Human leukocyte antigen profile in HIV-1 infected individuals and AIDS patients from Chongqing, China

HIV/AIDS is currently the leading cause of infectious disease mortality around the world. Since many alleles and/or haplotypes of HLA have been reported to be associated with progressive HIV infection, more detailed information on the HLA profile in HIV‐1 infected individuals in Chongqing, southwest China would facilitate further understanding of HIV‐1 infection, help AIDS vaccine design and the planning of effective preventive strategies. In this study, we performed 4‐digit resolution HLA‐A, B, DRB1 genotyping of 759 HIV‐1 seropositive individuals using PCR‐SSO methods. Six alleles were found at more than 10% high frequency: A*1101, A*0201, A*2402, B*4601, B*4001 and DRB1*0901. The most common 2‐ and 3‐locus haplotypes were A*0201‐B*4601, A*1101‐B*4001, A*1101‐B*4601, A*3303/1‐B*5801, A*0201‐B*4601‐DRB1*0901, A*1101‐B*4601‐DRB1*0901 and A*3303/1‐B*5801‐DRB1*0301. 690 HIV‐1 seropositive individuals with records of CD4 counts were divided into two groups: an AIDS patient group comprising 216 subjects with AIDS‐defining symptoms and CD4 counts below 200 cells/mm³ and an asymptomatic, HIV seropositive group of 474 subjects with a stable CD4 count of no less than 200 individuals. In the AIDS patient group, A*3303/1 and B*5801 alleles and the A*3303/1‐B*5801 haplotype were significantly underrepresented as compared to the HIV‐infected group, whereas A*1101‐B*4001, A*1101‐B*1502, A*2402‐B*4801 haplotypes and five common haplotypes from two groups were significantly overrepresented. HLA‐A or B and HLA‐Bw6‐Bw6 homozygotes were also overrepresented in the AIDS patients group. Our observations suggest that the presence of the B*3501 allele, A*2402‐B*4801, common 2‐locus and 3‐locus haplotypes, HLA‐A or B and Bw6‐Bw6 homozygosity may predict a poor disease outcome in HIV‐1 infection. However, HIV‐1 infected individuals who have B*5801 alleles, A*3303/1‐B*5801 haplotype and are heterozygous for Bw4‐Bw6 are more likely to be resistant to progression of AIDS in this Chinese population.     

High Resolution Human Leukocyte Antigen Class I Allele Frequencies and HIV-1 Infection Associations in Chinese Han and Uyghur Cohorts

Background

Host immunogenetic factors such as HLA class I polymorphism are important to HIV-1 infection risk and AIDS progression. Previous studies using high-resolution HLA class I profile data of Chinese populations appeared insufficient to provide information for HIV-1 vaccine development and clinical trial design. Here we reported HLA class I association with HIV-1 susceptibility in a Chinese Han and a Chinese Uyghur cohort.

Methodology/Principal Findings

Our cohort included 327 Han and 161 Uyghur ethnic individuals. Each cohort included HIV-1 seropositive and HIV-1 seronegative subjects. Four-digit HLA class I typing was performed by sequencing-based typing and high-resolution PCR-sequence specific primer. We compared the HLA class I allele and inferred haplotype frequencies between HIV-1 seropositive and seronegative groups. A neighbor-joining tree between our cohorts and other populations was constructed based on allele frequencies of HLA-A and HLA-B loci. We identified 58 HLA-A, 75 HLA-B, and 32 HLA-Cw distinct alleles from our cohort and no novel alleles. The frequency of HLA-B*5201 and A*0301 was significantly higher in the Han HIV-1 negative group. The frequency of HLA-B*5101 was significantly higher in the Uyghur HIV-1 negative group. We observed statistically significant increases in expectation-maximization (EM) algorithm predicted haplotype frequencies of HLA-A*0201-B*5101 in the Uyghur HIV-1 negative group, and of Cw*0304-B*4001 in the Han HIV-1 negative group. The B62s supertype frequency was found to be significantly higher in the Han HIV-1 negative group than in the Han HIV-1 positive group.

