Analysis of admixture and genetic structure of two Native American groups of Southern Argentinean Patagonia

Argentinean Patagonia is inhabited by people that live principally in urban areas and by small isolated groups of individuals that belong to indigenous aboriginal groups; this territory exhibits the lowest population density of the country. Mapuche and Tehuelche (Mapudungun linguistic branch), are the only extant Native American groups that inhabit the Argentinean Patagonian provinces of Río Negro and Chubut. Fifteen autosomal STRs, 17 Y-STRs, mtDNA full length control region sequence and two sets of Y and mtDNA-coding region SNPs were analyzed in a set of 434 unrelated individuals. The sample set included two aboriginal groups, a group of individuals whose family name included Native American linguistic root and urban samples from Chubut, Río Negro and Buenos Aires provinces of Argentina. Specific Y Amerindian haplogroup Q1 was found in 87.5 % in Mapuche and 58.82 % in Tehuelche, while the Amerindian mtDNA haplogroups were present in all the aboriginal sample contributors investigated. Admixture analysis performed by means of autosomal and Y-STRs showed the highest degree of admixture in individuals carrying Mapuche surnames, followed by urban populations, and finally by isolated Native American populations as less degree of admixture. The study provided novel genetic information about the Mapuche and Tehuelche people and allowed us to establish a genetic correlation among individuals with Mapudungun surnames that demonstrates not only a linguistic but also a genetic relationship to the isolated aboriginal communities, representing a suitable proxy indicator for assessing genealogical background.     

HLA genetic profile of Mapuche (Araucanian) Amerindians from Chile

Amerindian Mapuche (Araucanians) are now living in Chile and Argentina at both sides of Andean Mountains. They are anthropologically and genetically different from southernmost South America Patagonian Amerindians. Most of the HLA alleles found in our Mapuche sample are frequent or very frequent in North and South America Amerindians: (1) Class I: A*02:01, A*03:01, A*68:01, B*39:09, B*51:01, (2) Class II: DRB1*03:01, DRB1*04:03, DRB1*07:01, DRB1*08:02, DRB1*14:02, DRB1*16:02. One of the nine most frequent extended haplotypes seems to be from European origin, suggesting the existence of a degree of admixture with Europeans in our Mapuche sample. It has been calculated of about 11 % admixture. Three of the extended haplotypes are also found in other Amerindians and five of them are newly found in Mapuche Amerindians: A*68:01-B*39:09-DRB1*08:02-DQB1*04:02; A*68:01-B*51:01-DRB1*04:03-DQB1*03:02; A*29:01-B*08:01-DRB1*03:01-DQB1*02:01; A*02:01-B*15:01-DRB1*04:03-DQB1*03:02; A*33:01-B*14:02-DRB1*07:01-DQB1*03:03. The medical importance of calculating HLA profile is discussed on the diagnostic (HLA and disease) and therapeutical bases of HLA pharmacogenomics and on the construction of a virtual transplantation HLA list profile. Also, anthropological conclusions are drawn.     

MHC Class II haplotypes of Colombian Amerindian tribes

We analyzed 1041 individuals belonging to 17 Amerindian tribes of Colombia, Chimila, Bari and Tunebo (Chibcha linguistic family), Embera, Waunana (Choco linguistic family), Puinave and Nukak (Maku-Puinave linguistic families), Cubeo, Guanano, Tucano, Desano and Piratapuyo (Tukano linguistic family), Guahibo and Guayabero (Guayabero Linguistic Family), Curripaco and Piapoco (Arawak linguistic family) and Yucpa (Karib linguistic family). for MHC class II haplotypes (HLA-DRB1, DQA1, DQB1). Approximately 90% of the MHC class II haplotypes found among these tribes are haplotypes frequently encountered in other Amerindian tribes. Nonetheless, striking differences were observed among Chibcha and non-Chibcha speaking tribes. The DRB1*04:04, DRB1*04:11, DRB1*09:01 carrying haplotypes were frequently found among non-Chibcha speaking tribes, while the DRB1*04:07 haplotype showed significant frequencies among Chibcha speaking tribes, and only marginal frequencies among non-Chibcha speaking tribes. Our results suggest that the differences in MHC class II haplotype frequency found among Chibcha and non-Chibcha speaking tribes could be due to genetic differentiation in Mesoamerica of the ancestral Amerindian population into Chibcha and non-Chibcha speaking populations before they entered into South America.     

