Human leukocyte antigen class I and class II allele frequencies and HIV-1 infection associations in a Chinese cohort

China has one of the most rapidly spreading HIV-1 epidemics. To develop a vaccine targeted to specific human leukocyte antigen (HLA) epitopes in this population, allele distribution analysis is needed. We performed low-resolution class I and II HLA typing of a cohort of 393 subjects from mainland China using a polymerase chain reaction with sequence-specific primers (PCR-SSPs). We found 10 class I alleles present in more than 10% of the population: HLA-A*02, HLA-A*11, HLA-A*24, HLA-B*13, HLA-B*15, HLA-B*40, HLA-Cw*03, HLA-Cw*07, HLA-Cw*01, and HLA-Cw*06. Several class II alleles were found at high frequency (>or=10%): HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DRB1*0701, HLA-DRB1*1501, HLA-DRB1*0401, HLA-DRB1*0901, HLA-DRB1*1201, HLA-DQB1*0601, HLA-DQB1*0301, HLA-DQB1*0201, HLA-DQB1*0501, and HLA-DQB*0303. We also estimated 2- and 3-locus haplotype frequencies. Because this cohort contained 280 HIV-1-seropositive and 113 HIV-1-seronegative individuals, we compared allele and haplotype frequencies between the infected and control groups to explore correlations between HLA antigens and susceptibility/resistance to HIV infection. The HLA-B*14 allele was only found in the HIV-1-seropositive group, and many 2-locus haplotypes were significantly overrepresented in this group: HLA-B*14/Cw*08, HLA-B*51/Cw*14, HLA-A*02/B*13, HLA-A*31/Cw*14, HLA-A*02/Cw*06, and the class II haplotype HLA-DRB1*1301/DQB1*0601. Alleles significantly increased in the HIV-1-seronegative controls were HLA-B*44, HLA-Cw*04, and HLA-DRB1*1402. Overrepresented 2-locus haplotypes in the control group were HLA-B*44/Cw*04, HLA-A*31/Cw*03, HLA-A*03/Cw*07, HLA-A*11/B*13, HLA-A*11/B*38, HLA-A*24/B*52, and HLA-A*11/Cw*01. The 3-locus haplotypes HLA-A*24/Cw*03/B*40 and HLA-A*02/B*15/DRB1*1201 were found to be increased significantly in the control group. These data contribute to the database of allele frequencies and associations with HIV infection in the Chinese population.     

HLA-Cw*0409N is associated with HLA-A*2301 and HLA-B*4403-carrying haplotypes

The associations of HLA-B*4402 and HLA-B*4403 with alleles of HLA-A and HLA-Cw were investigated in panels of HLA-B*4403 and HLA-B*4402 homozygous individuals and in selected individuals carrying HLA-Cw*04 and HLA-B*4403. Some of these individuals were genotyped and also carried (HLA-DRB1*0701, DQB1*02). Among the latter, we studied individuals carrying the conserved extended haplotype (CEH) [HLA-Cw*04, B*4403, FC31, DRB1*0701, DQB1*02]. Four different common (HLA-Cw*, B*44) haplotypes were identified that extended to the HLA-A locus: HLA-A*0201, Cw*0501, B*4402; HLA-A*2902, Cw*1601, B*4403; HLA-A*2301, Cw*0401, B*4403; and HLA-A*2301, Cw*0409N, B*4403. We identified eight unrelated examples of the allele HLA-Cw*0409N. HLA-A*2301 was associated with both HLA-Cw*0401 and HLA-Cw*0409N, suggesting that HLA-Cw*0409N may have arisen from a mutation in a CEH. We estimate that approximately 2 to 5 in 1000 Caucasian individuals carry the allele HLA-Cw*0409N, making it one of the most frequent null HLA alleles known to date. Our findings demonstrate the first example of three different HLA-Cw-determined subtypes of a common or CEH carrying a shared HLA-B allele, in this case HLA-B*4403.     

