Estimation of human leukocyte antigen class I and class II high-resolution allele and haplotype frequencies in the Italian population and comparison with other European populations

The high-resolution (HR) allele and haplotype frequencies of class I and II human leukocyte antigen (HLA) system were determined in the Italian population from a sample of donors recruited in the Italian Bone Marrow Donor Registry (IBMDR). This study analyzed the HLA-A, -B, -C, -DRB1, and -DQB1 loci. Two different samples were used: donors HR typed at least for one allele, usually when selected for donor-recipient matching (respectively: 3596, 7591, 4715, 57345, and 8196), to make a list of the observed alleles and determine the relative frequencies of the alleles in each class of the corresponding antigen; donors HR randomly typed for both the alleles (respectively: 975, 1643, 1569, 22114, and 2087) to estimate the allele and haplotype frequencies, and two loci linkage disequilibrium. The number of alleles showing a frequency >1% on the total number of observed alleles are 18/75 HLA-A, 28/142 -B, 17/57 -C, 23/154 -DRB1, and 13/31 -DQB1. In each locus they account for more than 88% of the total cumulative frequencies. The most frequent alleles are A*02: 01, B*35: 01, C*04:01, DRB1*07:01, DQB1*03:01. The most frequent five-locus haplotype in the 338 donors randomly typed is A*01: 01-C*07:01-B*08: 01-DRB1*03:01-DQB1*02:01. The genetic comparison of the Italian population with 16 European populations shows a south-north gradient.     

Sequence-based HLA-A,B, C,DP, DQ,and DR typing of 714 adults from Colombo,Sri Lanka

DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on 714 healthy adult blood bank donors from Colombo, Sri Lanka, to characterize allele frequencies in support of studies on T cell immunity against pathogens, including Dengue virus. Deviations from Hardy Weinberg proportions were not detected at any locus. Several alleles were found in >30% of individuals, including the class II alleles DPB1?*?04:01, DPB1?*?02:01, DQB1?*?06:01 and DRB1?*?07:01, and the class I alleles A?*?33:03 and A?*?24:02. Genotype data will be available in the Allele Frequencies Net Database.     

The influence of the HLA-DRB, HLA-DQB and polymorphic positions of the HLA-DRβ1 and HLA-DQβ1 molecules on risk of Iranian type 1 diabetes mellitus patients

Type 1 Diabetes mellitus (T1D) is an autoimmune and multifactorial disease. HLA-DRB1 and DQB1 loci have the strongest association with T1D. This study aimed at investigating (i) susceptibility or protection of alleles, genotypes and haplotypes of HLA-DRB1 and DQB1 loci; and (ii) highly polymorphic amino acid residues of HLA-DRβ1 and DQβ1 in 105 Iranian T1D patients and 100 controls. The results indicated that DRB1*04:01, 03:01, DQB1*03:02, 02:01 alleles, DRB1*03:01/04:01, 03:01/13:03, DQB1*02:01/03:02 genotypes, DRB1*04:01-DQB1*03:02, DRB1*03:01-DQB1*02:01, DRB1*07:01-DQB1*03:03 haplotypes had positive association with T1D. In contrast, HLA-DRB1*15:01, 13:01, DQB1*03:01, 06:01 alleles, DRB1*11:01/15:01, DQB1*03:01/06:01, 03:01/05:01 genotypes and DRB1*15:01-DQB1*06:01, DRB1*11:01-DQB1*03:01 haplotypes had negative association with T1D. Analysis of amino acid sequence of HLA-DRβ1 and DQβ1 revealed that DRβ1(Lys71+) and DQβ1(Asp57-) were significantly more frequent in patients than in controls and had a positive effect in the development of T1D. Haplotype analysis demonstrated that HLA-DRB1(Lys71+) allele provided major susceptibility for T1D, and DQβ1(Asp57-) had an additive effect. We designed an allele-specific primer to develop an easy, quick and cost-benefit method to detect the DRβ1(Lys71+) . This method can identify all 114 DRB1 alleles encoding DRβ1(Lys71+) by three PCR reactions. The PcPPV and PcNPV were also calculated to determine the impact of HLA genotype testing at amino acid positions. It showed that the DRβ1(Lys71+/+) genotype carrier had 1% absolute risk of developing T1D.     

