationship with susceptibility or protection to HCV infection also in recipients awaiting kidney transplantation.     

Human leukocyte antigen class I alleles and haplotypes associated with primary hepatocellular carcinoma in persistent HBV-infected patients

Many studies have shown that Human leukocyte antigen (HLA) class I alleles are associated with the development of various cancers. However, its role in hepatocellular carcinoma (HCC) is still unknown. To investigate whether HLA class I allelic polymorphism is related to the development of hepatitis B virus(HBV)-associated HCC, a total of 326 HBV-infected patients (138 individuals with HCC and 188 well-matched controls without HCC) were enrolled in this study. HLA-A, -B, and -C were genotyped by polymerase chain reaction–sequencing based typing (PCR-SBT) method. We identified HLA-B^∗35:01:01G as a risk factor for HBV-related HCC development independent of our previous findings in HLA region (OR, 12.04; p, 0.0028; pc, 0.04). HLA-A^∗11:01:01G, B^∗58:01:01G, C^∗03:02:01G and some of their extended haplotypes were found as potential susceptible factors for HCC development. HLA-B^∗46:01:01G and some of its extended haplotypes were found as potential protective factors for HCC development. Our results support that specific HLA class I alleles and haplotypes may affect the risk of HBV-related HCC development. The findings may help to determine better approaches for prevention and treatment of HCC in these patients.     

Frequent human leukocyte antigen class I alleles are associated with higher viral load among HIV type 1 seroconverters in Thailand

The loss of viral control by the host may be due to the evolution of viruses with mutations that limit presentation by human leukocyte antigen (HLA) to cytotoxic T cells. The authors hypothesized that the consequence of such evolution might be that persons with common HLA class I alleles would be less able to control viremia, on average, than would those with rare alleles. HLA class I typing was completed for 128 injection drug users who seroconverted in a prospective cohort study in Bangkok, Thailand. Logistic regression was used to model viral load (greater than or equal to the median) at 9 and 12 months after seroconversion with an HLA score that profiled the relative prevalence of each individual's alleles. At 12 months after seroconversion, injection drug users with the most common HLA alleles (highest quartile HLA score) had an almost 4-fold increased risk for higher viral load (> or = 32,055 copies/mL) than injection drug users with less common HLA alleles (adjusted odds ratio, 3.92; 95% confidence interval, 1.3-11.8). These findings support the importance of frequency-dependent effects of host genes on HIV type 1 evolution in different populations and suggest that HLA-driven viral evolution critically influences control of viremia in early HIV type 1 infection.     

Evolution and selection of human leukocyte antigen alleles by Plasmodium falciparum infection

Infection by Plasmodium falciparum malaria was one of the major driving forces for the selection of various genes, some of which might be involved in protection against this infection. The human leukocyte antigen (HLA) system is a highly polymorphic supergene complex with extensive diversity across different populations. In areas traditionally endemic for malaria for centuries, there seems to be some selection of certain HLA alleles that may somehow be involved in protection against the infection. One of the major conundrums is the lack of homogeneity in the HLA alleles selected by P. falciparum across different populations. Various factors like microheterogeneity in parasite species, genetic drift in parasitic antigens, varying intensities of transmission, different polymorphisms of red cell antigens, and diversity in the HLA system have exerted selection pressure, which probably determined the emergence of different dominant HLA antigens in different endemic populations. The complex life cycle of P. falciparum, with different antigens becoming important at different phases of the cycle and invasion of different tissues causing different clinical manifestations of the same disease, is also another significant factor contributing to a selection pattern. Evolutionary selection pressure probably selected different HLA antigens for modulations of different components of the disease as well as the severity of the disease. A coevolution, where the parasite polymorphisms meet the host heterogeneity, is likely to have occurred, resulting in the selection of a few HLA antigens associated with P. falciparum infection. Data might have been overwhelmed by the noise of additional selection pressure exerted by other infectious agents prevalent in endemic areas of P. falciparum malaria.     

Generic human leukocyte antigen class II (DRB1 and DQB1) alleles in patients with paracoccidioidomycosis.