HLA class I diversity in Kolla Amerindians

Human leukocyte antigen (HLA) class I polymorphism was studied within a population of 70 unrelated Kolla Amerindians from the far northwest of Argentina close to the Bolivian border. The results indicate that the HLA-A, -B, and -C alleles typical of other Amerindian populations also predominate in the Kolla. These alleles belong to the following allele groups: HLA-A*02, *68, *31, *24, HLA-B*35, *15, *51, *39, *40, *48, and Cw*01, *03, *04, *07, *08, and *15. For the HLA-A locus, heterogeneity was seen for HLA-A*02 with A*0201, *0211, and *0222; and for A*68 with *68012 and *6817, the latter being a novel allele identified in this population. Analysis of HLA-B identified heterogeneity for all Amerindian allele groups except HLA-B*48, including the identification of the novel B*5113 allele. For HLA-C heterogeneity was identified within the Cw*07, *04, and *08 groups with Cw*0701/06, *0702, *04011, *0404, *0803, and *0809 identified. The most frequent "probable" haplotype found in this population was B*3505-Cw*04011. This study supports previous studies, which demonstrate increased diversity at HLA-B compared with HLA-A and -C. The polymorphism identified within the Kolla HLA-A, -B, and -C alleles supports the hypothesis that HLA evolution is subject to positive selection for diversity within the peptide binding site.     

MHC class I and class II phenotype, gene, and haplotype frequencies in Greeks using molecular typing data

In the present study, DNA typing for HLA-A, C, B, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, and DPB1 was performed for 246 healthy, unrelated Greek volunteers of 20-59 years of age. Phenotype, genotype frequencies, Hardy-Weinberg equilibrium fit, and 3-locus haplotype frequencies for HLA-A, C, B, HLA-A, B, DRB1, HLA-DRB1, DQA1, DQB1, and HLA-DRB1, DQB1, DPB1 were calculated. Furthermore, linkage disequilibrium, deltas, relative deltas and p-values for significance of the deltas were defined. The population studied is in Hardy-Weinberg equilibrium, and many MHC haplotypes are in linkage disequilibrium. The most frequent specificities were HLA-A*02 (phenotype frequency = 44.3%) followed by HLA-A*24 (27.2%), HLA-B*51 (28.5%), HLA-B*18 (26.8%) and HLA-B*35 (26.4%) and HLA-Cw*04 (30.1%) and HLA-Cw*12 (26.8%). The most frequent MHC class II alleles were HLA-DRB1*1104 (34.1%), HLA-DQB1*0301 (54.5%) and HLA-DPB1*0401 with a phenotype frequency of 59.8%. The most prominent HLA-A, C, B haplotypes were HLA-A*24, Cw*04, B*35, and HLA-A*02, Cw*04, B*35, each of them observed in 21/246 individuals. The most frequent HLA-A, B, DRB1 haplotype was HLA-A*02, B*18, DRB1*1104 seen in 20/246 individuals, while the haplotype HLA-DRB1*1104, DQB1*0301, DPB1*0401 was found in 49/246 individuals. Finally, the haplotype DRB1*1104, DQA1*0501, DQB1*0301 was observed in 83/246 individuals. These results can be used for the estimation of the probability of finding a suitable haplotypically identical related or unrelated stem cell donor for patients of Greek ancestry. In addition, they can be used for HLA and disease association studies, genetic distance studies in the Balkan and Mediterranean area, paternity cases, and matching probability calculations for the optimal allocation of kidneys in Greece.     

HLA class-I and class-II allele frequencies and two-locus haplotypes in Melanesians of Vanuatu and New Caledonia

HLA class-I and class-II allele frequencies and two-locus haplotypes were examined in 367 unrelated Melanesians living on the islands of Vanuatu and New Caledonia. Diversity at all HLA class-I and class-II loci was relatively limited. In class-I loci, three HLA-A allelic groups (HLA-A*24, HLA-A*34 and HLA-A*11), seven HLA-B alleles or allelic groups (HLA-B*1506, HLA-B*5602, HLA-B*13, HLA-B*5601, HLA-B*4001, HLA-B*4002 and HLA-B*2704) and four HLA-C alleles or allelic groups (HLA-Cw*04, HLA-Cw*01, HLA-Cw*0702 and HLA-Cw*15) constituted more than 90% of the alleles observed. In the class-II loci, four HLA-DRB1 alleles (HLA-DRB1*15, HLA-DRB1*11, HLA-DRB1*04 and HLA-DRB1*16), three HLA-DRB3-5 alleles (HLA-DRB3*02, HLA-DRB4*01 and HLA-DRB5*01/02) and five HLA-DQB1 alleles (HLA-DQB1*0301, HLA-DQB1*04, HLA-DQB1*05, HLA-DQB1*0601 and HLA-DQB1*0602) constituted over 93, 97 and 98% of the alleles observed, respectively. Homozygosity showed significant departures from expected levels for neutrality based on allele frequency (i.e. excess diversity) at the HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB3/5 loci on some islands. The locus with the strongest departure from neutrality was HLA-DQB1, homozygosity being significantly lower than expected on all islands except New Caledonia. No consistent pattern was demonstrated for any HLA locus in relation to malaria endemicity.     