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.     

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).     

Refined information on alleles belonging to the C*07:01/07:06/07:18 group in the Korean population

Alleles of the C*07:01/07:06/07:18 group is distinguished by polymorphisms in exons 5-6. In a previous study, we focused on exons 2-3 of the gene and showed that 6.8% of Koreans express alleles in this group. In this study, we identified allelic and haplotypic diversities of the C*07:01/07:06/07:18 group in Koreans. Among 118 C*07:01/07:06/07:18-positive, unrelated, healthy samples, 96.6% were C*07:06 and 3.4% were C*07:01. Each allele was exclusively associated with a specific set of other alleles consisting of the conserved haplotypes A*01:01-C*07:01-B*08:01-DRB1*03:01-DQB1*02:01 (100%) and A*33:03-C*07:06-B*44:03-DRB1*07:01-DQB1*02:02 (95.6%), respectively. None carried C*07:18. With the continuous discovery of novel alleles, periodic updates with testing for newer alleles will be useful to support related research and clinical settings in each population.     

HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1 allele frequencies of North Tanzanian Maasai

Locus-specific amplicon sequencing was used to HLA type 336 participants of Maasai ethnicity at the HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci. Participants were recruited from three study villages in North Tanzania, for the purpose of investigating risk factors for trachomatous scarring in children. Other than HLA-A, all loci significantly deviated from Hardy-Weinberg equilibrium, possibly due to high relatedness between individuals: 238 individuals shared a house with at least one another participant. The most frequent allele for each locus were A*68:02 (14.3 %), B*53:01 (8.4 %), C*06:02 (19.2 %), DRB1*13:02 (17.7 %), DQB1*02:01 (16.9 %) and DPB1*01:01 (15.7 %), while the most common inferred haplotype was A*68:02 ～ B*18:01 ～ C*07:04 ～ DRB1*08:04 ～ DQB1*04:02 ～ DPB1*04:01 (1.3 %).     

HLA class II susceptibility pattern for type 1 diabetes (T1D) in an Iranian population

This study aimed to determine the HLA‐DRB1/HLA‐DQB1 susceptibility and protection pattern for type 1 diabetes (T1D) in a population from Hamadan, north‐west of Iran. A total of 133 patients with T1D were tested for HLA‐DRB1 and HLA‐DQB1 alleles using PCR‐SSP compared to 100 ethnic‐matched healthy controls. Alleles and haplotypes frequencies were compared between both groups. The most susceptible alleles for disease were HLA‐DRB1*03:01, DRB1*04:02, DQB1*02:01 and DQB1*03:02, and protective alleles were HLA‐DRB1*07:01, *11:01, *13:01, *14:01 and DRB1*15 and HLA‐DQB1*06:01, *06:02 and *06:03. Haplotype analysis revealed that patients with T1D had higher frequencies of DRB1*03:01–DQB1*02:01 (OR = 4.86, P < 10^?7) and DRB1*04:02–DQB1*03:02 (OR = 9.93, P < 10^?7) and lower frequencies of DRB1*07:01–DQB1*02:01 (P = 0.0005), DRB1*11:01–DQB1*03:01 (P = 0.001), DRB1*13:01–DQB1*06:03 (P = 0.002) and DRB1*15–DQB1*06:01 (P = 0.001) haplotypes compared to healthy controls. Heterozygote combination of both susceptible haplotypes (DR3/DR4) confers the highest risk for T1D (RR = 18.80, P = 4 × 10^?5). Additionally, patients with homozygote diplotype, DR3/DR3 and DR4/DR4, showed a similar risk with less extent to heterozygote combination (P = 0.0004 and P = 0.01, respectively). Our findings not only confirm earlier reports from Iranians but also are in line with Caucasians and partly with Asians and some African patients with T1D. Remarkable differences were the identification of DRB1*04:01–DQB1*03:02, DRB1*07:01–DQB1*03:03 and DRB1*16–DQB1*05:02 as neutral and DRB1*13:01–DQB1*06:03 as the most protective haplotypes in this study.     

