Complement C4A, C4B and BF haplotypes in Koreans

Specific alleles at C4A, C4B and BF loci occur in populations and are inherited in complotypes, which are linked with particular HLA haplotypes. Considerable differences in complement allele and complotype frequencies have been observed among various ethnic groups. In the present study, 109 Korean families were analyzed for complement and complotype polymorphism. Thirty-four different complotypes were detected: the most common was BF*S-C4A*3-C4B*1 (S31) with a frequency of 42.2%, followed by S42 (14.3%) and F31 (13.8%). Three complotypes, S42, F31, and FQ01, showed positive linkage disequilibrium. Some of the complotypes were linked with characteristic HLA haplotypes. Two complotypes carrying duplicated C4A genes, S3+31 (BF*S-C4A*3-C4A*3-C4B*1) and S3+2Q0(BF*S-C4A*3-C4A*2-C4B*Q0), were exclusively associated with HLA-A24-Cw7-B7-DR1-DQ1 and A24-CBL-B52-DR15-DQ1 haplotypes, respectively. Twelve families showed recombinant haplotypes, nine in the class I region, three between the HLA-B and HLA-DR loci, and none in the class III region. Maternal recombination occurred twice as frequently as paternal. The results obtained in this study represent the frequencies of complotypes and extended HLA haplotypes of well-defined Koreans, based on a family study.     

C4 polymorphism and extended HLA haplotypes in Namibian San and Khoi and in South African Xhosa

We studied C4A and C4B polymorphisms and HLA-B and -DR associations in the San, Khoi and Xhosa. C4A and C4B alleles were determined using conventional protein allotyping methods. The C4A*3, C4B*1 haplotype had a high frequency (30–55%) in all populations. The frequency of C4A*3, C4B*Q0 was 7–19%. The C4A*Q0, C4B*1 haplotype was frequent (15%) in the Khoi but very rare in the San (P0.001). C4A*12 A*91, C4B*Q0 was frequent in the Xhosa (15%) but rare in the San and Khoi (P0.001). Alleles C4A*5 and C4A*6, and the C4B*2 B*92 duplication were only found in the Xhosa. C4A alleles A*4, A*45, A*58, A*12, A*14, A*19 and the C4A*3 A*91 duplication were only found in the San/Khoi population group. In the San, fourteen extended haplotypes were found in a relatively high frequency (2–7%). In the Xhosa, one extended haplotype (B42, C4A*12 A*91, C4B*Q0, DR18) was found in a very high frequency (13%) and was characteristic for this group; five other extended haplotypes were found with a low frequency (3%).     

HLA haplotypes and class II molecular alleles in Sardinian and Italian patients with pemphigus vulgaris

HLA class II antigens and DRB1, DQA1, DQB1 alleles were studied in 16 Italian and in 16 Sardinian patients with pemphigus vulgaris (PV). In the last group the complete HLA A-DQ haplotypes, including the complotypes, were defined by family studies. As in other populations, two PV susceptibility haplotypes were found: HLA-DRB 1*0402, DQA1*0301, DQB1*0302 and HLA-DRB 1*1401, DQA1*0104, DQB 1*0503. The first haplotype was largely prevalent in the Sardinian patients and was a part of the extended haplotype HLA-A2, Cw4, B35, S31, DR4, DQ8. The strength of the allele associations to PV is in agreement with the view that the main PV susceptibility genes are the DRB 1*0402 and DQB 1*0503 alleles. A genetic resistance to PV seems to be conferred by the HLA-DR3, DQ2 haplotype in the Sardinian population.     

Distributions of HLA class I alleles and haplotypes in Northern Han Chinese

Human leukocyte antigen (HLA) class I allelic genotypes were determined in 105 unrelated Han ethnic individuals inhabiting the northern China area. A total of 19 HLA-A alleles, 49 HLA-B alleles and 24 HLA-Cw alleles were detected. Through the analyses of two and three loci haplotypes of HLA-A, HLA-B, and HLA-C loci, 11 HLA-A-B-Cw haplotypes, 19 HLA-A-B haplotypes, 18 HLA-A-Cw haplotypes, and 24 HLA-B-Cw haplotypes with the frequencies of higher than 0.01 were revealed. The Nei's genetic distance (GD) was estimated, and the NJ dendrogram showed that Northern Han had a higher GD to Southern Han (0.233) than those to the Korean (0.138) or other Northern ethnic groups, suggesting that Northern Han had more mixed blood with the ethnic groups originally in Northeast Asia. Our results provide useful information on the further study of evolution and relationships of Chinese ethnic groups and disease association in terms of HLA class I genes.     

