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.     

Exploring the ancestry and admixture of Mexican Oaxaca Mestizos from Southeast Mexico using next-generation sequencing of 11 HLA loci

The Mestizos of Oaxaca resulted from the admixture of Zapotecan Natives with Spaniards and Africans. We selected 112 donors from Oaxaca and applied next-generation sequencing to characterize exon and intron variants in complete or extended HLA genes. Some alleles found, are unique to Mexican Natives and most likely will be absent in most major ethnicities, namely: Caucasians, Africans or Asians. Among these are HLA-A*68:03:01, HLA-A*68:05:01, HLA-C*03:04:01:02, HLA-C*15:09, HLA-C*3:05, HLA-C*03:06:01, HLA-B*39:05:01, HLA-B*35:14:01, HLA-B*35:12:01, HLA-B*35:43:01, HLA-B*40:05, HLA-B:40:08, HLA-B*51:02:01, HLA-B*35:24:01 and HLA-B*39:08. HLA-DQA1*05:05:01:05 and some HLA-DRB1 alleles were only present in Amerindians/Mestizos. Three haplotypes are unique to Mexican Natives, five to Middle-Eastern and Sephardi-Jews. We detected a novel HLA-DQA1*04:01:01 exon 4 variant. Any novel allele may have been positively selected to enlarge the peptide-binding repertoire, and some, like HLA-B*39:02:02 and HLA-B*39:05:01 were found with unique haplotype associations, suggesting convergent evolution events and/or allele lineage diversification. The allele frequencies were fairly evenly distributed in most HLA loci with the exception of HLA-DPB1. The application of NGS in Oaxaca is novel and will lead to better use in the clinical setting. It offers deep knowledge on the population structure, origins, migration, and discovery of new alleles and haplotypes that other techniques did not achieve.     

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 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.     

HLA in Uros from Peru Titikaka Lake: Tiwanaku,Easter and Pacific Islanders

Uros people live in floating reed islands in Titikaka Lake in front of Puno town (Peru). They could have started Tiwanaku culture and shared genes and culture with Pacific Islanders; it is particularly relevant the giant hat covered men statues found in both Tiwanaku at Titikaka Lake shore and Easter Island (3700 km far from Chile in Pacific Ocean). These giants monoliths are very similar one another and unique in America and Pacific Islands. The following HLA alleles are shared in a specifically high frequency between Uros and Pacific Islanders : HLA-A*24:02, HLA-B*35:05, HLA-B*48:01, HLA-DRB1*04:03, HLA-DRB1*08:02 and HLA-DRB1*09:01. Uros also have 3 unique HLA haplotypes: A*24:02-B*15:04 ? DRB1*14:02-DQB1*03:01, A*68:01:02-B*35:05-DRB1*04:03-DQB1*03:02, A*24:02-B*48:01-DRB1*04:03-DQB1*03:02. Also Uros seem to be one of the most ancient population in Titikaka Lake that could have started Tiwanaku culture. Prehistoric contacts between Amerindians and Pacific Islanders are strongly suggested by genetic and cultural traits. It is not discarded that Uros could have come from Pacific Islands: Uros show melanic skin and are dolichocephalic; in contrast, surrounding Aymara people have a clear skin and are brachicephalic. The Kon-Tiki project led by Thor Heyerdahl showed that a simple sailing is possible between Peru and Polynesia Islands; also, the most ancient skull found in America is of black origin: Luzia, suggesting that first America peopling was also carried out by Black/coloured people.     

Seven novel HLA alleles reflect different mechanisms involved in the evolution of HLA diversity: Description of the new alleles and review of the literature

The human leukocyte antigen (HLA) loci are among the most polymorphic genes in the human genome. The diversity of these genes is thought to be generated by different mechanisms including point mutation, gene conversion and crossing-over. During routine HLA typing, we discovered seven novel HLA alleles which were probably generated by different evolutionary mechanisms. HLA-B*41:21, HLA-DQB1*02:10 and HLA-DQA1*01:12 likely emerged from the common alleles of their groups by point mutations, all of which caused non-synonymous amino acid substitutions. In contrast, a deletion of one nucleotide leading to a frame shift with subsequent generation of a stop codon is responsible for the appearance of a null allele, HLA-A*01:123N. Whereas HLA-B*35:231 and HLA-B*53:31 were probably products of intralocus gene conversion between HLA-B alleles, HLA-C*07:294 presumably evolved by interlocus gene conversion between an HLA-C and an HLA-B allele. Our analysis of these novel alleles illustrates the different mechanisms which may have contributed to the evolution of HLA polymorphism.     