6-Locus HLA allele and haplotype frequencies in a population of 1075 Russians from Karelia

A total of 1075 Russians from the Russian part of Karelia were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 using next generation sequencing methods. The haplotypic and allelic profiles as well as Hardy-Weinberg proportions of this population sample were evaluated. As the most frequent 6-locus haplotype, A*03:01 g ～ B*07:02 g ～ C*07:02 g ～ DRB1*15:01 g ～ DQB1*06:02 g ～ DPB1*04:01 g was identified with an estimated frequency of 3.5%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Russia Karelia” and the identifier AFN3430.     

HLA-A, -B, -DRB1 and -DQB1 polymorphisms among Iraqi Arabs

In this report, HLA polymorphisms (A, B, DRB1 and DQB1 loci) were determined in 149 unrelated Iraqi Arab potential bone marrow and kidney donors. Molecular genotyping was carried out by polymerase chain reaction followed by specific oligonucleotide probe hybridizations. Data were analyzed by Arlequin software. HLA-A, -B and -DRB1 genotype frequencies were significantly deviated from Hardy-Weinberg equilibrium, while HLA-DQB1 frequencies showed no deviation. A*03, B*35, DRB1*11 and DQB1*02 were the most frequent allele groups, while A*02-B*07-DRB1*04-DQB1*03 was the most frequent haplotype. HLA data are available in the Allele Frequencies Net Database (AFND: 3680) under the population name “Iraq Arabs”.     

Common and well-documented (CWD) alleles of human leukocyte antigen-A, -B, -C, -DRB1, and -DQB1 loci for the Chinese Han population do not quite correlate with the ASHI CWD alleles

Human leukocyte antigen (HLA), which is extremely polymorphic, plays an important role in stem cell transplantation. The Chinese Han comprise a large population of approximately 1.3 billion with diverse HLA alleles that need to be characterized. Data from 3,296 independent, unrelated Chinese Han individuals (1,457 recipients and 1,839 donors) were provided by the China Marrow Donor Program (CMDP) for donor-recipient confirmatory typing. Sequence-based typing, sequence-specific oligonucleotide probe (SSOP)/High Definition-SSOP, and sequence-specific primer methods were used to obtain 4-digit alleles. A total of 49, 86, 50, 63, and 24 HLA-A, -B, -C, -DRB1, and -DQB1 alleles were observed. Following American Society for Histocompatibility and Immunogenetics (ASHI) common and well-documented (CWD) criteria, CWD alleles for Chinese Han in our laboratory test and other laboratory reports do not quite correlate with the ASHI CWD alleles: A*11:53, A*02:34, A*02:53N, B*27:24, B*46:02, B*55:12, C*01:06, C*03:17, C*06:06, C*07:66, C*07:67, C*08:22, DRB1*12:10, DQB1*03:13, and DQB1*06:05 are CWD, but are not included in the ASHI CWD list. A series of alleles are well-documented alleles and are listed in the ASHI CWD list. Conversely, A*26:03, B*51:03, C*12:05, C*15:09, C*15:11, C*17:03, DRB1*11:07, DRB1*11:11, DRB1*13:05, DRB1*13:13, DRB1*14:06, DRB1*14:12, DRB1*14:22, DRB1*14:25, and DQB1*06:11 are rare alleles, but are included in the ASHI CWD list. HLA ethnic diversity is the main reason for the differences in HLA alleles worldwide. The ASHI HLA CWD alleles help reduce the workload and expenses in high-resolution donor registries and the HLA allele frequencies provide a basis from which to predict the chances of finding HLA matching donors. Our data will be meaningful for the CMDP, for other worldwide donor registries, and for an updated ASHI CWD allele list.     