Conclusions

At the four-digit level, several HLA class I alleles and haplotypes were associated with lower HIV-1 susceptibility. Homogeneity of HLA class I and Bw4/Bw6 heterozygosity were not associated with HIV-1 susceptibility in our cohort. These observations contribute to the Chinese HLA database and could prove useful in the development of HIV-1 vaccine candidates.     

内蒙古地区蒙古族HLA-A、B、DRB1基因座多态性分析

应用序列特异性寡核苷酸探针反向斑点杂交技术对内蒙古地区蒙古族106名无关健康个体的HLA-A、B和DRB1 基因座进行基因分型, 以研究内蒙古地区蒙古族人群HLA-A、B、DRB1基因座的等位基因及其组成的单倍型频率分布特征。 采用最大数学预期值算法计算HLA基因座的等位基因频率和单倍型频率。106 名内蒙古地区蒙古族个体的HLA-A、B、DRB1基因座分别检出13、29、13个等位基因。高频单倍型分别为 HLA-A*02-B*46 (0.0510); HLA-A*02-B*13(0.0495); HLA-A*02-B*51(0.0442); HLA-B*13-DRB1*07 (0.0555); HLA- B*46-DRB1*09(0.0378); HLA-B*35-DRB1*13(0.03300); HLA-A*02-B*13-DRB1*07(0.033019); HLA-A*02-B*46- DRB1*09(0.031985)。研究表明: 内蒙古地区蒙古族人群HLA基因座的等位基因和单倍型具有较高的遗传多态性。HLA- A*24-B*14, HLA-A*32-B*63在该民族具有极强的连锁不平衡。     

中国新疆维族人群HLA-B等位基因与HIV-1感染易感性或抗性

通过对中国维吾尔族人群HLA-B等位基因的分布频率的研究,探讨HLA-B等位基因与HIV感染的易感 或抵抗性的相关性。本研究用PCR-SSP的方法对新疆维吾尔族110例无相关的健康对照者(HIV阴性)和128例 HIV阳性感染者进行HLA-B等位基因分型。用POPGEN软件对健康对照者人群进行Hardy-Weinberg平衡检 测,用卡方检验分析HLA-B等位基因在健康对照者和HIV阳性感染者频率分布的差异。在HIV-1阳性感染者 中,B*4901等位基因频率显著性增加(B*4901:P=0．02．OR=3．06,95%CI=1．16～8．10)。而在健埭对照者 中,B*40等位基因顿率增加具有统计意义(B*40:P=0．02．OR=0．39．95％CI=0．07～0．92)。由此可见,B* 4901等位基因可能与HIV-1感染的易感性有关,而B*40等位基因可能与与HIV-1感染的抵抗性有关。     

中国新疆维族人群HLA-B等位基因与HIV-1感染易感性或抗性

通过对中国维吾尔族人群HLA-B等位基因的分布频率的研究,探讨HLA-B等位基因与HIV感染的易感/或抵抗性的相关性.本研究用PCR-SSP的方法对新疆维吾尔族110例无相关的健康对照者(HIV阴性)和128例HIV阳性感染者进行HLA-B等位基因分型.用POPGEN软件对健康对照者人群进行Hardy-Weinberg平衡检测,用卡方检验分析HLA-B等位基因在健康对照者和HIV阳性感染者频率分布的差异.在HIV-1阳性感染者中,B*4901等位基因频率显著性增加(B*4901P=0.02,OR=3.06,95%CI=1.16～8.10).而在健康对照者中,B*40等位基因频率增加具有统计意义(B*40P=0.02,OR=0.39,95%CI=0.07～0.92).由此可见,B*4901等位基因可能与HIV-1感染的易感性有关,而B*40等位基因可能与与HIV-1感染的抵抗性有关.     