Allele and haplotype frequencies at human leukocyte antigen class I and II genes in Venezuela's population

Population studies represent an integral part and link in understanding the complex chain of host-pathogen interactions, disease pathogenesis, and MHC gene polymorphisms. Genes of Mongoloid, Caucasoid, and Negroid populations have created a distinctive HLA genetic profile in the Venezuelan population. Our objective was to determine the predominant HLA class I and II alleles and haplotype frequencies in the hybrid population of Venezuela. The study population consisted of 486 healthy unrelated native Venezuelans and 180 families. We examined the frequency of HLA A-B-C, HLA-DQ and HLA-DR genes by polymerase chain reaction and subsequent hybridization with sequence-specific oligonucleotide probes. Phenotypic, allelic and haplotype frequencies were estimated by direct counting and using the maximum-likelihood method. The predominant HLA class I alleles were A*02, A*24, A*68, B*35, B*44, B*51, B*07, B*15 and Cw*07. Regarding HLA class II, the most frequent alleles were DQB1*03 and DRB1*04, DRB1*15, DRB1*13, DRB1*07. The prevailing haplotype was HLA-A*02B*35 DQB1*03 DRB1*04. Some of these alleles and haplotype frequencies were predominantly present in Amerindians (A*02, A*24, B*35, Cw*07, DRB1*04, A*24 B*35). Previous reports have shown high incidence of A*02, B*44, B*51, DRB1*15, DRB1*13, DRB1*07 alleles in several European populations and A*68, B*07, B*15 alleles in African Americans, which could have contributed to the ethnic admixture of the Venezuelan population. We conclude that our results provide strong evidence that Venezuela's population represents an admixture of the primitive Mongoloid Aborigines, Caucasoid Europeans and Western African Negroid migrants.     

HLA class-I and HLA class-II phenotypic, gene and haplotypic frequencies in Tunisians by using molecular typing data

The aim of this study is to define a reliable reckoning of gene frequencies and six-locus haplotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1 and HLA-DPB1 in the Tunisian population. One hundred unrelated random, healthy people originating from various parts of Tunisia were typed for the alleles of the loci mentioned above by using the molecular techniques polymerase chain reaction--hybridization with oligonucleotide probe (PCR-SSO) and sequence specific primers (SSP). The population studied appeared to be in Hardy-Weinberg equilibrium. Allelic frequency distributions were observed at each locus. The most frequent HLA-A alleles were HLA-A*02 (39%) HLA-A*0101 (25%), HLA-A*30 (21%) and HLA-A*2301 (18%). Moreover, HLA-3A*3601, HLA-1A*6601, HLA-1A*3402 and HLA-2A*8001 were found; however, no HLA-A*4301 was detected. For the HLA-B locus, the most common in descending order were HLA-B*44 (22%), HLA-B*5001 (19%), HLA-B*51 (16%) and HLA-B*18 (15%). Among the 28 alleles HLA-Cw detected, HLA-Cw*6 and HLA-Cw*7 were highly predominant with the frequencies of 33 and 30%, respectively. For the HLA class-II loci, HLA-DRB1*0701, HLA-DRB1*11, HLA-DRB1*13 and HLA-DRB1*03 were the most frequent DR alleles. For the HLA-DPB1, HLA-DPB1*0401, HLA-DPB1*0301 and HLA-DPB1*0201 were the most frequent DP alleles. Many haplotypes were in a strong positive-linkage disequilibrium. The most frequent haplotypes for HLA-A, HLA-B, HLA-C and HLA-DRDQ were HLA-A*3301, HLA-B*1402, HLA-Cw*0802, HLA-DRB1*0102, HLA-DQA1*0101 and HLA-DQB1*0501; HLA-A*2402, HLA-B*0801, HLA-Cw*0702, HLA-DRB1*0301, HLA-DQA1*0501 and HLA-DQB1*0201; HLA-A*2902, HLA-B*4403.1, HLA-Cw*1601, HLA-DRB1*0701, HLA-DQA1*0201 and HLA-DQB1*0202; HLA-A*3002, HLA-B*1801, HLA-Cw*0501, HLA-DRB1*0301, HLA-DQA1*0501 and HLA-DQB1*0201, with frequencies between 0.025 and 0.015. These data can be used as control data for HLA disease associations and paternity studies, but they are also important for the evaluation of the probability rate of success in determining the optimal matched donor in unrelated stem transplantation for Tunisian patients or patients of Tunisian origin.     