HLA class I and class II haplotypes in admixed families from several regions of Mexico

We studied HLA class I and class II alleles in 191 Mexican families (381 non-related individuals) to directly obtain the HLA-A/B/DRB1/DQB1 haplotypes and their linkage disequilibrium (LD). The most frequent HLA haplotypes observed were: A*02-B*39-DRB1*04-DQB1*0302, A*02-B*35-DRB1*04-DQB1*0302, A*68-B*39-DRB1*04-DQB1*0302, A*02-B*35-DRB1*08-DQB1*04, A*33-B*1402-DRB1*01-DQB1*05, and A*24-B*35-DRB1*04-DQB1*0302. The four most common haplotypes found by our study involve those previously reported in Amerindian populations. LD analysis of HLA-A-B and HLA-B-DRB1 loci showed significant associations between A29(19)-B44(12), A33(19)-B65(14), A1-B8, A26(19)-B44(12), A24(9)-B61(40), B65(14)-DR1, B8-DR17(3), B44(12)-DR7, B7-DR15(2), and B39(16)-DR4. Also, all DRB1-DQB1 associations showed significant LD values. Admixture estimations using a trihybrid model showed that Mexicans from the State of Sinaloa (Northern Mexico) have a greater proportion of European genetic component compared with Mexicans from the Central area of Mexico, who have a greater percentage of Amerindian genes. Our results are important for future comparative genetic studies of different Mexican ethnic groups with special relevance to disease association and transplantation studies.     

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.     

Los primeros pobladores de América y sus relaciones con poblaciones del Océano Pacífico según los genes HLA

HLA allele frequencies were compared with those of other First American Natives and also those of other worldwide populations in order to clarify the still unclear peopling of the Americas and the origins of Amerindians. All possible HLA data already obtained on early Native American populations are used. Genetic distances and N-J dendrogram methods are applied. Results and discussion have led to the following conclusions: 1) North West Canadian Athabaskans have had gene flow with close neighbouring populations, Amerindians, Pacific Islanders, including East Australians, and Siberians, since they share DRB1-DQB1 haplotypes with these populations (i.e.: DRB1*14:01-DQB1*05:03, DRB1*09:01-DQB1*03:03); 2) Amerindians entrance to America may have been different to that of Athabaskans, Aleuts and Eskimos; Amerindians may have been in their lands long before Athabaskans and Eskimos as they present an altogether different set of HLA-DRB1 allele frequencies; 3) Amerindians show very few “particular” single-locus alleles (i.e.: DRB1*04:11, DRB1*04:17), but have unique extended haplotypes (i.e.: A*02-B*35-DRB1*04:07-DQB1*03:02, A*02-B*35-DRB1*08:02-DQB1*04:02); 4) Our results do not support the three-wave model of American peopling but another model, where the Pacific Coast is also an entrance point. Pacific Ocean sea voyages may have contributed to the HLA genetic American profile. Reverse migration (America to Asia) is not discarded, and different movements of people in either direction in different times are supported by the Athabaskan population admixture with Asian-Pacific population and with Amerindians.     

HLA genes in Amerindians from Mexico San Vicente Tancuayalab Teenek/Huastecos

Huastecos or Teenek Amerindians are presently living at North East Mexico (San Luis Potosi State). They have probably one of the most ancient culture of Mexico and Central America together with Mayas and Olmec groups with which also show close relationships. Proximity to Atlantic Ocean/Mexican Gulf originated that Spaniards had very early contact with them at about 1519 CE or before. In the present paper we have aimed to study HLA gene profile which may be useful for HLA and disease epidemiology and transplant programs in Teeneks. HLA-DRB1*04:07, -DRB1*14:06 and -DRB1*04:11 have been found in high frequency like in other Amerindian groups. High frequency typical Amerindians HLA extended haplotypes have been found, such as A*02-B*35-DRB1*04:07-DQB1*03:02; A*68-B*39-DRB1*04:07-DQB1*03:02 and A*02-B*39-DRB1*04:07-DQB1*03:02; also new haplotypes have been described, like A*02-B*52-DRB1*04:11-DQB1*03:02, A*68-B*35-DRB1*14:02-DQB1*03:01 and A*68-B*40-DRB1*16:02-DQB1*03:01. Genetic proximity is observed not only to linguistically close Mayans, but also to Mazatecans, Mixtecans and Zapotecans, who speak an altogether different languages; it shows once more that genes and languages do not correlate. This population was greatly diminished after European contact between 1500 and 1600 years CE; in fact, North and South America First Inhabitants population was brought from 80 down to 8 million people because of diseases (i.e.: measles, smallpox or influenza), slavery and war.     