Human leukocyte antigen (HLA) class II alleles are involved in antigen processing and in the presentation of antigens to T lymphocytes. Few studies have investigated HLA genes in paracoccidioidomycosis. In the present investigation, we analyzed the distribution of the HLA class II alleles DRB1 and DQB1 in 45 healthy volunteers and in 80 patients with paracoccidioidomycosis. The patients presented with various clinical forms of the disease, and allele distribution was evaluated individually in each presentation type. In patients with the unifocal chronic form of the disease, a mild clinical presentation in which lesions are restricted or localized, the HLA allele most commonly seen was DRB1*11 (p<0.039). This suggests that the participation of HLA antigens may influence the outcome of the host-parasite interaction in paracoccidioidomycosis, regulating the immune response to Paracoccidioides brasiliensis antigens.     

Effect of human leukocyte antigen class I and II alleles on hepatitis C viral load among chronic hepatitis C patients in Southern Taiwan

The viral load of hepatitis C virus (HCV) in chronic hepatitis C patients affects clinical outcomes and response to interferon treatment. Various factors may be involved in determining the viral load, including host genetic factors. The aim of this study was to investigate the relationship between HCV viral load and human leukocyte antigen (HLA) class I and class II alleles. One hundred and six HCV RNA positive subjects were enrolled, and viral load was measured. HLA-A, -B, -C, -DR, and -DQ loci were determined by sequence-based genotyping. Univariate analysis indicated that HLA-B^∗40 and HLA-C^∗07 alleles had significantly higher HCV RNA levels (P < 0.05). Patients with the HLA-C^∗15 allele exhibited a trend toward a lower HCV viral load (P = 0.06). After controlling for confounding factors, multivariate analysis revealed that only HLA-C^∗15 allele was identified as a significant determinant for HCV-RNA level (slope = −0.91, 95% CI: −1.58, −0.24; Holm’s P < 0.01). Patients expressing the HLA-C^∗15 allele had significantly lower HCV RNA levels. HCV genotype 1 was significantly associated with high HCV RNA levels (P < 0.05 by Mann–Whitney U test). In conclusion, HLA-C^∗15 is an important host immunogenetic factor with an inverse association to HCV viral load in CHC patients in Taiwan. HCV genotype 1 is the viral factor that associated with high viral load.     

Role of class I human leukocyte antigen molecules in early steps of echovirus infection of rhabdomyosarcoma cells

Several echoviruses use decay accelerating factor (DAF) as a cell surface receptor. However, most of them require additional cell surface coreceptors. We investigated the respective roles of DAF and class I human leukocyte antigen (HLA) molecules in the early steps of the echovirus 11 (EV11) lifecycle in rhabdomyosarcoma (RD) cells. EV11 infection was inhibited at an early stage by anti-β2-microglobulin (β2m) and anti-HLA monoclonal antibodies and by a soluble monochain HLA class I molecule. Expression of class I HLA molecules restored the early steps of the EV11 lifecycle, but its expression was not sufficient for EV11 replication and particle production. Expression of HLA class I molecules was associated with leukocyte cell line permissiveness to EV11 infection. In conclusion, HLA class I molecules are involved in the early steps of EV11 infection of RD cells and appear to participate in a complex interplay of surface molecules acting as coreceptors, including DAF.     

Human leukocyte antigen class II alleles in Caucasian women with primary biliary cirrhosis

In the current study, we investigated human leukocyte antigen (HLA) class II alleles in Caucasian women with primary biliary cirrhosis (PBC), a disease that preferentially affects women. Alleles of DRB1, DQA1, and DQB1 were determined by DNA-based HLA typing for women with PBC (n = 72) and healthy women (n = 381). All study subjects were Caucasian. HLA DRB1*08 was significantly increased in women with PBC compared to healthy women. The increase was primarily due to the DRB1*0801 allele, also the most common DRB1*08 allele among controls. DQB1*04 and DQA1*0401 were significantly increased. DRB1*1501, DQA1*0102, and DQB1*0602 were associated with decreased risk. Analyses conducted comparing parous women with PBC to parous healthy women (n = 68 and n = 282, respectively) yielded similar significant results. Although the DRB1*08-DQA1*0401-DQB1*04 haplotype was significantly associated with PBC, consistent with other studies, this haplotype nevertheless represented only 19% (14/72) of all PBC patients and can account for only a minority of the risk of PBC.     