Analysis of HLA class II haplotypes in the Cayapa Indians of Ecuador: a novel DRB1 allele reveals evidence for convergent evolution and balancing selection at position 86.

PCR amplification, oligonucleotide probe typing, and sequencing were used to analyze the HLA class II loci (DRB1, DQA1, DQB1, and DPB1) of an isolated South Amerindian tribe. Here we report HLA class II variation, including the identification of a new DRB1 allele, several novel DR/DQ haplotypes, and an unusual distribution of DPB1 alleles, among the Cayapa Indians (N = 100) of Ecuador. A general reduction of HLA class II allelic variation in the Cayapa is consistent with a population bottle-neck during the colonization of the Americas. The new Cayapa DRB1 allele, DRB1*08042, which arose by a G-->T point mutation in the parental DRB1*0802, contains a novel Val codon (GTT) at position 86. The generation of DRB1*08042 (Val-86) from DRB1*0802 (Gly-86) in the Cayapa, by a different mechanism than the (GT-->TG) change in the creation of DRB1*08041 (Val-86) from DRB1*0802 in Africa, implicates selection in the convergent evolution of position 86 DR beta variants. The DRB1*08042 allele has not been found in > 1,800 Amerindian haplotypes and thus presumably arose after the Cayapa separated from other South American Amerindians. Selection pressure for increased haplotype diversity can be inferred in the generation and maintenance of three new DRB1*08042 haplotypes and several novel DR/DQ haplotypes in this population. The DPB1 allelic distribution in the Cayapa is also extraordinary, with two alleles, DPB1*1401, a very rare allele in North American Amerindian populations, and DPB1*0402, the most common Amerindian DPB1 allele, constituting 89% of the Cayapa DPB1.(ABSTRACT TRUNCATED AT 250 WORDS)     

HLA class II alleles in Ainu living in Hidaka district,Hokkaido, northern Japan

The Ainu people are considered to be the descendants of preagricultural native populations of northern Japan, while the majority of the population of contemporary Japan (Wajin) is descended mainly from postneolithic migrants. Polymorphisms of the HLA-DRB1, DRB3, and DQB1 alleles were investigated in DNA samples of 50 Ainu living in Hidaka district, Hokkaido. Unique features of the Ainu in this study were high incidences of DRB1*1401, DRB1*1406, and a newly described allele, DRB1*1106 (20%, 17%, and 5%, respectively). On the other hand, several common alleles in Wajin (DRB1*1502, 1302, 0803, and 1501) were found at relatively low frequencies (1–2%) in Ainu. Previously DRB1*1406 was described as a characteristic allele of some Native American or northeast Asian ethnic groups, and DRB1*1106 had been found in only two Singapore Chinese and one Korean. Principal component analysis of various populations based on HLA class II allele frequencies places the Ainu population midway between other east Asian populations, including Wajin, and Native Americans. These observations may support the hypothesis that the Ainu people are the descendants of some Upper Paleolithic populations of northeast Asia from which Native Americans are also descended. © 1996 Wiley-Liss, Inc.     

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.     

HLA class II polymorphism in autochthonous population of Gorski kotar, Croatia

The aim of this study was to examine frequencies and haplotypic associations of HLA class II alleles in autochthonous population of Gorski kotar (Croatia). HLA-DRB1, -DQA1 and -DQB1 alleles were determined by DNA based PCR typing in 63 unrelated inhabitants from Gorski kotar whose parents and ancestors were born and lived in tested area for at least over four generations. A total of 13 HLA-DRB1, 12 DQA1 and 14 DQB1 alleles were identified. The most frequent HLA class II genes in Gorski kotar population are: HLA-DRB1*13 (af = 0.150), -DRB1*03 (af = 0.142), -DRB1*07 (af = 0.119), and -DRB1*11 (af = 0.119), HLA-DQA1*0501 (af = 0.278), -DQA1*0102 (af = 0.183), -DQA1*0201 (af = 0.127) and HLA-DQB1*0301 (af = 0.157), -DQB1*0201 (af = 0.139), -DQB1*0501 (af = 0.111). We have identified 24 HLA class II three-locus haplotypes. The most common haplotypes in Gorski kotar population are DRB1*03-DQA* 0501-DQB1*0201 (0.120), DRB1*11-DQA1*0501-DQB1*0301 (0.111) and DRB1*07-DQA1*0201-DQB1*0202 (0.094). The allelic frequencies and populations distance dendrogram revealed the closest relationships of Gorski kotar population with Slovenians, Germans, Hungarians and general Croatian population, which is the result of turbulent migrations within this microregion during history.     