Frequency of HLA-A*03 associates with HIV-1 infection in a Chinese cohort

During the early mid-1990s, a number of rural farmers across central China were employed to the unregulated plasmaselling-activity and many of them were infected by HIV-1. However, AIDS progression in the former blood donors (FBDs) is various. The aim of this study is to assess human leukocyte antigen (HLA) class I allele distribution in FBDs and evaluate its association with HIV-1 infection and disease progression. A total of 353 FBDs were enrolled in the cohort including 294 ART naïve HIV-1 seropositive and 59 HIV-1 seronegative age-matched subjects. The viral load and CD4/CD8 T cell counts were assessed in all subjects. Compared with HIV-seropositive group, the frequency of HLA-A*03 in control was significantly higher. After classifying the HLA-B alleles of the subjects according to the presence of Bw4/Bw6 serological epitopes, detrimental effect of HLA Bw6/ Bw6 homozygosity was also confirmed in the HIV-seropositive subjects. This study provides novel evidence on HLA class I allele distribution and association of HLA-A*03 frequency with HIV-1 infection and viremia in the HIV-1 infected FBDs, which may throw light on intervention strategy for the HIV-1 infection and our understanding how host immunity and genetic background affect HIV infection and AIDS progression.     

Analysis of HLA DR2&;DQ6 (DRB1*1501, DQA1*0102, DQB1*0602) Haplotypes in Iranian Patients with Multiple Sclerosis

Multiple sclerosis (MS) is prototype of inflammatory demyelinating disease of the central nervous system .The etiology of MS remains unclear, but according to current data the disease develops in genetically susceptible individuals and may require additional environmental triggers. The human leukocyte antigen (HLA) class II alleles (DRB1*1501, DQA1*0102, DQB1*0602) may have the strongest genetic effect in MS. In this study, the role of these alleles were investigated in 183 Iranian patients with multiple sclerosis and compared with 100 healthy individuals. HLA typing for DRB1*1501, DQA1*0102, DQB1*0602 was performed by polymerase chain reaction (PCR) amplification with sequence-specific primers (PCR-SSP) method. The results show that, HLA DR B1*1501 was significantly more frequent among MS patients (46% vs. 20%, PV = 0.0006) but DQA1*0102 haplotype was negatively associated with MS (30% vs. 50%, PV = 0.0049) and no significant association was found with DQB1*0602 and MS patients in comparison with control group (24% and 30%, PV = 0.43). No significant correlation was observed among these alleles with sex, type of disease; initial symptoms, expanded disability status scale (EDSS), as well as age at onset and familial MS. This study therefore indicates that there is no association of above HLA haplotypes with clinical presentation, disease duration, and disability in Iranian patients with MS which is in line with other previous studies in different ethnic groups.     

Relationship of HLA-A,-Cw polymorphisms with HIV/AIDS in Chinese Yi ethnic group of Sichuan province

The relationship of HLA-A,-Cw alleles on HIV infection and AIDS disease progression in the Chinese Yi ethnic group of Sichuan province were investigated. The genetic polymorphisms of HLA-A,-Cw alleles of 102 unrelated healthy Chinese Yi ethnic individuals, 68 HIV-1 infected and 21 HIV positive long-time survivors were typed by PCR-SSP assay. Statistic significance was determined by the x ² test with the SPSS software. No significant differences were observed between the HLA-A,-Cw alleles of the 68 HIV-1 infected and 102 non-infected Chinese Yi control individuals. Whereas the prevalence of A*3601,Cw*14(01-03)and Cw*0304 was significantly higher in 21 long time survivors compared with 102 healthy controls with P values of 0.016, 0.016 and 0.000 by x ² or the Fisher exact test respectively. The result implies that A*3601,Cw*14(01-03) and Cw*0304 may be associated with slow AIDS disease progression in the Chinese Yi ethnic group, further studies on this association may yield insight on the pathogenesis of HIV-1 infection. Foundation items: the 10^th Five-Years Key Technologies R&D Program (2004BA719A01) and 973 Program (2006 CB 504207)     