Gluten-dependent enteropathy and atypical human leukocyte antigen alleles

The risk for developing celiac disease is associated with the major histocompatibility complex class II human leukocyte antigen DQ2 and DQ8. We retrospectively reviewed the medical records of 127 consecutive cases of adult-onset celiac disease evaluated at a single United States center to determine the distribution of the associated human leukocyte antigen DQA1 and DQB1 alleles. The median patient age of diagnosis was 41 (range, 16-81) years. Ninety-five adults underwent human leukocyte antigen DQ typing. Eighty patients were DQ2 positive, 24 were DQ8 positive, and 11 were DQ2 and DQ8 positive. Four patients carried the uncommon, low-risk haplotype DQ2.2 (DQA1*02 and DQB1*02) without DQA1*05. Two patients did not carry human leukocyte antigen DQ2 or DQ8. All of the patients with atypical human leukocyte antigen DQ responded to a gluten-free diet. Although the majority of patients carry the human leukocyte antigen DQ2 or DQ8, gluten-dependent enteropathy periodically presents in adults with low-risk alleles.     

A crypto-Dravidian origin for the nontribal communities of South India based on human leukocyte antigen class I diversity

The Dravidian communities are considered to be the original inhabitants of India, now restricted to South India. The southern most state, Kerala, is socio-culturally stratified into Hindus, Muslims and Christians on the basis of religion. The origin of these religious communities in Kerala is considered to be unique in comparison with that in other parts of the country. These communities were later influenced by the hierarchical caste structure established by the Hindu Brahmins. In the present study, we compared six nontribal (Namboothiri, Nair, Ezhava, Pulaya, Malabar Muslim and Syrian Christian) communities belonging to the major religious groups in Kerala (Hindu, Muslim and Christian) based on the human leukocyte antigen (HLA)-A, -B and -C diversity. Our aim was to understand the genomic substructuring associated with the changing social scenario in various caste and religious groups and compare it with the Dravidian tribal and other world populations. The present study reveals that the HLA diversity of the Dravidian communities is very distinct from that in the other world populations. It is obvious that the nontribal communities of Kerala display a greater Dravidian influence, but traces of genetic admixture with the Mediterranean, western European, central Asian and East Asian populations can be observed. This characterizes the crypto-Dravidian features of the nontribal communities of Kerala. Demic diffusion of the local progressive communities with the migrant communities may have given rise to crypto-Dravidian features among the nontribal communities of Kerala.     

MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India

Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA-DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P<0.0001), DQA1*0101 (P=0.001), and DQB1*0503 (P<0.0001). These associations were due to the increased frequencies of the haplotype HLA-DRB 1 * 1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p<0.0001). Also, patients from Ahmedabad had a significant increase in HLA-DQB 1*0302 (p=0.03). An identical amino acid sequence (Leu-Leu-Glu-Arg-Arg-Arg-Ala-Glu), in positions 67–74 of the P domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA-DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB 1*0503 and the association with HLA-DR14 alleles would be the result of linkage disequilibrium. Third, the HLA-DRB 1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared by several HLA-DR14 alleles.     

Structural aspects of human leukocyte antigen class I epitopes detected by human monoclonal antibodies

This study addresses the concept that human leukocyte antigen (HLA) class I–specific alloantibodies are specific for epitopes that correspond to HLAMatchmaker-defined eplets. Eplets are essential parts of so-called structural epitopes that make contact with the 6 complementarity determining regions of an antibody. From published molecular models of crystallized protein antigen–antibody complexes, we have calculated that contact residues on structural HLA epitopes should reside within a 15-Å radius of a mismatched eplet. This study addresses the structural basis of high-frequency HLA class I epitopes reacting with human monoclonal antibodies (mAbs) derived from women sensitized during pregnancy. All mAbs were tested in Luminex assays with single HLA allele panels. The HLAMatchmaker algorithm was used to determine their specificity in context with eplet sharing between the immunizing allele and antibody-reactive alleles. To assess the autoreactive B cell origin of these antibodies, we have applied the recently developed nonself–self paradigm of epitope immunogenicity to analyze residue differences between the immunizer and the alleles of the antibody producer. A total of 9 mAbs were specific for epitopes associated with the 41T, 80NRG, 163LW, 69AA, or 80ERILR eplets. In each case, the immunizing allele had within 15 Å of the mismatched eplet, no residue differences with 1 of the alleles of the antibody producer. This observation is consistent with the concept that these mAbs originated from B cells with self HLA immunoglobulin receptors. Eplet-carrying alleles exhibited different levels of reactivity, which, when compared with the immunizing allele, ranged from high to intermediate to very low. In many cases, lower reactivities were associated with differences from self to nonself residues in surface locations within 15 Å of the specific eplet. Apparently, such locations may serve as critical contact sites for the antibody. In other cases, other residue differences did not appear to affect binding with the antibody, suggesting that these locations do not play a major role in antibody binding. For these mAbs we did not obtain convincing evidence that residue differences in hidden positions below the molecular surface had significant effects on antibody binding. These findings have increased our understanding of the structural basis of the immunogenicity and antigenicity of HLA class I epitopes and provide a basis for interpreting HLA antibody reactivity patterns in Luminex assays with single alleles.     