The association of human leucocyte antigen (HLA) alleles with COVID-19 severity: A systematic review and meta-analysis

Due to their pivotal role in orchestrating the immune response, HLA loci were recognized as candidates for genetic association studies related to the severity of COVID-19. Since the findings on the effects of HLA alleles on the outcome of SARS-CoV-2 infection remain inconclusive, we aimed to elucidate the potential involvement of genetic variability within HLA loci in the molecular genetics of COVID-19 by classifying the articles according to different disease severity/outcomes and by conducting a systematic review with meta-analysis. Potentially eligible studies were identified by searching PubMed, Scopus and Web of Science literature databases. A total of 28 studies with 13,073 participants were included in qualitative synthesis, while the results of 19 studies with 10,551 SARS-CoV-2-positive participants were pooled in the meta-analysis. According to the results of quantitative data synthesis, association with COVID-19 severity or with the lethal outcome was determined for the following alleles and allele families: HLA-A*01, HLA-A*03, HLA-A*11, HLA-A*23, HLA-A*31, HLA-A*68, HLA-A*68:02, HLA-B*07:02, HLA-B*14, HLA-B*15, HLA-B*40:02, HLA-B*51:01, HLA-B*53, HLA-B*54, HLA-B*54:01, HLA-C*04, HLA-C*04:01, HLA-C*06, HLA-C*07:02, HLA-DRB1*11, HLA-DRB1*15, HLA-DQB1*03 and HLA-DQB1*06 (assuming either allelic or dominant genetic model). We conclude that alleles of HLA-A, -B, -C, -DRB1 and -DQB1 loci may represent potential biomarkers of COVID-19 severity and/or mortality, which needs to be confirmed in a larger set of studies.     

Polymorphism of HLA class I genes in Meizhou Han population of Guangdong, China

Human leukocyte antigen (HLA) is an invaluable marker for anthropological studies because of its extreme polymorphism. Most of the studies carried out in Chinese populations are about HLA class II genes, but few about class I genes. In the present study, we investigated HLA class I polymorphism using polymerase chain reaction-sequencing-based typing (PCR-SBT) method in 104 unrelated Han individuals in Meizhou of Guangdong, southern China. Twenty-three HLA-A, 43 HLA-B and 27 HLA-C alleles were identified and allele frequencies and two-locus (C/B) and three-locus (A/C/B) haplotypes were statistically analysed. The most frequent HLA-A allele is A*110101 with a frequency of 30.3%, followed by A*24020101 (22.2%) and A*2420 (11.6%). Among the 43 detected HLA-B alleles, B*5801 (17.0%), B*400101 (15.5%) and B*4601 (10.0%) were frequently observed. Among the 27 detected C alleles, the most predominant one is Cw*07020101 (25.8%), followed by Cw*0717 (14.7%). The most frequent HLA-C/B two-locus haplotype is Cw*07020101/B*400101 (10.1%). The most common HLA-A/C/B three-locus haplotype in Meizhou Han is A*110101/Cw*07020101/B*400101 (3.4%). Phylogenetic tree based on HLA class I allele frequencies genetically suggested that Meizhou Han has an affinity to southern Asian populations. The result may also reflect an admixture of Han and ethnic minorities of southern China.     