Allele and haplotype frequencies of human leukocyte antigen-A, -B, -C,-DRB1, and -DQB1 in Chinese patients with hematological diseases

The human leukocyte antigen (HLA) system plays a central role in the immune response to pathogens, as well as in organ and allogenic hematopoietic stem cell transplantation (HSCT). Finding a five-locus (i.e., HLA-A, -B, -C, -DRB1, and -DQB1) matched unrelated donor for a patient awaiting HSCT is a major clinical challenge, due to the lack of HLA-identical sibling donors and the high polymorphism of HLA. To date, most studies providing HLA allele frequencies (AF) and haplotype frequencies (HF) in Chinese populations have focused on donors instead of the recipients and have provided data for three loci (HLA-A, -B, and -DR); however, data from five-locus HLA typing in a large sample of patients, especially those with hematological diseases, remains unavailable. Therefore, this study was designed to determine HLA AF and two-, three-, four- and five-locus HF in a large cohort of Chinese Han patients with hematological diseases. The AF and the HF were determined using high-resolution HLA typing data from 2,878 patients. The total number of HLA-A, -B, -C, -DRB1, and -DQB1 alleles was determined to be 48, 92, 49, 52, and 24, respectively. Hardy-Weinberg equilibrium (HWE) analyses indicated significant deviations from HWE for HLA-A, -C, -DRB1, and -DQB1 AF, but not for HLA-B locus. The three most common alleles at each locus were A*11:01, A*24:02, A*02:01; B*46:01, B*40:01, B*13:02; C*01:02, C*07:02, C*06:02; DRB1*09:01, DRB1*15:01, DRB1*07:01; DQB1*03:01, DQB1*03:03, and DQB1*06:01. Our data may help to determine whether the current bone marrow registry contains sufficient diversity to meet the demand.     

HIV-1 disease-influencing effects associated with ZNRD1, HCP5 and HLA-C alleles are attributable mainly to either HLA-A10 or HLA-B*57 alleles

A recent genome-wide association study (GWAS) suggested that polymorphisms in or around the genes HCP5, HLA-C and ZNRD1 confer restriction against HIV-1 viral replication or disease progression. Here, we also find that these alleles are associated with different aspects of HIV disease, albeit mainly in European Americans. Additionally, we offer that because the GWAS cohort was a subset of HIV-positive individuals, selected based in part on having a low viral load, the observed associations for viral load are magnified compared with those we detect in a large well-characterized prospective natural history cohort of HIV-1-infected persons. We also find that because of linkage disequilibrium (LD) patterns, the dominant viral load- and disease-influencing associations for the ZNRD1 or HLA-C and HCP5 alleles are apparent mainly when these alleles are present in HLA-A10- or HLA-B*57-containing haplotypes, respectively. ZNRD1 alleles lacking HLA-A10 did not confer disease protection whereas ZNRD1-A10 haplotypes did. When examined in isolation, the HCP5-G allele associates with a slow disease course and lower viral loads. However, in multivariate models, after partitioning out the protective effects of B*57, the HCP5-G allele associates with disease-acceleration and enhanced viral replication; these associations for HCP5-G are otherwise obscured because of the very strong LD between this allele and a subset of protective B*57 alleles. Furthermore, HCP5 and HLA-C alleles stratify B*57-containing genotypes into those that associate with either striking disease retardation or progressive disease, providing one explanation for the long-standing conundrum of why some HLA-B*57-carrying individuals are long-term non-progressors, whereas others exhibit progressive disease. Collectively, these data generally underscore the strong dependence of genotype-phenotype relationships upon cohort design, phenotype selection, LD patterns and populations studied. They specifically demonstrate that the influence of ZNRD1 alleles on disease progression rates are attributable to HLA-A10, help clarify the relationship between the HCP5, HLA-C and HLA-B*57 alleles, and reaffirm a critical role of HLA-B*57 alleles in HIV disease. Furthermore, as the protective B*57-containing genotypes convey striking salutary effects independent of their strong impact on viral control, it is conceivable that T cell-based therapeutic vaccine strategies aimed at reducing viral loads may be inadequate for limiting AIDS progression, raising the potential need for complementary strategies that target viral load-independent determinants of pathogenesis.     