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.     

基诺族、毛南族和佤族人类白细胞抗原C等位基因及Ⅰ类区域内 C-B和 A-C-B 单倍型的分布特征

目的 研究中国西南地区基诺族、佤族和毛南族中人类白细胞抗原(human leukocyte antigen,HLA)C等位基因及HLAⅠ类区域内C-B和A-C-B单倍型分布特点.方法 采用聚合酶链反应-序列特异性寡核苷酸分型技术(polymerase chain reaction- sequence specific oligonucleotide,PCR-SSO)对中国西南地区基诺族99名、佤族115名和毛南族85名进行HLA-C高分辨率基因分型,结合前期发表的HLA-A、-B分型结果,构建HLAⅠ类区域内HLA-A,-B和-C位点的单倍型.结果 3个群体中共检出HLA-C等位基因18种,其中基诺族中17种、毛南族中13种和佤族中15种.基因频率>10%的等位基因在这3个群体中的分布为:基诺族中从高到低依次为C*08:01、C*01:02、C*03:04和C*07:02;毛南族中依次为C*03:04、C*01:02、C*07:02和C*08:01;佤族依次为 C*12:03、C*08:01、C*07:02和C*04:01.基诺族中优势A-C-B单倍型包括A*02:07-C*01:02-B*46:01、A*11:01-C*08:01-B*15:02和A*11:01-C*03:04-B*13:01;毛南族中包括A*11:01-C*03:04-B*13:01、A*02:07-C*01:02-B*46:01、A*11:01-C*08:01-B*15:02和A*02:03-C*07:02-B*38:02;佤族中包括A*11:01-C*08:01-B*15:02、A*11:01-C*12:03-B*15:32和A*11:01-C*04:01-B*35:01.结论 基诺族、佤族、毛南族中HLA-C等位基因与HLA-A、-B位点构建的单倍型具有各自的分布特点,但单倍型C*08:01-B*15:02和A*11:01-C*08:01-B*15:02在3个群体中共有并呈高频分布,推测这两种单倍型可能是中国南方群体的祖先单倍型.另外,在基诺族、佤族和毛南族中各自具有其独特的优势单倍型.因此,HLA基因型和单倍型分布特点对这些群体的起源、迁徙、进化和疾病关联研究具有参考价值.

Abstract：

Objective To investigate the distribution of human leukocyte antigen(HLA) classⅠgenes and haplotypes in Jinuo, Maonan and Wa ethnic populations in southwest China.Methods Polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) typing by Luminex was performed to genotype the HLA-C alleles in unrelated healthy individuals in the three populations. HLA C-B, A-C-B haplotypes were computed by combining the previous HLA-A and -B genotyping data using Pypop7.0 software.Results Eighteen HLA-C genes were identified in the three populations, with 17, 13 and 15 HLA-C genes in Jinuo, Maonan and Wa populations respectively. The alleles with frequency of more than 10% from high to low were C*08:01,C*01:02,C*03:04 and C*07:02 in the Jinuo, C*03:04,C*01:02,C*07:02 and C*08:01 in the Maonan, and C*12:03,C*08:01, C*07:02 and C*04:01 in the Wa. The predominant HLA A-C-B haplotypes were A*02:07-C*01:02-B*46:01, A*11:01-C*08:01-B*15:02 and A*11:01-C*03:04-B*13:01 in the Jinuo, A*11:01-C*03:04-B*13:01, A*02:07-C*01:02-B*46:01, A* 11:01-C*08:01-B*15:02 and A*02:03-C*07:02-B*38:02 in the Maonan, and A*11:01-C*08:01-B*15:02,A*11:01-C*12:03-B*15:32 and A*11:01-C*04:01-B*35:01 in the Wa, respectively.Conclusion There were different characteristics in the distributions of HLA-C genes and HLA C-B, A-C-B haplotypes in the Jinuo, Maonan and Wa populations. However, haplotypes C*08:01-B*15:02 and A*11:01-C*08:01-B*15:02 with high frequencies were common in the three populations, which might be the common ancient haplotypes of southern Chinese population. The study of HLA genes and haplotypes in these populations may be of significance in the study of population genetics, transplantation and disease association.     