HLA class II antigens positively and negatively associated with hepatosplenic schistosomiasis in a Chinese population

To identify possible associations between host genetic factors and the onset of liver fibrosis following Schistosoma japonicum infection, the major histocompatibility class II alleles of 84 individuals living on an island (Jishan) endemic for schistosomiasis japonica in the Poyang Lake Region of Southern China were determined. Forty patients exhibiting advanced schistosomiasis, characterised by extensive liver fibrosis, and 44 age and sex-matched control subjects were assessed for the class II haplotypes HLA-DRB1 and HLA-DQB1. Two HLA-DRB1 alleles, HLA-DRB1*0901 (P=0.012) and *1302 (P=0.039), and two HLA-DQB1 alleles, HLA-DQB1*0303 (P=0.012) and *0609 (P=0.037), were found to be significantly associated with susceptibility to fibrosis. These associated DRB1 and DQB1 alleles are in very strong linkage disequilibrium, with DRB1*0901-DQB1*0303 and DRB1*1302-DQB1*0609 found as common haplotypes in this population. In contrast, the alleles HLA-DRB1*1501 (P=0.025) and HLA-DQB1*0601 (P=0.022) were found to be associated with resistance to hepatosplenic disease. Moreover, the alleles DQB1*0303 and DRB1*0901 did not increase susceptibility in the presence of DQB1*0601, indicating that DQB1*0601 is dominant over DQB1*0303 and DRB1*0901. The study has thus identified both positive and negative associations between HLA class II alleles and the risk of individuals developing moderate to severe liver fibrosis following schistosome infection.     

Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis

The importance of the HLA-DR locus to multiple sclerosis (MS) susceptibility was assessed in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 alleles, we confirmed the well-established association of MS with HLA-DRB1*15 (HLA-DRB1*1501 and HLA-DRB5*0101), by the transmission/disequilibrium test (chi2=138.3; P<.0001). We obtained significant evidence of linkage throughout the whole data set (mlod=4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1*15 allele (mlod=1.56; 62.7% sharing; P=.0081). Our findings suggest that the notion that HLA-DRB1*15 is the sole major-histocompatibility-complex determinant of susceptibility in northern-European populations with MS may be incorrect. It remains possible that the association of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1*15-negative haplotypes.     

Association of the HLA-DRB1 with Scleroderma in Chinese Population

Multiple alleles of the Human leukocyte antigen (HLA) DRB1 have been strongly associated with systemic sclerosis (SSc) and its clinical or serological subsets. However, the associations vary in different ethnic populations. To define SSc-risk and/or -protective alleles of HLA-DRB1 in Chinese population, we studied a Han Chinese cohort containing 585 patients with SSc and 458 gender-matched, unrelated controls. The HLA-DRB1 genotyping was performed with sequence-based typing method. Exact p-values were obtained (Fisher’s test) from 2×2 tables of allele frequency and disease status. The major SSc-risk allele subtypes of HLA-DRB1 are the DRB1*15∶02 and *16∶02 in this Chinese cohort. Particularly, DRB1*15∶02 was most significantly associated with anti-centromere autoantibodies (ACA) positive, and DRB1*16∶02 with anti-topoisomerase I autoantibodies (ATA) positive patients. On the other hand, DRB1*01∶01 and *04∶06 were strong SSc-protective alleles in Chinese, especially in patients who were ACA positive and had diffuse cutaneous SSc (dcSSc), respectively. In addition, DRB1*11 and *07∶01 also showed significant association with SSc as a risk for and protection from SSc, respectively, and which is consistent with the studies of Spanish, US Caucasian and Hispanic populations. DRB1*15 was associated with ATA positive Chinese SSc that is consistent with Black South African and Korean SSc. These findings of HLA-DRB1 alleles in association with Chinese SSc provide the growing knowledge of genetics of SSc, and indicate that the genetic heterogeneity among ethnicities may significantly impact the complex trait of SSc.     