Polymorphism, recombination, and linkage disequilibrium within the HLA class II region.

Thirty-nine CEPH (Centre d'Etude du Polymorphisme Humain) families, comprised of 502 individuals, have been typed for the HLA class II genes DRB1, DQA1, DQB1, and DPB1 using nonradioactive sequence-specific oligonucleotide probes to analyze polymerase chain reaction amplified DNA. This population, which consists of 266 independent chromosomes, contains 27 DRB1, 7 DQA1, 12 DQB1, and 17 DPB1 alleles. Analysis of the distribution of allele frequencies using the homozygosity statistic, which gives an indication of past selection pressures, suggests that balancing selection has acted on the DRB1, DQA1, and DQB1 loci. The distribution of DPB1 alleles, however, suggests a different evolutionary past. Family data permits the estimation of recombination rates and the unambiguous assignment of haplotypes. No recombinants were found between DRB1, DQA1, and DQB1; however, recombinants were detected between DQB1 and DPB1, resulting in an estimated recombination fraction of greater than or equal to 0.008 +/- 0.004. Only 33 distinct DRB1-DQA1-DQB1 haplotypes were found in this population which illustrates the extreme nonrandom haplotypic association of alleles at these loci. A few of these haplotypes are unusual (previously unreported) for a Caucasian population and most likely result from past recombination events between the DR and DQ subregions. Examination of disequilibrium across the HLA region using these data and the available serologic HLA-A and HLA-B types of these samples shows that global disequilibrium between these loci declines with the recombination fraction, approaching statistic nonsignificance at the most distant interval, HLA-A to HLA-DP.DR-DQ haplotypes in linkage disequilibrium with DPB1 and B are noted and, finally, the evolutionary origin of certain class II haplotypes is addressed.     

Molecular analysis of human leukocyte antigen class I and class II allele frequencies and haplotype distribution in Pakistani population

AIM:

Distribution of HLA class I and II alleles and haplotype was studied in Pakistani population and compared with the data reported for Caucasoid, Africans, Orientals and Arab populations.

MATERIALS AND METHODS:

HLA class I and II polymorphisms in 1000 unrelated Pakistani individuals was studied using sequence-specific primers and polymerase chain reaction and assay.

RESULTS:

The most frequent class I alleles observed were A*02, B*35 and CW*07, with frequencies of 19.2, 13.7 and 20%, respectively. Fifteen distinct HLA-DRB1 alleles and eight HLA-DQB1 alleles were recognized. The most frequently observed DRB1 alleles which represented more than 60% of the subjects were DRB1 *03, *07, *11 and *15. The rare DRB1 alleles detected in this study were HLADRB1 *08 and *09, having frequencies of 0.9 and 1.7%, respectively. In addition, at DRB1-DQB1 loci there were 179 different haplotypes and 285 unique genotypes and the most common haplotype was DRB1*15-DQB1*06 which represented 17% of the total DRB1-DQB1 haplotypes. In our population, haplotype A*33-B*58-Cw*03 comprised 2.8% of the total class I haplotypes observed. This haplotype was seen only in the oriental populations and has not been reported in the African or European Caucasoid.

CONCLUSION:

Our study showed a close similarity of HLA class I and II alleles with that of European Caucasoid and Orientals. In Pakistani population, two rare loci and three haplotypes were identified, whereas haplotypes characteristic of Caucasians, Africans and Orientals were also found, suggesting an admixture of different races due to migration to and from this region.     