HLA repertoire of 115 UAE nationals infected with SARS-CoV-2

The class I and class II Human Leucocyte Antigens (HLA) are an integral part of the host adaptive immune system against viral infections. The characterization of HLA allele frequency in the population can play an important role in determining whether HLA antigens contribute to viral susceptibility. In this regard, global efforts are currently underway to study possible correlations between HLA alleles with the occurrence and severity of SARS-CoV-2 infection. Specifically, this study examined the possible association between specific HLA alleles and susceptibility to SARS-CoV-2 in a population from the United Arab Emirates (UAE). The frequencies of HLA class I (HLA-A, -B, and -C) and HLA class II alleles (HLA-DRB1 and -DQB1); defined using Next Generation Sequencing (NGS); from 115 UAE nationals with mild, moderate, and severe SARS-CoV-2 infection are presented here. HLA alleles and supertypes were compared between hospitalized and non-hospitalized subjects. Statistical significance was observed between certain HLA alleles and supertypes and the severity of the infection. Specifically, alleles HLA-B*51:01 and HLA-A*26:01 showed a negative association (suggestive of protection), whilst genotypes HLA-A*03:01, HLA-DRB1*15:01, and supertype B44 showed a positive association (suggestive of predisposition) to COVID-19 severity. The results support the potential use of HLA testing to differentiate between patients who require specific clinical management strategies.     

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.     

中国北京男男同性恋艾滋病感染者HLA 分型及与疾病进展分析

目的:分析中国北京男男同性恋艾滋病感染者HLA-A、HLA-B、HLA-C 基因频率以及HLA 基因分型与疾病进展关系。方法:序列特异性引物的PCR 扩增(PCR-sequence specific primer typing,PCR-SSP)对310 名随机中国北京男男同性恋艾滋病感染者HLA-A、HLA-B、HLA-C 基因进行分型,采用HIV Molecular Immunology Database 中HLA Analysis Tools 方法计算等位基因频率。结果:在北京男男同性恋艾滋病感染者队列中,HLA-A*1101(34.52%)基因频率最高,其次为HLA-A*0201(31.94%)、HLA-C*0102(27.10%)以及HLA-A*2402(26.45%)。根据艾滋病感染者1 年内CD4 细胞计数变化来判断感染者是否为快速进展者,结果发现快速进展者134 例,非快速进展者176 例。快速进展者中存在低水平的HLA-B*4403(快速进展者1.12%,非快速进展者为4.27%,P = 0.0276),HLA-B*1511(非快速进展者5.98%,快速进展者2.25%,P =0.0282),HLA-B*5701(非快速进展者2.56%,快速进展者0.37%,P =0.0491)表达,而HLA-C*0304 则在快速进展者中高表达(非快速进展者4.56%,快速进展者8.96%,P =0.0319)。结论:本研究获得了中国北京男男同性恋艾滋病感染者HLA-A、HLA-B、HLA-C 基因的等位基因分布频率数据,并发现HLA-B*4403、HLA-B*1511、HLA-B*5701 与延缓艾滋病疾病进展有关,而HLA-C*0304 则与加速艾滋病疾病进展相关。     

Next-generation sequencing-based HLA typing reveals the association of HLA-B*46:01:01 and HLA-DRB1*09:01:02 alleles with carbamazepine-induced hypersensitivity reactions in Vietnamese patients with epilepsy