The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis

The objective of this study was to examine HLA-DRB1 and HLA-DQB1 genotypes in patients with severe extra-articular rheumatoid arthritis (ExRA) and to compare them with the genotypes of rheumatoid arthritis (RA) patients without extra-articular manifestations. Patients with severe ExRA were recruited from a large research database of patients with RA, from two cohorts of prevalent RA cases, and from a regional multicenter early RA cohort. Cases with ExRA manifestations (n = 159) were classified according to predefined criteria. Controls (n = 178) with RA but no ExRA were selected from the same sources. Cases and controls were matched for duration of RA and for clinical center. PCR based HLA-DRB1 and HLA-DQB1 genotyping was performed using the Biotest SSP kit, with additional sequencing in order to distinguish DRB1*04 subtypes. Associations between alleles and disease phenotypes were tested using multiple simulations of random distributions of alleles. There was no difference in global distribution of HLA-DRB1 and HLA-DQB1 alleles between patients with ExRA and controls. DRB1*0401 (P = 0.003) and 0401/0401 homozygosity (P = 0.002) were more frequent in Felty's syndrome than in controls. The presence of two HLA-DRB1*04 alleles encoding the shared epitope (SE) was associated with ExRA (overall odds ratio 1.79, 95% confidence interval 1.04-3.08) and with rheumatoid vasculitis (odds ratio 2.44, 95% confidence interval 1.22-4.89). In this large sample of patients with ExRA, Felty's syndrome was the only manifestation that was clearly associated with HLA-DRB1*0401. Other ExRA manifestations were not associated with individual alleles but with DRB1*04 SE double dose genotypes. This confirms that SE genes contribute to RA disease severity and ExRA. Other genetic and environmental factors may have a more specific impact on individual ExRA manifestations.     

Association between HLA-DRB1, HLA-DRQB1 alleles,and CD4<Superscript>+</Superscript>CD28<Superscript>null</Superscript> T cells in a Chinese population with coronary heart disease

CD4⁺CD28^null T cells are present in increased numbers in the peripheral blood of patients with acute coronary syndrome. However, the triggers of expansion of these cells are unclear. Susceptibility to coronary heart disease (CHD) is strongly associated with alleles of human leukocyte antigen (HLA), but it is not equally strong in different human populations. The objective of the study was to investigate association between CD4⁺CD28^null T cells and HLA-DRB1 alleles. The HLA alleles were determined by polymerase chain reaction with sequence-specific primers (PCR-SSP) method, in a group of CHD patients and control subjects from the same area. The number of CD4⁺CD28^null T cells was measured using the flow cytometry technique. The HLA-DRB1*01 (RR = 4.705, P < 0.005) and DRB1*04 (RR = 3.554, P < 0.005) alleles showed the strongest association with CHD in the Chinese population, and increased numbers of CD4⁺CD28^null T cells were found in association with HLA-DRB1*04 (17.1%) and DRB*01 (12.9%), while decreased numbers of CD4⁺CD28^null T cells were present in subjects with DRB1*15 (0.8%). CHD in Chinese population is strongly associated with HLA-DRB1*01 and DRB1*04 haplotypes, and formation of CD4⁺CD28^null T cells was related to HLA-DRB1*01, DRB1*04, and DRB1*15 alleles.     

Polymorphism of human HLA-DRB1 leukocyte antigen alleles and its association to juvenile rheumatoid arthritis in a sample of Colombian mestizo children