Strong association between HLA-Cw*0706 and HLA-B*44032 in the Bubi population from Equatorial Guinea

Unrelated Bubi, native to the island of Bioko (Equatorial Guinea), were previously typed by low-resolution polymerase chain reaction using sequence-specific primers (PCR-SSP) and serology for HLA-A, -B and -C. HLA-B*44 was found frequently and associated with Cw*07. We have studied the HLA subtypes of 20 B*44pos/Cw*07pos Bubi individuals. HLA-B and -C were typed by sequencing exons 2 and 3. To distinguish the alleles Cw*1701/02/03, Cw*07011/012/06 and Cw*1801/02 additional sequencing of exon 1 or 5 was performed. All 20 B*44pos/Cw*07pos individuals of the Bubi population were typed Cw*0706 positive. Nineteen of them carried the B*44032 allele and one B*4407. In addition, 19 B*44neg/ Cw*07pos Bubi individuals were typed for HLA-C and none of them proved Cw*0706 positive. To determine whether the association between Cw*0706 and B*44032 was limited to the Bubi, 19 individuals from Dutch Caucasian families were typed in which B44 and Cw7 segregated on one haplotype. None of these individuals showed the presence of B*44032 or Cw*0706. The haplotypes found in the Dutch Caucasians were B*4402-Cw*0704, B*44031-Cw*07011 and B*44031-Cw*0702. The present observation indicates a strong association between B*44032 and Cw*0706 in the Bubi population.     

HLA class I diversity among rural rainforest inhabitants in Cameroon: identification of A*2612-B*4407 haplotype

The population distribution of alleles of the classical HLA class I loci in Cameroon has not been well studied but is of particular interest given the AIDS and malarial epidemics afflicting this population. We investigated the genetic diversity of HLA-A, HLA-B and HLA-C alleles in remote populations of Cameroon. Subjects from seven small, isolated, indigenous populations (N = 274) in the rainforest of southern Cameroon were typed for HLA-A, HLA-B and HLA-C alleles using a polymerase chain reaction/sequence-specific oligonucleotide probe assay and sequence analysis. Multiple alleles of the HLA-A (N = 28), HLA-B (N = 41) and HLA-C (N = 21) loci were identified, of which A*2301[allele frequency (AF) = 12.8%], B*5802 (AF = 10.9%) and Cw*0401 (AF = 16.6%) were the most frequent individual alleles and A*02 (AF = 19.0%), B*58 (AF = 15.9%) and Cw*07 (AF = 22.4%) the most common serologically defined groups of alleles. Twenty-six (28.9%) alleles with a frequency of less than 1% (AF < 1%), 39 (43%) with a frequency of 2.0-15.0% (AF = 2.0-15.0%), three globally uncommon alleles [A*2612 (AF = 2.0%), B*4016 (AF = 0.7%) and B*4407 (AF = 1.4%)], and the A*2612-Cw*0701/06/18-B*4407 haplotype (haplotype frequency = 1.3%) were also identified. Heterozygosity values of 0.89, 0.92 and 0.89 were determined for HLA-A, HLA-B and HLA-C, respectively. The extensive allelic and haplotypic diversity observed in this population may have resulted from varied natural selective pressures on the population, as well as intermingling of peoples from multiple origins. Thus, from an anthropologic perspective, these data highlight the challenges in T-cell-based vaccine development, the identification of allogeneic transplant donors and the understanding of infectious disease patterns in different populations.     

Study of HLA genes in Mexico Mayo/Yoremes Amerindians: Further support of gene exchange with Pacific Islanders

Mexican Mayo Amerindians live in southern Sonora and North Sinaloa states. They probably come from North or are related to First American Inhabitants established further North. A non-related sample of them have volunteered to HLA study in order to achieve a profile useful for their epidemiology and future transplant interstate programs, in addition to ascertain ancestry and anthropological studies. HLA typing was carried out by a standard methodology. HLA-B*48 allele(s) was found, which is characteristic of Pacific Amerindians and Pacific Islanders/southern Asians. Also, HLA-A*24 (most likely HLA-A*24:02) shows specific high frequencies in this population and also in indigenous people, like Aleuts, Alaska Yupik, Japan, Taiwan, Australia, New Zealand, Papua New Guinea, southern China and other Pacific Islands. Other Andean Amerindians also show a high HLA-A*24:02 frequencies. This confirms our previous results of a possible direct gene flow between Pacific Islanders/southern Asians and Amerindians.In addition, typical Amerindian haplotypes have been found in high frequency like HLA-A*24-B*39-DRB1*04:07-DQB1*03:02, HLA-A*02-B*35-DRB1*04:07-DQB1*03:02 and HLA-A*24-B*35-DRB1*04:07-DQB1*03:02, and new haplotypes are also described like HLA-A*02-B*35-DRB1*14:06-DQB1*03:01, HLA-A*02-B*48-DRB1*04:04-DQB1*03:02, and HLA-A*02-B*08-DRB1*04:07-DQB1*03:02. This study also supports that Americas peopling was not only carried out through Bering Strait but also through Pacific and Atlantic Oceans in an earlier time than proposed.     