Striking conservation of three extended HLA-DR13 haplotypes in the Japanese population

Abstract: HLA class II DNA typing was conducted for 1335 unrelated Japanese individuals. The study on the linkage disequilibrium revealed a striking conservation of HLA DR13 haplotypes. Among these Japanese, 155 were typed for HLA-DR13 serologically, and they were correspondent to three DRB1 alleles, DRB1*1301, 1302 and 1307 defined by using the polymerase-chain reaction and sequence-specific oligonucleotide probe (PCR-SSOP) method. The two alleles, DRB1*1301 and 1307 were exclusively associated with each specific DRB3-DQA1-DQB1 combination which was DRB1*1301-DRB3*0101-DQA1*0103-DQB1*0603, and DRB1*1307-DRB3*0202-DQA1*0501-DQB1*0301, respectively. DRB1* 1302, the most common DR13 allele in Japanese, had two significant associations with DRB3*0301-DQA1*0102-DQB1*0604 (DRB1*1302A) and with DRB3*0301-DQA1*0102-DQB1*0605 (DRB1*1302B). In this study, no other DR13 class II combinations were found. Ony the DRB1*1302A halotype was associated with the DPB1*0401 allele while the DRB1*1302B haplotype was not. The complete conservation of these DR13 class II haplotypes was found to extend toward the HLA class I region. They were HLA A3-B44-DRB1*1301, A33-B44-DRB1*1302A and A33-B17-DRB1*1302B. Japanese could be characterized with these three extended haplotypes which were remakrably different from those in Caucasian, Black and Asian other than Korean populations.     

Differentiation between African populations is evidenced by the diversity of alleles and haplotypes of HLA class I loci

The allelic and haplotypic diversity of the HLA-A, HLA-B, and HLA-C loci was investigated in 852 subjects from five sub-Saharan populations from Kenya (Nandi and Luo), Mali (Dogon), Uganda, and Zambia. Distributions of genotypes at all loci and in all populations fit Hardy-Weinberg equilibrium expectations. There was not a single allele predominant at any of the loci in these populations, with the exception of A*3002 [allele frequency (AF) = 0.233] in Zambians and Cw*1601 (AF = 0.283) in Malians. This distribution was consistent with balancing selection for all class I loci in all populations, which was evidenced by the homozygosity F statistic that was less than that expected under neutrality. Only in the A locus in Zambians and the C locus in Malians, the AF distribution was very close to neutrality expectations. There were six instances in which there were significant deviations of allele distributions from neutrality in the direction of balancing selection. All allelic lineages from each of the class I loci were found in all the African populations. Several alleles of these loci have intermediate frequencies (AF = 0.020-0.150) and seem to appear only in the African populations. Most of these alleles are widely distributed in the African continent and their origin may predate the separation of linguistic groups. In contrast to native American and other populations, the African populations do not seem to show extensive allelic diversification within lineages, with the exception of the groups of alleles A*02, A*30, B*57, and B*58. The alleles of human leukocyte antigen (HLA)-B are in strong linkage disequilibrium (LD) with alleles of the C locus, and the sets of B/C haplotypes are found in several populations. The associations between A alleles with C-blocks are weaker, and only a few A/B/C haplotypes (A*0201-B*4501-Cw*1601; A*2301-B*1503-Cw*0202; A*7401-B* 1503-Cw*0202; A*2902-B*4201-Cw*1701; A*3001-B*4201-Cw*1701; and A*3601-B*5301-Cw*0401) are found in multiple populations with intermediate frequencies [haplotype frequency (HF) = 0.010-0.100]. The strength of the LD associations between alleles of HLA-A and HLA-B loci and those of HLA-B and HLA-C loci was on average of the same or higher magnitude as those observed in other non-African populations for the same pairs of loci. Comparison of the genetic distances measured by the distribution of alleles at the HLA class I loci in the sub-Saharan populations included in this and other studies indicate that the Luo population from western Kenya has the closest distance with virtually all sub-Saharan population so far studied for HLA-A, a finding consistent with the putative origin of modern humans in East Africa. In all African populations, the genetic distances between each other are greater than those observed between European populations. The remarkable current allelic and haplotypic diversity in the HLA system as well as their variable distribution in different sub-Saharan populations is probably the result of evolutionary forces and environments that have acted on each individual population or in their ancestors. In this regard, the genetic diversity of the HLA system in African populations poses practical challenges for the design of T-cell vaccines and for the transplantation medical community to find HLA-matched unrelated donors for patients in need of an allogeneic transplant.     