Oligotypes of the human leukocyte antigen HLA Class II, DRB1 alleles were characterized at the molecular level in a group of Colombian children suffering juvenile rheumatoid arthritis (JRA). The distribution of these alleles was examined in a group of Colombian mestizo children (genetic admixture of Amerindians, Europeans and Africans) suffering from clinically distinct JRA subsets in order to detect HLA allele frequency differences in patients with different JRA subsets. A group of 65 patients with JRA and 65 controls were characterized for the subtypes of the HLA-DRB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide probes (PCR-SSOP). The oligotyping protocol recommended by the 12th International Histocompatibility Workshop held in St. Malo, Paris, in 1996, was used. Subtype HLA-DRB1*1104 was the allele most strongly associated with susceptibility to JRA (Fisher's p = 0.013, odds ratio (OR) = 16.79, etiologic fraction (EF) = 0.93). HLA-DRB1*1602 was also associated with susceptibility to a lesser degree (Fisher's p = 0.016, OR = 8.98, EF = 0.88). HLA-DRB1 alleles participating in JRA protection were HLA-DRB1*1501 (preventive fraction (PF) = 0.466, p = 0.005) and HLA DRB1*1402 (PF = 0.49, p = 0.009). The relationship between some HLA-DRB1 alleles and clinical features was also compared. The presence of rheumatic factor was associated with the alleles HLA-DRB1*0407 (p = 0.05, OR = 11.2, EF = 0.45) and HLA-DRB1*1302 (p = 0.02, OR = 22.8, EF = 0.63). There was also an association between HLA-DRB1*0701 (p = 0.001, OR = 58, EF = 0.73) with expressing ANA +. We found that in the oligoarticular subset, the allele HLA-DRB1*1104 (p = 0.0034, OR = 41.53, EF = 0.97) was the one expressed most commonly. In the poliarticular group, the alleles most frequently expressed were HLA-DRB1*0404 (Fisher's p = 0.012, OR = 8.75, EF = 0.88). In patients with systemic JRA, the HLA-DRB1*1602 allele (p = 0.005, OR = 21.33, EF = 0.95) was most frequent. These results suggested that the MHC genes of mestizo children influence not only the clinical expression of the disease, but also the susceptibility to its development.     

Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients

Background

A strong genetic influence by the MHC class II region has been reported in sarcoidosis, however in many studies with different results. This may possibly be caused by actual differences between distinct ethnic groups, too small sample sizes, or because of lack of accurate clinical subgrouping.

Subjects and methods

In this study we HLA typed a large patient population (n = 754) recruited from one single centre. Patients were sub-grouped into those with Löfgren''s syndrome (LS) (n = 302) and those without (non-Löfgren''s) (n = 452), and the majority of them were clinically classified into those with recovery within two years (resolving) and those with signs of disease for more than two years (non-resolving). PCR was used for determination of HLA-DRB1 alleles. Swedish healthy blood donors (n = 1366) served as controls.

Results

There was a dramatic difference in the distribution of HLA alleles in LS compared to non-LS patients (p = 4 × 10^-36). Most notably, DRB1*01, DRB1*03 and DRB1*14, clearly differed in LS and non-LS patients. In relation to disease course, DRB1*07, DRB1*14 and DRB1*15 generally associated with, while DRB1*01 and DRB1*03 protected against, a non-resolving disease. Interestingly, the clinical influence of DRB1*03 (good prognosis) dominated over that of DRB1*15 (bad prognosis).

Conclusions

We found several significant differences between LS and non-LS patients and we therefore suggest that genetic association studies in sarcoidosis should include a careful clinical characterisation and sub-grouping of patients, in order to reveal true genetic associations. This may be particularly accurate to do in the heterogeneous non-LS group of patients.     

HLA in Jaidukama: an Amerindian secluded Colombian population with new haplotypes and Asian and Pacific-shared alleles

America first inhabitants and peopling are still debated. In order to increase knowledge about these questions, we have aimed to detect HLA genes of an Amerindian secluded community: Jaidukama, who lives in North Colombia Equatorial forest. HLA genotyping and extended haplotype calculations were carried out in 39 healthy individuals belonging to 13 families. HLA frequencies were compared to other Amerindians and worldwide populations by calculating genetic distances, relatedness dendrograms and correspondence analyses. Only four DRB1 alleles were found (*0404, *0407, *1402 and *1602); however a total of 17 Amerindian different extended class I–class II HLA haplotypes were directly counted from the family studies, nine of them were specific of Jaidukamas. Some of the alleles or group of alleles within an extended haplotype (i.e. DQB1–DRB1) were also found in Asians and Pacific Islanders, further supporting existence of Asian and Pacific gene flow with Amerindians or a common founder effect. It is further supported that HLA extended haplotypes vary faster than alleles in populations. It is concluded that this unique model of Amerindian secluded families study suggests that rapid HLA haplotype variation may be more important than allele variation for survival (starting immune responses). This work may also be useful for future transplant programs in the area.     