The influence of human leukocyte antigen class I alleles and their population frequencies on human immunodeficiency virus type 1 control among African Americans

Populations of African ancestry continue to account for a disproportionate burden of the human immunodeficiency virus type 1 (HIV-1) epidemic in the United States. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in 2 cohorts: Reaching for Excellence in Adolescent Care and Health (REACH) and HIV Epidemiology Research Study (HERS). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4(+) T cells were examined both separately and combined to represent 3 categories of HIV-1 disease control (76 controllers, 169 intermediates, and 93 noncontrollers). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with 1 or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and nongenetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection cross the boundaries of race and viral subtype, whereas others appear confined within one or the other of those boundaries.     

Novel human leukocyte antigen class I and class II alleles identified by sequence-based typing in the Genetics of Kidneys in Diabetes (GoKinD) study population

Nine novel HLA class I and class II alleles were identified by sequence-based typing (SBT) in Caucasian participants from the Genetics of Kidneys in Diabetes (GoKinD) study. All novel alleles were single nucleotide substitutions. Seven alleles resulted in an amino acid change and two alleles were silent substitutions. The new alleles are as follows: five HLA-A alleles (*0132, *020121, *0344, *030107, *2507), one HLA-C allele (*0619), two HLA-DQB1 alleles (*0204, *0318), and one HLA-DPB1 allele (*1802). Eight of these new alleles were identified in participants with type 1 diabetes, three of whom also had diabetic nephropathy, and one new allele was identified in an unaffected parent of a participant with type 1 diabetes. All new alleles were isolated and characterized by use of single allele amplification (SAA) SBT; the new alleles were confirmed by sequence-specific primer (SSP) amplification.     

Human leukocyte antigen class II alleles and risk of cervical cancer in China

Human leukocyte antigen (HLA) class II alleles have been associated with an increased or decreased risk of developing cervical cancer through infection with oncogenic forms of human papillomavirus (HPV). To verify whether HLA class II allelic polymorphism is related to cervical cancer in China, 133 cervical cancers and 98 healthy controls were analyzed for HLA typing. Our results showed that DPB1*1301 allele frequency was significantly higher in the cervical cancers compared with healthy controls (OR, 3.793; p = 0.002; Pc = 0.04). A significant relationship was found between DRB1*150101-DQB1*0602 haplotype (OR, 0.180; p < 0.0001; Pc < 0.003), DRB1*070101-DQB1*0201 haplotype (OR, 0.110; p = 0.001; Pc = 0.03), and decreased risk for cervical cancer. Similar tendencies were observed for DRB1*150101-DQB1*0602 haplotype with HPV16 positive cervical cancers (OR, 0.182; p = 0.001; Pc = 0.021), and for DRB1*070101-DQB1*0201 haplotype (OR, 0.144; p =0.003; Pc = 0.063). These results indicate that HLA-DPB1*1301 may confer susceptibility to cervical cancer, and the haplotypes DRB1*150101-DQB1*0602 and DRB1*070101-DQB1*0201 may contribute to the resistance to the development of cervical cancer among Chinese women. The study suggests that specific HLA class II alleles and haplotypes may influence the immune response to specific HPV-encoded epitopes and affect the risk of cervical cancer in a Chinese population from an area with a high incidence of this neoplasia.     