Heterogeneity of HLA-DRB1*04 alleles and haplotypes in the Croatian population

Analysis of allele distribution at the HLA-DRB1*04 gene, as one of the frequent ones among Croatians, and their HLA-A-B-DRB1 haplotypes in the Croatian population was performed in this study. Using LABType(?) SSO and PCR-SSP method, 11 DRB1*04 subtypes were observed, of which DRB1*04:01 was the most frequent (28.0%) followed by DRB1*04:02 (26.3%), DRB1*04:03 (22.3%), and DRB1*04:04 (14.2%). The significant haplotypes (with highest P value) for given DRB1*04 allele were the following combinations: HLA-B*15:01-DRB1*04:01, HLA-B*38:01-DRB1*04:02, HLA-B*35:03-DRB1*04:03, HLA-B*35:03-DRB1*04:08, HLA-B*14:01-DRB1*04:04, and HLA-B*49-DRB1*04:05. Marked differences in the distribution of our most frequent haplotypes of HLA-B-DRB1*04 (HLA-B*38:01-DRB1*04:02 and HLA-B*15:01-DRB1*04:01) were found in comparison to other European populations investigated so far. Additionally, comparison of HLA-A-B-DRB1*04 haplotypes showed that although there are similarities in the haplotype structure between our and other populations, there are also noteworthy differences. In summary, the identification of conserved and unusual DRB1*04 haplotypes in the present study of Croats should have important clinical implications for donor-recipient matching in the hematopoietic stem cell transplantation program, help in the understanding of HLA polymorphisms in different European populations, and also prove to be very useful in the determination of possible susceptibility genes involved in HLA-DRB1*04-associated diseases.     

造血干细胞移植受-供者HLA抗原识别部位的核苷酸匹配研究

目的 研究中国人群等待造血干细胞移植受-供者人类白细胞抗原(human leukocyte antigens,HLA)-A、-B、-Cw、-DRBl、-DQB1 5个位点的等位基因及核苷酸匹配情况,从单核苷酸水平探讨最佳供选择方案.方法 采用聚合酶链反应测序分型法(polymerase chain reaction-sequence-based typing,PCR-SBT),对537对中国人群等待造血干细胞移植受-供者HLA-A、-B、-Cw、-DRB1、-DQB1位点的等位基因进行序列分型,应用BLAST工具分析受-供者HLA核苷酸差异.结果 37对受-供者中HLA-A、-B、-Cw、-DRB1、-DQB1五位点核苷酸完全匹配占16.20%,单个等位基因错配的受-供者对分别占8.38%,0.74%,12.29%,2.42%和2.79%,两个或两个以上等位基因错配比率占42.65%.检出A*02:01-A*02:06,A*02:06-A*02:07,Cw*03:04-Cw*15:02,Cw*03:03-Cw*04:01,Cw*03:04-Cw*14:02,Cw *03:03-Cw*08:01,DRB1*04:03:01-DRB1*04:05不容许错配等位基因对.两对受-供者B*07:05:01-B*07:06,Cw*07:01:01-Cw*07:06抗原识别区外核苷酸错配.结论 在造血干细胞移植选择HLA错配的无关供者时注意受-供核苷酸匹配差异,对HLA抗原识别区内的核苷酸匹配差异和抗原识别区外的核苷酸匹配差异应当加以区别.本研究结果为优化供者选择顺序提供科学参考数据.     

HLA Allele Frequencies in 5802 Koreans: Varied Allele Types Associated with SJS/TEN According to Culprit Drugs

Purpose

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea.

Materials and Methods

We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01.

Results

HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03.

Conclusion

HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN.     