Class II HLA in Georgia Caucasus Tbilisi Georgians and their Mediterranean ancestry: The Usko Mediterranean languages

Georgia (or Sakartvelo in its own language) is a South Caucasus Mts. country with its easternmost part is enigmatically named Iberia, like the Iberian Peninsula, which may refer to rivers “Kura” and “Ebro” or their valleys respectively. Most of their inhabitants speak Georgian which is included within Dene-Caucasian group and Usko-Mediterranean subgroup of languages. The latter includes Basque, Berber, ancient Iberian-Tartessian, Etruscan, Hittite, Minoan Lineal A and others. In the present paper, HLA class II -DRB1 and -DQB1 alleles has been studied and extended haplotypes calculated. Most frequent haplotypes are also of Mediterranean origin (i. e.: (A*02-B*51)-DRB1*11:01-DQB1*03:01, (A*02-B*51)-DRB1*13:01-DQB1*06:03, or (A*24-B*35)-DRB1*01:01-DQB1*05:01) and DA genetic distances show that closest world populations to Georgians are Mediterraneans. Georgians also show common extended haplotypes ((A*02-B*51)-DRB1*11:01-DQB1*03:01, (A*02-B*13)-DRB1*07:01-DQB1*02:01 and (A*03-B*35)-DRB1*11:01-DQB1*03:01) with Svan people, a secluded population in North Georgia mountains. We can conclude that Georgians belong to a very old Mediterranean substratum according to both linguistics (Usko Mediterranean languages) and HLA genetics.     

5-Locus high-resolution HLA allele and haplotype frequencies in Costa Ricans from the Central Valley

A total of 221 Costa Rican Mestizos from the Central Valley were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, -DRB1, and -DQB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*40:02:01-C*03:05-DRB1*08:02:01-DQB1*04:02:01, with an estimated frequency of 2.04%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Costa Rica Central Valley Mestizo” and the identifier AFN3606.     

HLA-DRB and -DQB1 polymorphism in the Macedonian population

HLA-DRB1, DRB3/4/5 and DQB1 polymorphism has been studied in a population of 80 unrelated healthy Macedonians using molecular methods. Twenty-five different DRB1 alleles were identified of which DRB1*1104, *1501, *1601, and *1101 were found most frequently. Among the 15 identified DQB1 alleles, two were predominant: DQB1*0301 and *0502. The most frequent three-locus haplotypes were DRB1*1104-DRB3*02-DQB1*0301 (18%/), DRB1*1101-DRB3*02-DQB1*0301 (9%) and DRB1*1601-DRB5*02-DQB1*0502 (10%). Polymorphism for DRB1*04, *13 and *15 haplotypes was extensive. Eleven different DR2-related haplotypes were found, some of which were unusual for European populations: DRB1*1501-DRB5*0102-DQB1*0502, DRB1*1501-DRB5*02-DQB1*0502, DRB1*1501-DRB5*0102-DQB1*0601.     

HLA-DQ association and allele competition in Chinese narcolepsy

In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1*06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1*15:01/3 and DQB1*06:02 in most populations. In this study, we studied human leucocyte antigen (HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1*06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1*06:02 and DRB1*15:01, we found that the presence of DQB1*06:02 and not DRB1*15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1*15:01-DQA1*01:02-DQB1*06:01 and DRB1*15:01-DQA1*01:02-DQB1*05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1*01 (non-DQA1*01:02) and susceptibility effects of DQB1*03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1*15:01 has no effect on narcolepsy susceptibility in the absence of DQB1*06:02. The results are also in line with a previously proposed 'HLA-DQ allelic competition model' that involves competition between non-DQA1*01:02, non-DQB1*06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQα*01:02/ DQβ*06:02 narcolepsy heterodimer to reduce susceptibility.     

4-Locus high-resolution HLA allele and haplotype frequencies in Amerindians from Costa Rica

A total of 125 Costa Ricans of Amerindian descent were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*40:02:01-C*03:05-DRB1*04:07:01G, with an estimated frequency of 8.26%. A deviation from Hardy-Weinberg Equilibrium was detected at the DRB1 locus (p = 0.099). The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Costa Rica Amerindians” and the identifier AFN3608.