Association of HLA class I antigens and HLA class II alleles with vitiligo in a Turkish population

As is the case with many other autoimmune diseases, there is an association between vitiligo and HLA complex. HLA subtypes vary with racial/ethnic background. The purpose of this study was to determine which HLA class I antigens and HLA class II alleles are associated with Turkish vitiligo patients. Forty-one patients with vitiligo and 61 healthy control subjects were typed for HLA class II alleles. Thirty-three out of 41 patients with vitiligo and 100 healthy transplant donors were typed for HLA class I antigens. HLA DNA typing was performed by polymerase chain reaction/sequence specific primer method for class II. HLA typing for class I was performed by serological method. The frequency of HLA DRB1*03 was 0.6340 in patients compared to 0.2950 in controls (P = 0.0014). The frequency of HLA DRB1*04 was found to be 0.6830 in patients compared to 0.2950 in controls (P = 0.00026). The allele HLA DRB1*07 was present in 0.390 of patients compared to 0.0820 of the controls (P = 0.0004). A preventive antigen for the manifestation of vitiligo has not been identified in this study. Our findings suggest that DRB1*03, DRB1*04 and DRB1*07 alleles are genetic markers for general susceptibility to vitiligo in a Turkish population.     

HLA Class I and Class II Associations with ESRD in Saudi Arabian Population

Background

Chronic renal failure (CRF) leads in the majority of instances to end stage renal disease (ESRD) requiring renal replacement therapy. Our interest was to evaluate the possible associations of HLA class I and class II antigens with ESRD independent of other factors, in Saudi Arabia population.

Methodology

A retrospective study to determine the HLA class I and class II polymorphisms and their association with ESRD, was performed on 350 patients with ESRD, and 105 healthy unrelated control. Patients and control groups were typed by SSOP lumenix techniques. The alleles positively associated to the ESRD were: HLA-B*15, B*18, B*49 - DRB1*03, negatively associated alleles were A*26, HLA-B*39, B*50. The haplotypes positively associated with ESRD were: HLA-A*01-DRB1*13 and HLA-A*30-DRBI*03. The negatively associated haplotypes were: HLA-A*02-B*39, A*02-B*50, A*24-B*35, A*24-B*58, A*24-DRB1*16, A*68-DRB1*04, A*02-DQB1*03, A*29-DQB1*02, A*29-DOB1*05 and B*27-DRB1*07 and the last one is the most significant protective haplotypes.

Conclusion

The high Relative Risk (RR) observed and its statistical correlation reflect the strength of the described association between HLA antigens and ESRD.     

Human leukocyte antigen B58 supertype and human immunodeficiency virus type 1 infection in native Africans

Human leukocyte antigen (HLA) class I alleles can be grouped into supertypes according to their shared peptide binding properties. We examined alleles of the HLA-B58 supertype (B58s) in treatment-na?ve human immunodeficiency virus type 1 (HIV-1)-seropositive Africans (423 Zambians and 202 Rwandans). HLA-B and HLA-C alleles were resolved to four digits by a combination of molecular methods, and their respective associations with outcomes of HIV-1 infection were analyzed by statistical procedures appropriate for continuous or categorical data. The effects of the individual alleles on natural HIV-1 infection were heterogeneous. In HIV-1 subtype C-infected Zambians, the mean viral load (VL) was lower among B*5703 (P = 0.01) or B*5703-Cw*18 (P < 0.001) haplotype carriers and higher among B*5802 (P = 0.02) or B*5802-Cw*0602 (P = 0.03) carriers. The B*5801-Cw*03 haplotype showed an association with low VL (P = 0.05), whereas B*5801 as a whole did not. Rwandans with HIV-1 subtype A infection showed associations of B*5703 and B*5802 with slow (P = 0.06) and rapid (P = 0.003) disease progression, respectively. In neither population were B*1516-B*1517 alleles associated with more favorable responses. Overall, B58s alleles, individually or as part of an HLA-B-HLA-C haplotype, appeared to have a distinctive impact on HIV-1 infection among native Africans. As presently defined, B58s alleles cannot be considered uniformly protective against HIV/AIDS in every population.     

Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus

Human leukocyte antigen (HLA) class I and class II alleles are implicated as genetic risk factors for many autoimmune diseases. However, the role of the HLA loci in human systemic lupus erythematosus (SLE) remains unclear. Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, we identified three distinct haplotypes that encompassed the class II region and exhibited transmission distortion. DRB1 and DQB1 typing of founders showed that the three haplotypes contained DRB1*1501/ DQB1*0602, DRB1*0801/ DQB1*0402, and DRB1*0301/DQB1*0201 alleles, respectively. By visualizing ancestral recombinants, we narrowed the disease-associated haplotypes containing DRB1*1501 and DRB1*0801 to an approximately 500-kb region. We conclude that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE.     

Rapid HIV-1 Disease Progression in Individuals Infected with a Virus Adapted to Its Host Population

HIV-1 escape from CTL is predictable based on the Human Leukocyte Antigen (HLA) class I alleles expressed by the host. As such, HIV-1 sequences circulating in a population of hosts will harbor escape mutations specific to the HLA alleles of that population. In theory, this should increase the frequency of escape mutation transmission to persons expressing the restricting HLA allele, thereby compromising host immunity to the incoming HIV-1 strain. However, the clinical impact of infection with HIV-1 containing immune escape mutations has not conclusively been demonstrated. Japan’s population features limited HLA diversity which is driving population-level HIV adaptation: for example, >60% of Japanese express HLA-A*24:02 and its associated Nef-Y135F escape mutation represents the population consensus. As such, Japan is an ideal population in which to examine this phenomenon. Here, we combine genetic and immunological analyses to identify A*24:02-positive individuals likely to have been infected with Y135F-containing HIV-1. Over a ~5 year follow-up, these individuals exhibited significantly lower CD4 counts compared to individuals inferred to have been infected with wild-type HIV-1. Our results support a significant negative clinical impact of pathogen adaptation to host pressures at the population level.     

Importance of human leukocyte antigen (HLA) class I and II alleles on the risk of multiple sclerosis

Multiple sclerosis (MS) is a complex disease of the central nervous system of unknown etiology. The human leukocyte antigen (HLA) locus on chromosome 6 confers a considerable part of the susceptibility to MS, and the most important factor is the class II allele HLA-DRB1*15:01. In addition, we and others have previously established a protective effect of HLA-A*02. Here, we genotyped 1,784 patients and 1,660 healthy controls from Scandinavia for the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes and investigated their effects on MS risk by logistic regression. Several allele groups were found to exert effects independently of DRB1*15 and A*02, in particular DRB1*01 (OR = 0.82, p = 0.034) and B*12 (including B*44/45, OR = 0.76, p = 0.0028), confirming previous reports. Furthermore, we observed interaction between allele groups: DRB1*15 and DRB1*01 (multiplicative: OR = 0.54, p = 0.0041; additive: AP = 0.47, p = 4 × 10(-06)), DRB1*15 and C*12 (multiplicative: OR = 0.37, p = 0.00035; additive: AP = 0.58, p = 2.6 × 10(-05)), indicating that the effect size of these allele groups varies when taking DRB1*15 into account. Analysis of inferred haplotypes showed that almost all DRB1*15 bearing haplotypes were risk haplotypes, and that all A*02 bearing haplotypes were protective as long as they did not carry DRB1*15. In contrast, we found one class I haplotype, carrying A*02-C*05-B*12, which abolished the risk of DRB1*15. In conclusion, these results confirms a complex role of HLA class I and II genes that goes beyond DRB1*15 and A*02, in particular by including all three classical HLA class I genes as well as functional interactions between DRB1*15 and several alleles of DRB1 and class I genes.     

Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandular syndrome type III in Japanese population

BACKGROUND: It has been reported that HLA class II haplotypes DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0901-DQA1*0302-DQB1*0303 are major susceptibility haplotypes for type 1 diabetes mellitus (DM) in Japanese population. However, little has been reported on the susceptibility HLA class II haplotypes in Japanese patients with autoimmune polyglandular syndrome type II and type III (APS III). PATIENTS AND METHODS: HLA class II haplotypes of DRB1-DQA1-DQB1 in 31 patients with APS III, 14 patients with Hashimoto's thyroiditis alone, and 15 patients with Graves' disease alone were examined in Japanese population. APS III patients were divided into three groups (A, B, and C) depending on the combination of autoimmune endocrine diseases. RESULTS: In 13 APS III patients with both Hashimoto's thyroiditis and type 1 DM (group A), the haplotype frequencies of the HLA DRB1*0802-DQA1*0401-DQB1*0402 and DRB1*0901-DQA1*0302-DQB1*0303 were significantly higher than in the controls. In patients with Hashimoto's thyroiditis alone, the haplotype frequency of DRB1*0901-DQA1*0302-DQB1*0303 was significantly higher than in controls, whereas the frequency of DRB1*0802-DQA1*0401-DQB1*0402 did not differ significantly from those in the controls. In 11 APS III patients with both Graves' disease and type 1 DM (group B), the haplotype frequencies of HLA DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0802-DQA1*0301-DQB1*0302 were significantly higher than in controls. In patients with Graves' disease alone, the haplotype frequency of DRB1*0803-DQA1*0103-DQB1*0601 were significantly higher than those in controls, suggesting that the susceptibility haplotypes for group B APS III differed from those for Graves' disease alone. In 7 APS III patients with both autoimmune thyroid diseases and pituitary disorders (group C), the haplotype frequency of HLA DRB1*0405-DQA1*0303-DQB1*0401 was significantly higher than in controls. CONCLUSIONS: Susceptible HLA class II haplotypes of DRB1-DQA1-DQB1 for APS III differ between the Japanese and Caucasian populations. More interestingly, the susceptible HLA class II haplotypes differ among the three types of Japanese APS III and are not merely a combination of susceptibility haplotypes of each endocrine disease.     

HLA association with nasopharyngeal carcinoma in southern Tunisia

In order to study the association of HLA-A, -B and/or DRB1, DQB1 and the nasopharyngeal carcinoma (NPC), 141 patients affected with NPC were typed for the HLA class I by serology method of microlymphocytotoxicity. Among these patients 101 were genotyped for HLA class II system by the PCR-SSP technique. HLA typing results were compared to those of 116 controls. We found that the HLA-A31 and -A33 antigens were significantly more expressed in patients than in the controls (P = 0.016 and 0.010, respectively) and the HLA-A19 antigen, was significantly more frequent in patients when compared to the controls (P = 0.007). The HLA-DRB1*03 and DRB1*13 alleles were significantly more frequent in patients as compared to the controls. The DRB1*01 allele was expressed with a frequency of 20.69% in the controls whereas it was only detected in 3.96% of the NPC patients. Furthermore, the DQB1*05 allele was expressed at a frequency which was significantly less important in affected patient (P = 0.03), whereas, the DQB1*02 allele was more frequent in patients (P = 0.643 × 10⁻⁴). Thus our study revealed a significant increase of HLA-A31, A33, A19, B16, B53 and DRB1*03, DRB1*13 and DQB1*02 alleles in our patients. These markers could play a predisposing role in the development of NPC. In contrast, a decrease of HLA-B14, -B35 and DRB1*01 and DQB1*05 alleles was found suggesting a likely protective effect.