西北地区汉族人群HLA-A、-B、-DRB1基因座单倍型分析

目的 分析西北地区汉族群体HLA-A、-B和-DRB1基因座等位基因频率和HIA-A-B、B-DRB1和A-B-DRB1单倍型，获得单倍型频率数据。方法 采用序列特异性寡核苷酸探针反向斑点杂交技术对西北地区62个家系和101个无关个体HLA-A、-B和-DRB1基因座进行基因分型，分析HLA单倍型。结果 在西北地区汉族人群中检出15个HLA-A等位基因，28个HLA-B等位基因，13个HLA-DRB1等位基因，A02、A11、A24、B13、B15、1340、DRB1＊04、DRB1＊07、DRB1＊09和DRB1＊15基因频率较高（〉10％），A02（0．3244）、B13（0．1200）和DRB1＊15（0．1400）等位基因频率最高。分析得出HLA-A-B、B-DRB1、A-B-DRB1单倍型分别有122、147和278种，83种A-B-DRB1单倍型有至少两条以上相同的单倍型，占总单倍型数的18．44％（83／450）。A30-B13-DRB1＊07、A02-B46-DRB1＊09、A01-B37-DRB1＊10、A24-B15-DRB＊15、A02-B46-DRB1＊08、A33-B58-DRB1＊03是最常见的单倍型。结论 西北地区汉族群体HLA单倍型多态性较为丰富，等位基因频率和单倍型频率数据可用于骨髓移植供者的选择、法医学亲权鉴定以及人类学研究。     

Human leukocyte antigen-A, -B, and -Cw polymorphism in a Berber population from North Morocco using sequence-based typing

Class I human leukocyte antigen (HLA) polymorphism was examined in a Berber population from North Morocco, named Metalsa (ME). All data were obtained at high-resolution level, using sequence-based typing. The most frequent alleles were: HLA-A*0201 and A*0101; HLA-B*44 (B*4403 and B*4402); B*0801 and the B*50 allele group (B*5001 and B*5002); HLA-Cw*0602; and Cw*07 group (Cw*070101, Cw*070102, Cw*0702, Cw*0704, and Cw*0706), and Cw*040101. The novel HLA-B*570302 allele was identified. It differs at position 486 and position 855 from B*570301, resulting in synonymous Thr and Val. The analysis also evidenced some alleles common in Africans (A*3402, A*6802, A*7401, B*1503, B*4102, B*4202, B*7801, B*5802, Cw*1701, and Cw*1703) and some uncommon alleles (A*3004, B*2702, B*2703, B*5001,02, B*3503, and Cw*0706). The predominant HLA-A-Cw-B-DRB1-extended haplotypes in ME population were A*0101-Cw*0501-B*4402-DRB1*0402, A*240201-Cw*0701-B*0801-DRB1*030101, A*2301-Cw*040101-B*4403-DRB1*040501, A*0201-Cw*040101-B*4403-DRB1*1302, and A*3002-Cw*0602-B*5002-DRB1*0406. This study demonstrates a strong relatedness of ME to other Moroccan and North African populations, some characteristics of sub-Saharan Africans and evidenced the influence of various immigrations during centuries. Nevertheless, this study highlights some unique genetic traits of the ME population compared to other ethnic groups within Morocco, which could be of great interest for clinical aims, transplantation, and diseases.     

Allelic distribution of HLA class I genes in the Tibetan ethnic population of China

Tibetans live in Qinghai-Tibet Plateau rising about 4000 m a.s.l. in south-west China. Archaeological evidences suggested that there have been humans living in Tibet at least 5000 years ago. However, Tibetan earlier history remains elusive. In the present study, allelic distribution of human leucocyte antigen (HLA)-A, -B and -Cw in 158 unrelated Tibetan Chinese was investigated using sequencing-based typing methods, and a total of 25 HLA-A, 45 HLA-B and 20 HLA-Cw alleles were identified. A*24G1 (27.2%), B*51G1 (16.8%), Cw*04G1 (13.3%) and Cw*070201G1 (13.3%) are the most common HLA-A, -B and -Cw alleles. The most frequently detected haplotypes were A*24G1-B*51G1-Cw*140201 (3.6%), A*24G1-B*51G1 (6.8%), A*02G1-Cw*070201G1 (6.5%) and B*51G1-Cw*140201 (5.0%). Chi-squared test suggested that all three loci fitted the Hardy-Weinberg expectations. No evidence for a departure from selective neutrality at the HLA-A and -B loci was observed. However, significant departure of the observed homozygosity from the expected values was found for HLA-Cw. Though the contemporary Tibetans inhabit the south-west China, Nei's genetic distance measure based on frequencies of HLA-A, -B and -Cw indicated that Tibetans were closer to northern Han Chinese, Mongolian Chinese, Koreans and Japanese rather than to southern Han Chinese. The corresponding dendrogram constructed according to the neighbour-joining method supported that Tibetans separated from southern Han and located in North-East Asian cluster which included northern Han Chinese and Mongolian Chinese. These data were in good agreement with language classification and with a recent hypothesis that Tibetan might originate from northern China along Yellow river.     