Several studies have reported an association between certain human leukocyte antigen (HLA) alleles and carbamazepine (CBZ)-induced hypersensitivity reactions in patients with epilepsy. Here, the relationship between the clinical spectrum and the HLA allele profiles in patients with CBZ-induced hypersensitivity reactions was investigated using next-generation sequence (NGS) data obtained from 65 Vietnamese patients with epilepsy, including 33 with CBZ-tolerance and 32 patients with CBZ-hypersensitivity, in which only 8 with severe cutaneous adverse drug reactions and 24 were mild-hypersensitive patients. Three loci of HLA class I (HLA-A, -B, and -C) and two loci of HLA class II (HLA-DQA1 and -DRB1) were included in our analysis. We observed a higher prevalence of three alleles, HLA-B*46:01:01, HLA-DQA1*03:02:01, and HLA-DRB1*09:01:02, in the CBZ hypersensitivity group compared to that in the CBZ tolerant group. Notably, all hypersensitive patients with HLA-DQA1*03:02:01 also harbored HLA-DRB1*09:01:02. We also used molecular modeling to gain mechanistic insight into the interactions of HLA-B*46:01 and HLA-DRB1*09:01 with CBZ. Our findings proposed the direct interaction of CBZ with peptide-binding pockets of these HLA proteins. The sensitivity and specificity of HLA-B*46:01:01 in considering with the appearance of HLA-DRB1*09:01:02 were 46.88% and 84.85%, respectively. Our data suggest that the presence of HLA-B*46:01:01/HLA-DRB1*09:01:02 is a potential marker of CBZ-induced hypersensitivity reactions in Vietnamese patients.     

Human leucocyte antigens class II allele and haplotype association with Type 1 Diabetes in Madeira Island (Portugal)

This study confirms for Madeira Island (Portugal) population the Type 1 Diabetes (T1D) susceptible and protective Human leucocyte antigens (HLA) markers previously reported in other populations and adds some local specificities. Among the strongest T1D HLA associations, stands out, as susceptible, the alleles DRB1*04:05 (OR = 7.3), DQB1*03:02 (OR = 6.1) and DQA1*03:03 (OR = 4.5), as well as the haplotypes DRB1*04:05‐DQA1*03:03‐DQB1*03:02 (OR = 100.9) and DRB1*04:04‐DQA1*03:01‐DQB1*03:02 (OR = 22.1), and DQB1*06:02 (OR = 0.07) and DRB1*15:01‐DQA1*01:02‐DQB1*06:02 (OR = 0.04) as protective. HLA‐DQA1 positive for Arginine at position 52 (Arg52) (OR = 15.2) and HLA‐DQB1 negative for Aspartic acid at the position 57 (Asp57) (OR = 9.0) alleles appear to be important genetic markers for T1D susceptibility, with higher odds ratio values than any single allele and than most of the haplotypes. Genotypes generated by the association of markers Arg52 DQA1 positive and Asp57 DQB1 negative increase T1D susceptibility much more than one would expected by a simple additive effect of those markers separately (OR = 26.9). This study also confirms an increased risk for DRB1*04/DRB1*03 heterozygote genotypes (OR = 16.8) and also a DRB1*04‐DQA1*03:01‐DQB1*03:02 haplotype susceptibility dependent on the DRB1*04 allele (DRB1*04:01, OR = 7.9; DRB1*04:02, OR = 3.2; DRB1*04:04, OR = 22.1).     

Human leukocyte antigen–A, -B, -C, -DRB1 allele and haplotype frequencies in Americans originating from southern Europe: Contrasting patterns of population differentiation between Italian and Spanish Americans

High-resolution DNA sequencing was used to identify the human leukocyte antigen (HLA) –A, -B, -C, and -DRB1 alleles found in 552 individuals from the United States indicating Southern European (Italian or Spanish) heritage. A total of 46 HLA-A, 80 HLA-B, 32 HLA-C, and 50 DRB1 alleles were identified. Frequent alleles included A*02:01:01G (allele frequency = 0.26 in Italian Americans and 0.22 in Spanish Americans); B*07:02:01G (Italian Americans allele frequency = 0.11); B*44:03 (Spanish Americans allele frequency = 0.07); C*04:01:01G and C*07:01:01G (allele frequency = 0.13 and 0.16, respectively, in Italian Americans; 0.15 and 0.12, respectively, in Spanish Americans); and DRB1*07:01:01 (allele frequency = 0.12 in each population). The action of balancing selection was inferred at the HLA-B and -C loci in both populations. The A*01:01:01G-C*07:01:01G-B*08:01:01G-DRB1*03:01:01 haplotype was the most frequent A-C-B-DRB1 haplotype in Italian Americans (haplotype frequency = 0.049), and was the second most frequent haplotype in Spanish Americans (haplotype frequency = 0.021). A*29:02:01-C*16:01:01-B*44:03-DRB1*07:01:01 was the most frequent A-C-B-DRB1 in Spanish Americans (haplotype frequency = 0.023), and was observed at a frequency of 0.015 in Italian Americans. Pairwise F′_st values measuring the degree of differentiation between these Southern European American populations as well as European and European American populations suggest that Spanish Americans constitute a distinct subset of the European American population, most similar to Mexican Americans, whereas Italian Americans cannot be distinguished from the larger European American population.     