云南澜沧拉祜族HLA-DRB1基因多态性研究

采用我们改进的高分辨率基于内含子的PCR-SBT分型方法,首次检测云南拉祜族HLA-DRB1基因多态性。在55例拉祜族个体中共检出16种HLA-DRB1等位基因,最常见的DRB1等位基因是HLA-DRB1*12021、09012、15011,基因频率分别为30.909%、15.455%、13.636%,共占拉祜族可检出等位基因的60%,其中DRB1*0413、11081、1312、1418、1504首次在我国人群中检出,并且在世界各地人群中也比较罕见。对拉祜族和世界各地人群的HLA-DRB1频率进行了比较,分析了HLA-DRB1等位基因在各人种中的分布特点,并用Neighbor-joining法进行了聚类分析。比较分析的结果显示拉祜族明显属于中国南方族群,未显示出其族源来自北方的痕迹。对此遗传数据和民族学、历史学研究的矛盾,做了初步的分析。 Abstract:The HLA-DRB1 gene polymorphism in Lahu ethnic of Yunnan,China was the first time investigated using high resolution PCR-SBT method,which is based on sequences of HLA-DRB1 Intron 1 and Intron 2 and with our improvement.From 55 individuals of Lahu ethnic 16 DRB1 alleles were detected.The three most common alleles were HLA-DRB1*12021(30.909%),09012(15.455%),15011(13.636%),and they covered 60% of the total alleles detected from Lahu ethnic.HLA-DRB1*1413,*11081,*1312,*1418,*1504 were the first time detected in the Chinese,and were very rare in worldwide ethnic groups.With comparison of HLA-DRB1 gene frequencies between various ethnic groups we analysized the characteristics of HLA-DRB1 gene distribution in worldwide populations,and constructed the phylogenetic tree by Neighbor-joining method and Nei measure of genetic distance.The result showed Lahu ethnic obviously belong to the Chinese South ethnic groups and can't trace its origin from northern groups with the HLA-DRB1 genetic data.The preliminary explanations about the contradiction were given in this paper.     

HLA Class I and II Blocks Are Associated to Susceptibility,Clinical Subtypes and Autoantibodies in Mexican Systemic Sclerosis (SSc) Patients

IntroductionHuman leukocyte antigen (HLA) polymorphism studies in Systemic Sclerosis (SSc) have yielded variable results. These studies need to consider the genetic admixture of the studied population. Here we used our previously reported definition of genetic admixture of Mexicans using HLA class I and II DNA blocks to map genetic susceptibility to develop SSc and its complications.MethodsWe included 159 patients from a cohort of Mexican Mestizo SSc patients. We performed clinical evaluation, obtained SSc-associated antibodies, and determined HLA class I and class II alleles using sequence-based, high-resolution techniques to evaluate the contribution of these genes to SSc susceptibility, their correlation with the clinical and autoantibody profile and the prevalence of Amerindian, Caucasian and African alleles, blocks and haplotypes in this population.ResultsOur study revealed that class I block HLA-C*12:03-B*18:01 was important to map susceptibility to diffuse cutaneous (dc) SSc, HLA-C*07:01-B*08:01 block to map the susceptibility role of HLA-B*08:01 to develop SSc, and the C*07:02-B*39:05 and C*07:02-B*39:06 blocks to map the protective role of C*07:02 in SSc. We also confirmed previous associations of HLA-DRB1*11:04 and –DRB1*01 to susceptibility to develop SSc. Importantly, we mapped the protective role of DQB1*03:01 using three Amerindian blocks. We also found a significant association for the presence of anti-Topoisomerase I antibody with HLA-DQB1*04:02, present in an Amerindian block (DRB1*08:02-DQB1*04:02), and we found several alleles associated to internal organ damage. The admixture estimations revealed a lower proportion of the Amerindian genetic component among SSc patients.ConclusionThis is the first report of the diversity of HLA class I and II alleles and haplotypes Mexican patients with SSc. Our findings suggest that HLA class I and class II genes contribute to the protection and susceptibility to develop SSc and its different clinical presentations as well as different autoantibody profiles in Mexicans.     