Susceptible and protective human leukocyte antigen class II alleles and haplotypes in bahraini type 2 (non-insulin-dependent) diabetes mellitus patients

Whereas the genetic risk for type 1 diabetes is linked to human leukocyte antigen (HLA) class II genes, the HLA association in type 2 (non-insulin-dependent) diabetes is less clear. The association between HLA class II genotypes and type 2 diabetes was examined in adult Bahrainis, an Arab population with a high prevalence of type 2 diabetes. HLA-DRB1* and -DQB1* genotyping of 86 unrelated type 2 diabetes patients (age, 51.6+/-8.2 years; mean duration of diabetes, 7.7+/-7.1 years) who had a strong family history of diabetes (52 of 72 versus 0 of 89 for controls, P<0.001) and 89 healthy subjects was done by PCR-sequence-specific priming. DRB1*040101 (0.1221 versus 0.0562, P=0.019) and DRB1*070101 (0.2151 versus 0.0843, P<0.001) were positively associated, while DRB1*110101 (0.0698 versus 0.1461, P=0.014) and DRB1*160101 (0.0640 versus 0.1236, P=0.038) were negatively associated with type 2 diabetes. DRB1*040101-DQB1*0302 (0.069 versus 0.0007; P=0.004), DRB1*070101-DQB1*0201 (0.178 versus 0.0761, P=0.007), DRB1*070101-DQB1*050101 (0.125 versus 0.0310, P=0.002), and DRB1*150101-DQB1*060101 (0.0756 versus 0.0281, P=0.008) were more prevalent among patients, while DRB1*160101-DQB1*050101 (0.0702 versus 0.0349, P=0.05) was more prevalent among controls, conferring disease susceptibility or protection, respectively. In Bahrainis with type 2 diabetes, there is a significant association with select HLA class II genotypes, which were distinct from those in type 1 diabetes.     

Particular human leukocyte antigen alleles are associated with biochemical traits in the Japanese population

We analyzed genetic associations among 7 biochemical traits (fasting plasma glucose, HbA1c, total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein cholesterol, triglyceride, and uric acid) and 6 HLA loci using 1,616 individuals who visited the Health Evaluation and Promotion Center at Tokai University Hospital. Significant differences between the individuals carrying particular HLA alleles and those not carrying the alleles in certain biochemical traits were observed by Mann-Whitney U test. In female subjects, DPB1*03:01 was significantly associated with HbA1c (p = 0.0000665), and DRB1*14:03 was associated with total cholesterol concentration (p = 0.0015). In male subjects, C*14:02 demonstrated significant associations with fasting plasma glucose with p values of 0.0041. By contrast, Fisher's exact test indicated that female DRB1*14:03 was associated with a high concentration of total cholesterol (p = 000323, odds ratio [OR] = 4.32, 95% confidence interval [95% CI] = 1.83-10.36), whereas female DPB1*02:01 had a protective effect against a high concentration of LDL cholesterol (p =0.0043, OR = 0.41, 95% CI = 0.19-0.79). These associations have a statistical power of more than 0.8 and still retain significance after Bonferroni correction.     

Human leucocyte antigen Class I and II alleles associated with anti-hepatitis C virus-positive patients of North India

Purpose: Humans are the only known natural hosts of hepatitis C virus (HCV). This study was undertaken to examine the frequencies of human leucocyte antigens (HLAs) Class I and Class II genotype profiles in anti-HCV-infected patients of Northern India. Materials and Methods: From a period of January 2013 to August 2014, 148 anti-HCV-positive patients of North India referred to the Department of Molecular Biology and Transplant Immunology, Indraprastha Apollo Hospitals, New Delhi, for performing HLA typing were included in the study. Results: A*02, A*31 allele frequency decreased significantly in anti-HCV-positive patients. Frequencies for HLA-B loci did not reach any statistical significance. Among the Class II alleles, HLA-DRB1*03 and HLA-DRB1*10 were significantly higher in the patient population, and HLA-DRB1*15 was significantly decreased in the patient population as compared to the controls. Conclusion: HLA-A*33 was significantly increased as compared to control population and showed geographic variation in HCV-infected individuals of India.