Full-length next-generation sequencing of HLA class I and II genes in a cohort from Thailand

The human leukocyte antigen (HLA) genes are highly variable and are known to play an important role in disease outcomes, including infectious diseases. Prior knowledge of HLA polymorphisms in a population usually forms the basis for an effective case-control study design. As a prelude to future disease association analyses, we report HLA class I and II diversity in 334 unrelated donors from a Dengue vaccine efficacy trial conducted in Thailand. Long-range PCR amplification of six HLA loci was performed on DNA extracted from saliva samples. HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1 were genotyped using a next-generation sequencing method presented at the 17th International HLA and Immunogenetics Workshop. In total, we identified 201 HLA alleles, including 35 HLA-A, 57 HLA-B, 28 HLA-C, 24 HLA-DPB1, 21 HLA-DQB1 and 36 HLA-DRB1 alleles. Very common HLA alleles with frequencies greater than 10 percent were A111:01:01, A133:03:01, A124:02:01, B146:01:01, C107:02:01, C101:02:01, C108:01:01, DPB1105:01:01, DPB1113:01:01, DPB1104:01:01, DPB1102:01:02, DQB1103:01:01, DQB1105:02:01, DQB1103:03:02, DRB1112:02:01, DRB1109:01:02, and DRB1115:02:01. A novel HLA allele, B115:450, had a non-synonymous substitution and occurred in more than one donor. Population-based full-length NGS HLA typing is more conclusive and provides a sound foundation for exploring disease association in a given population.     

Frequencies and haplotype associations of non-expressed HLA alleles in ethnically diverse populations on the National Marrow Donor Program’s Be The Match Registry

HLA allele matching is critical to successful bone marrow transplantation between a patient and donor. Non-functional HLA alleles, so called ‘null alleles’, are not well described within a large population of well HLA-typed ethnically diverse individuals despite their impact on donor selection. A retrospective analysis was performed on 833,789 unrelated donors (URDs) in the National Marrow Donor Program’s Be The Match Registry® typed for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 by next-generation DNA sequencing. Results showed that null alleles occur in low frequency (2.30E−04) compared to expressed alleles. Their overall frequency ranged from 6.00E−07 to 9.25E−04 with a median of 1.20E-06. The expected allele associations were commonly observed for HLA-A*24:09N, HLA-B*51:11N, and HLA-C*04:09N; however, associations outside of the expected were also observed. Notably, 82% of the National Marrow Donor Program Registry URDs carrying HLA-A*24:11N showed a different HLA-C allele association, HLA-C*05:01, compared to the allele described by prior published work characterizing German donor populations, HLA-C*04:01. The frequencies of these observed null alleles and linkage disequilibrium information could be invaluable and helpful in guiding the HLA testing decisions.     

A single center study of protective and susceptible HLA alleles and haplotypes with end-stage renal disease in China

Chronic kidney disease (CKD) is becoming a global public health problem and usually cause End-Stage Renal Disease (ESRD) in the end of progression. To analyze the associations of HLA-A, -B, -C, -DRB1 and -DQB1 alleles at high resolution with ESRD in Jiangsu province of China, a total of 499 unrelated patients with ESRD from the First Affiliated Hospital with Nanjing Medical University and 1584 healthy controls from Jiangsu Branch of Chinese Marrow Donor Program (CMDP) were genotyped at HLA-A, -B, -C, -DRB1 and -DQB1 loci. Statistical analysis was applied to compare the differences of HLA allele frequencies between patients with ESRD and healthy controls. As results, no protective allele at A locus was found and the susceptible alleles were A*11:01 and A*31:01. At B locus, B*15:01, B*55:02 and B*39:05 emerged as susceptible alleles, whereas no protective allele was found. At C locus, C*06:02 and C*07:01 emerged as protective alleles and no susceptible allele was found. At DRB1 locus, six alleles including DRB1*03:01, DRB1*04:03, DRB1*04:04, DRB1*04:05, DRB1*11:01 and DRB1*12:02 emerged as susceptible alleles, while DRB1*15:01 emerged as a protective allele. At DQB1 locus, DQB1*02:01, DQB1*03:01, DQB1*03:02 and DQB1*04:01 emerged as susceptible alleles, while DQB1*06:02 and DQB1*06:09 emerged as protective alleles. Haplotype A*11:01-C*03:03-B*15:01-DRB1*11:01-DQB1*03:01 containing four susceptible alleles was regarded as the most susceptible haplotype. The susceptible alleles and haplotypes might be used as some important risk classification markers. Besides, in the consanguineous renal transplantation, it would be very beneficial for the long-term survival of renal transplant patients to avoid the susceptible alleles and haplotypes in selecting optimal donors.     