Characteristics of HLA class I and class II polymorphisms in Rwandan women

OBJECTIVE: To define HLA class I and class II polymorphisms in Rwandans. METHODS: PCR-based HLA genotyping techniques were used to resolve variants of HLA-A, B, and C to their 2- or 4-digit allelic specificities, and those of DRB1 and DQB1 to their 4- or 5-digit alleles. RESULTS: Frequencies of 14 A, 8 C, and 14 B specificities and of 13 DRB1 and 8 DQB1 alleles were >/=0.02 in a group of 280 Rwandan women. These major HLA factors produced 6 haplotypes extending across the class I and class II regions: A*01-Cw*04-B* 4501-DRB1*1503-DQB1*0602 (A1-Cw4-B12- DR15 - DQ6), A * 01 - Cw * 04 - B * 4901 -DRB1 * 1302-DQB1*0604 (A1-Cw4-B21-DR13-DQ6), A*30 - Cw*04 - B*15 - DRB1*1101 - DQB1*0301 (A19-Cw4-B15-DR11-DQ7), A*68-Cw*07-B* 4901-DRB1*1302-DQB1*0604(A28-Cw7-B21- DR13 - DQ6), A*30 - Cw*07 - B*5703 - DRB1* 1303-DQB1*0301(A19 - Cw7 - B17 - DR13 - DQ7), and A*74-Cw*07-B*4901-DRB1*1302-DQB1* 0604 (A19-Cw7-B21-DR13-DQ6), respectively. Collectively, these extended haplotypes accounted for about 19% of the total. Other apparent class I-class II haplotypes (e.g., Cw*17-B*42-DRB1*0302-DQB1*0402, Cw*06- B*58-DRB1*1102-DQB1*0301, and Cw*03- B*15-DRB1*03011-DQB1*0201) did not extend to the telomeric HLA-A locus, and other 3-locus class I haplotypes (e.g., A*68-Cw*04-B*15, A*74-Cw*04-B*15, and A*23-Cw*07-B*4901) completely or partially failed to link with any specific class II alleles. DISCUSSION: Frequent recombinations appeared to occur between the three evolutionarily conserved HLA blocks carrying the class I and class II loci. The HLA class I profile seen in Rwandans was not directly comparable with those known in the literature, although the class II profile appeared to resemble those in several African populations. These data provide additional evidence for the extensive genetic diversity in Africans.     

HLA-B*15 subtypes in the population of north-eastern Thailand.

The HLA-B*15 group is the most polymorphic HLA-B allele and so has several subtypes. These subtypes have not been defined in the population of north-eastern Thailand (NET). In a previous study, using polymerase chain reaction-sequence-specific primers (PCR-SSP), subtypes were categorized into four groups, namely: group I: HLA-B*15 (01, 04-07, 12, 14, 19, 20, 24, 25, 26N, 27, 32, 33, 34 and 35); group II: HLA-B*15 (02, 08, 11, 15, 28 and 30); group III: HLA-B*1503/4802; group IV: HLA-B*1521. Groups I and II occurred frequently (allele frequency = 8.0 and 2.5%), and thus we optimized the polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) method to identify HLA-B*15 subtypes of groups I and II. Eighty samples of DNA carrying HLA-B*15 from 300 healthy unrelated individuals were tested. B*1502 (52.5%) and B*1525 (13.8%) were the most common subtypes found in NET. They also showed strong linkage disequilibrium with HLA-Cw and heterogeneity of HLA-A, DR, DQ haplotypes. Although limited conclusions can be drawn from this study because of the small number of DNA references used, the baseline data will be useful in the selection of common HLA-B*15 alleles when subtyping for unrelated donor transplantations.