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。     

The association of specific HLA class I and II alleles with type 1 diabetes among Filipinos

The genetic predisposition to type 1 diabetes among Filipinos was examined by PCR/SSOP HLA class I and II typing of 90 patients and 94 general population controls. The HLA-DRB1, DQB1, and the A, B, and C loci were typed using the reverse SSO probe line-blot method while the DPB1 and DPA1 loci were typed using the SSO probe dot blot method. The Filipino population has a distinctive frequency distribution of HLA class II alleles as well as linkage disequilibrium patterns: a DR-DQ haplotype, unique to Filipinos, contains a DRB1 allele (*0405) positively associated with type 1 diabetes in other populations and DQA1 and DQB1 alleles (*0101-*0503) that are negatively associated in other populations. Specific DR-DQ haplotypes or alleles could be identified as susceptible, neutral or protective based on the distribution among Filipino patients and controls. The DR9 and DR3 haplotypes showed the most dramatic increase among patients (0.156 vs 0.063) and (0.172 vs 0.042), respectively. Among Filipinos, the DR3/9 genotype confers approximately the same risk as the well-known high-risk DR3/4 genotype, similar to that for DR3/3 and DR9/9. The common DR2 haplotype in the Philippines (DRB1*1502-DQB1*0502) was only slightly decreased in type 1 diabetic patients (0.200 in patients vs 0.270 in controls). Another DR2 haplotype, DRB1*1502-DQB1*0501, was significantly decreased among patients. In addition, haplotypes containing DQB1*06 alleles, such as the DRB1*0803-DQB1*0601 (OR = 0.1), are strongly protective. The DR4 allele group was also increased in Filipino patients compared to controls. In this population there is, as in other populations, a hierarchy of type 1 diabetes associations among the many different DR4 haplotypes (n = 15). The high-risk haplotypes in this population are the very rare DRB1*0405-DQB1*0302 and DQB1*0405-DQB1*0201, followed by the more common DRB1*0405-DQB1*0401 and DRB1*0405-DQB1*0402. The DRB1*0403-DQB1*0302 is protective. The DRB1*0405-DQB1*05031 haplotype, which is unique to Filipinos, appears to be "neutral". HLA-DPB1*0202 was significantly increased among patients (0.056 vs 0.011; with OR = 5.3); this increase does not appear to simply reflect linkage disequilibrium with high risk DR-DQ haplotypes. The observed distribution of HLA class II alleles among Filipino patients and controls strongly supports the notion that specific combinations of alleles at the DRB1, DQB1, DQA1, and DPB1 loci are critical in determining the risk for type 1 diabetes. Specific HLA class I alleles also show significant associations with type 1 diabetes in this population. HLA-A*2402 and *2403 were increased among patients; however, 2407 was decreased. Inaddition, A *1101 was significantly decreased among patients (OR = 0.51). Moreover, these HLA-A associations do not appear attributable to linkage disequilibrium with the DR-DQ region. The allele B*5801 was increased in patients while B*1301 was decreased; both of these associations, however, reflected linkage disequilibrium with high-risk and with protective DR-DQ haplotypes, respectively. The HLA-C*0102 and *0302 alleles were increased (0.089 vs 0.037 and 0.122 vs 0.064) while C*1502 and *0702 (0.028 vs 0.080 and 0.217 vs 0.330) were decreased. The observed associations of C*0102 and C*1502 do not simply reflect linkage disequilibrium with high-risk DR-DQ haplotypes. Thus, specific HLA class I-A and C alleles were associated with type 1 diabetes in the Filipinos and may, in combination with high risk DR-DQ haplotypes, significantly modify disease risk.     