Human leukocyte antigen class I B and C loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset

Alleles of human leukocyte antigen (HLA) class II genes are well known to affect susceptibility to type 1 diabetes (T1D), but less is known about the contribution of HLA class I alleles to T1D susceptibility. In this study, molecular genotyping was performed at the HLA-B and HLA-C loci for 283 multiplex Caucasian families, previously typed for HLA-A and the class II loci. Allele frequencies were compared between affected siblings and affected family-based controls. Linkage disequilibrium coefficients were calculated for HLA-B-HLA-C haplotypes and for class I-lass II haplotypes. After adjustment for linkage disequilibrium, the following alleles remain associated with T1D: B*1801, B*3906, B*4403, C*0303, C*0802, and C*1601. B and C allele associations were tested for certain T1D-associated DRB1-DQB1 haplotypes, with the following results: B*3801 is protective on DRB1*0401-DQB1*0302 haplotypes, both C*0701 and C*0702 are predisposing on DRB1*0404-DQB1*0302 haplotypes, and B*3906 is predisposing on DRB1*0801-DQB1*0402 haplotypes. As with previous results for HLA-A, HLA-B and HLA-C are associated with age at T1D onset (mean 11.6 +/- 0.3 years). The protective allele B*4403 was associated with older age at onset (15.1 years; p < 0.04), and the predisposing alleles C*0702 and B*3906 were associated with younger age at onset (9.5 years, p < 0.001; and 7.8 years, p < 0.002, respectively). These data support a role for HLA class I alleles in susceptibility to and age at onset of T1D.     

HLA-A、B、DRB1等位基因多态性与中国南方鼻咽癌的相关性研究

目的：探讨南方人群中鼻咽癌（NPC）易感性与HLA多态性之间的关联。方法：应用聚合酶链反应／序列特异性引物（PCR-SSP）方法对35例NPC患者及60例正常对照进行HLA-A、HLA-B及DRBI基因分型。结果：NPC患者的HLA-A＊02、HLA-B＊58及HLA-DRBI＊03基因位点的频率高于正常对照组，HLA-B＊40基因位点的频率低于正常对照组。结论：HLA-A＊02、HLA—B＊58及HLA—DRB1＊03可能是NPC的易感性基因，HLA-B＊40可能是NPC的保护性基因。     

HLA genetic study in Iran Saqqez-Baneh Kurds: no genetic trace of Aryan invasions in Anatolian Turks and Kurds is found

Kurds are living at Middle East region comprising several countries (38 million people) and also have emigrated to Asia, Europe and America. Kurds from Iran have been HLA typed in the present work from Saqqez and Baneh towns, Kordestan province, Iran. Origin of Kurds is considered autochthonous from Anatolia and surrounding mountains :they have been referred as “the mountain people” by classic Persian, Greek and Roman authors. Present day Turks are also autochthonous from Anatolia, but they were not recognized by classical authors as living in the mountains and they speak a language of Asian origin that was imposed to Anatolia by a “elite” invasion without a noticeable high Asian gene input. Most frequent class I and class II HLA alleles found in Iranian Kurds population are: HLA-A*24:02, A*02:01 and HLA-B*35:01, and HLA-DRB1*11:01, DRB1*03:02 and HLA-DQB1*03:01; also, most frequent HLA extended haplotypes from this Iran Kurdish sample are not shared with Iranians but with Mediterranean, Turkish and Caucasus people. This is confirmed by Neighbour-Joining and correspondence analysis studied together with the corresponding populations. Finally, our studies show that both Kurds and Turks are genetically original from Anatolian Peninsula and surrounding countries and that an apparent Asian genetic or Aryan invasion does not exist in the area.