Association of HLA-DRB1 and DQB1 alleles with red blood cell alloimmunization in Chinese

Few systematic investigations have assessed the correlations between red blood cell (RBC) antibodies and human leukocyte antigen (HLA)-DRB1 alleles in the Chinese population. In this case-control study, we investigated whether specific HLA-DRB1 alleles were associated with RBC alloimmunization by calculating the odds ratios for the frequencies of HLA alleles associated with alloimmunization to different RBC antigens. Three hundred and eight patients harboring RBC alloantibodies were analyzed as the case group, and the frequencies of the HLA-DRB1and HLA-DQB1 alleles in control individuals were analyzed by collecting data from the China Marrow Donor Program (including more than 1.6 million healthy people). HLA alleles were genotyped by single specific primer-polymerase chain reaction. The development of anti-C was associated with DRB1*07, DQB1*06, and DQB1*08; anti-C,e was associated with DRB1*07 and DQB1*06; and anti-E and anti-M were associated with DQB1. Other associations were identified between anti-E and DRB1*09 and between anti-Le^a and DRB1*01. Thus, our findings confirmed that HLA-DRB1 and DQB1 restriction played an important role in the generation of RBC alloantibodies in Chinese individuals.     

PCR/oligonucleotide probe typing of HLA class II alleles in a Filipino population reveals an unusual distribution of HLA haplotypes.

We have analyzed the distribution of HLA class II alleles and haplotypes in a Filipino population by PCR amplification of the DRB1, DQB1, and DPB1 second-exon sequences from buccal swabs obtained from 124 family members and 53 unrelated individuals. The amplified DNA was typed by using nonradioactive sequence-specific oligonucleotide probes. Twenty-two different DRB1 alleles, including the novel Filipino *1105, and 46 different DRB1/DQB1 haplotypes, including the unusual DRB1*0405-DQB1*0503, were identified. An unusually high frequency (f = .383) of DPB1*0101, a rare allele in other Asian populations, was also observed. In addition, an unusual distribution of DRB1 alleles and haplotypes was seen in this population, with DR2 (f = .415) and DRB1*1502-DQB1*0502 (f = .233) present at high frequencies. This distribution of DRB1 alleles differs from the typical HLA population distribution, in which the allele frequencies are more evenly balanced. The distribution of HLA class II alleles and haplotypes in this Filipino population is different from that of other Asian and Pacific groups: of those populations studied to date; the Indonesian population is the most similar. DRB1*1502-DQB1*0502 was in strong linkage disequilibrium (D'' = .41) with DPB1*0101 (f = .126, for the extended haplotype), which is consistent with selection for this DR, DQ, DP haplotype being responsible for the high frequency of these three class II alleles in this population.     

Polymorphisms of HLA-DRB1, -DQA1 and -DQB1 in Inhabitants of Astana,the Capital City of Kazakhstan

Background

Kazakhstan has been inhabited by different populations, such as the Kazakh, Kyrgyz, Uzbek and others. Here we investigate allelic and haplotypic polymorphisms of human leukocyte antigen (HLA) genes at DRB1, DQA1 and DQB1 loci in the Kazakh ethnic group, and their genetic relationship between world populations.

Methodology/Principal Findings

A total of 157 unrelated Kazakh ethnic individuals from Astana were genotyped using sequence based typing (SBT-Method) for HLA-DRB1, -DQA1 and -DQB1 loci. Allele frequencies, neighbor-joining method, and multidimensional scaling analysis have been obtained for comparison with other world populations. Statistical analyses were performed using Arlequin v3.11. Applying the software PAST v. 2.17 the resulting genetic distance matrix was used for a multidimensional scaling analysis (MDS). Respectively 37, 17 and 19 alleles were observed at HLA-DRB1, -DQA1 and -DQB1 loci. The most frequent alleles were HLA-DRB1*07:01 (13.1%), HLA-DQA1*03:01 (13.1%) and HLA-DQB1*03:01 (17.6%). In the observed group of Kazakhs DRB1*07:01-DQA1*02:01-DQB1*02:01 (8.0%) was the most common three loci haplotype. DRB1*10:01-DQB1*05:01 showed the strongest linkage disequilibrium. The Kazakh population shows genetic kinship with the Kazakhs from China, Uyghurs, Mongolians, Todzhinians, Tuvinians and as well as with other Siberians and Asians.

Conclusions/Significance

The HLA-DRB1, -DQA1and -DQB1 loci are highly polymorphic in the Kazakh population, and this population has the closest relationship with other Asian and Siberian populations.