DNA typing of HLA class I (HLA-A) and class II genes (HLA-DR, -DQ and -DP) in Japanese patients with gastric cancer

Gastric cancer is multifactorial disease and several reports have described genetic factors involved in pathogenesis of gastric cancer. Recently, it was reported that HLA class II gene DQB1*0301 was strongly associated with gastric cancer in Caucasian population (20). We performed DNA typing of HLA class I (HLA-A) and HLA class II genes (HLA-DR, DQ and DP) to elucidate the HLA alleles or HLA haplotypes associated with gastric cancer in Japanese population using polymerase chain reaction-sequence-specific oligonucleotide probe analysis in 88 unrelated patients with gastric cancer and 525 unrelated healthy controls. We observed slight difference in frequencies of some HLA alleles and haplotypes between gastric cancer patients and controls; however, after Bonferroni correction, statistical significance was not confirmed. It is possible that environmental factors such as diet cover the contribution of genetic factors to the disease in Japanese population, which has a higher frequency of gastric cancer than do Caucasian populations, most likely due to more exposure to environmental risk factors.     

HLA associations in type 1 diabetes among patients not carrying high-risk DR3-DQ2 or DR4-DQ8 haplotypes

Type 1 diabetes is a complex disease where numerous genes are involved in the pathogenesis. Genes that account for approximately 50% of the familial clustering of the disease are located within or in the vicinity of the HLA complex on chromosome 6. Some DRB1, DQA1 and DQB1 genes are known to be involved, in addition to as yet unidentified HLA-linked genes. The DR4-DQ8 and DR3-DQ2 haplotypes are known to confer high risk for developing the disease, particularly when occurring together. Approximately 10% of patients, however, do not carry any of these high-risk HLA class II haplotypes. We have performed genotyping of DRB1, DQA1 and DQB1 alleles in non-DR3-DQ2/non-DR4-DQ8 patients and controls from Sweden and Norway to test if any HLA associations were observed in these patients. Our results clearly demonstrate several statistically significant differences in the frequency of HLA haplotypes between patients and controls. Case-control analysis including the relative predispositional effect test, and transmission disequilibrium test (TDT) analysis in Norwegian type 1 diabetes families revealed that the DQA1*03-DQB1*0301, DQA1*0401-DQB1*0402, DQA1*0101-DQB1*0501, DQA1*03-DQB1*0303 and DQA1*0102-DQB1*0604 haplotypes may also confer risk. Our analyses also supported independent risks of certain DRB1 alleles. The study clearly demonstrates that HLA associations in type 1 diabetes extends far beyond the well-known associations with the DR4-DQ8 and DR3-DQ2 haplotypes. Our data suggest that there is a hierarchy of HLA class II haplotypes conferring risk to develop type 1 diabetes.     

Linkage disequilibrium in HLA cannot be explained by selective recombination

Abstract: Some combinations of HLA-A,-B and -DR antigens occur more frequently than would be expected from their gene frequencies in the population. This phenomenon, referred to as Linkage Disequilibrium (LD) has been the origin of many speculations. One hypothesis to explain LD is that some haplotypes are protected from recombination. A second hypothesis is that these HLA antigens preferentially recombine after cross-over, to create an LD haplotype. We tested these 2 hypotheses: from a pool of over 10,000 families typed in our department, we analyzed 126 families in which HLA-A:B or B:DR recombinant offspring was documented. To overcome a possible bias in our material, we used the non-recombined haplotypes from the same 126 families as a control group. Our results show that the number of cross-overs through LD haplotypes is not significantly lower then would be expected if recombination occurred randomly. Also the number of LD haplotypes created upon recombination was not significantly increased.     

Association of four HLA class III region genomic markers with HLA haplotypes

Abstract: We have studied restriction fragment length polymorphism (RFLP) in the region 300 kb centromeric to the HLA-B locus. Four probes were used: one was genomic DNA derived from the tumor-necrosis factor (TNF)-β gene, one was a cDNA for the BAT3 gene, and two single-copy genomic probes, R5A and M20A. The order of these markers from HLA-B towards the centromere is M20A, R5A, TNF and BAT3. The BAT3 and TNF-β probes each detected two allelic bands with Taq I and Nco I digestion, respectively; the R5A and M20A probes each detected three polymorphic allelic bands with BstEII digestion. To determine if these restriction polymorphisms are preferentially associated with certain HLA-B and -DR haplotypes, a total of 153 HLA haplotypes was analyzed. The haplotypes Al, B8, DR3 and A3, B7, DR2 were each associated with a distinct combination of polymorphisms identified at these four sites, thereby demonstrating that the strong linkage disequilibrium characteristic of these haplotypes extends also to this segment of the class III region. In contrast, haplotypes that are not in positive linkage disequilibrium, such as A1,B8,DR4 and A2,B7,DR3, showed ho preferential association with any of these polymorphisms. The antigens HLA-B27 and B35 were also found to be in positive linkage disequilibrium with RFLP patterns at three of these sites, and HLA-B14,B35,B44,Bw57 and Bw62 were found preferentially associated with polymorphisms at one or two of these sites, independent of the DR antigen present. These data further demonstrate that genetic linkage disequilibrium in the HLA class III region is complex and variable among different HLA halpotypes.     

TNF-alpha promoter polymorphisms and extended HLA and TNF-alpha haplotypes in Koreans based on 100 families

We investigated five single-nucleotide polymorphism (SNP) sites of tumor necrosis factor-alpha (TNF-alpha) promoter, the distribution of five-locus TNF-alpha haplotypes, and extended human leukocyte antigen (HLA)/TNF-alpha haplotypes in 200 parents from 100 unrelated Korean families. TNF-alpha SNPs were typed using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and PCR restriction fragment length polymorphism (PCR-RFLP) methods. The frequencies of -1031C, -863A, -857T, -308A, and -238A alleles were 0.185, 0.145, 0.140, 0.060, and 0.040, respectively. The allele frequencies in Koreans were similar to those of Japanese. A total of five TNF-alpha haplotypes (-1031/-863/-857/-308/-238) were detected in 196 parents: TCCGG (frequency 0.617), CACGG (0.143), TCTGG (0.143), TCCAG (0.061), and CCCGA (0.036). Five most common extended HLA/TNF-alpha haplotypes (frequencies >0.020) accounted for 16% (63/392) of the total haplotypes. A total of 223 HLA haplotypes and 239 HLA/TNF-alpha haplotypes were detected, indicating that most HLA haplotypes are exclusively associated with particular TNF-alpha haplotypes.     

Linkage disequilibrium with predisposing DR3 haplotypes accounts for apparent effects of tumor necrosis factor and lymphotoxin-alpha polymorphisms on type 1 diabetes susceptibility

 Tumor necrosis factor (TNF) and lymphotoxin alpha (LT-α) are immunomodulators that have been hypothesized to contribute to susceptibility to type 1 diabetes (T1D). Several polymorphisms in the TNF and LT-α loci have been extensively studied for T1D association, with conflicting reports. In this study, we examined two TNF variants and one LT-α variant for T1D association in 283 Caucasian, multiplex T1D families for which complete human leukocyte antigen (HLA) genotyping data are available. Initially, association with T1D was seen for LT-α A1069G (intron A, p = 0.011, rs909253) and TNF G(−308)A (p < 1 × 10⁻⁵, rs1800629), but no association was observed for TNF G(−238)A (rs361525). After adjusting the data for linkage disequilibrium (LD) with DRB1-DQB1 haplotypes, however, only one polymorphism, TNF G(−238)A showed significant association with T1D (p < 0.006). When HLA-DR3 haplotypes were examined, the A allele of TNF G(−238)A was significantly overtransmitted to affected offspring (p < 0.009). Including HLA-B data in the analysis revealed that TNF (−238)A is present exclusively on DR3 haplotypes that also carry HLA-B18. Transmission proportion of B18-DR3 haplotypes did not differ between those with TNF (−238)A and those with TNF (−238)G. Thus, variation at TNF does not affect the T1D risk for B18-DR3 haplotypes, and the apparent association of TNF(−238)A with T1D may simply reflect its presence on a high-risk haplotype.     

海南汉族人群中α和β纤维蛋白原基因核苷酸多态性及其单倍型与缺血性脑卒中的关联分析

目的研究α纤维蛋白原基因的Taq Ⅰ多态性和β纤维蛋白原基因-455G／A、-249C／T、-148 C／T、＋1689T／G、βBsmA ⅠG／C、448G／A、Be／ⅠG／A、Hinf Ⅰ A／C单核苷酸多态性及其单倍型与缺血性脑卒中的关系。方法用比浊法测定160例海南籍缺血性脑卒中和130名海南籍对照个体的血浆纤维蛋白原浓度，用PCR-限制性片段长度多态法确定基因型。用EH＋程序分析核苷酸多态性的连锁不平衡关系及单倍型，用卡方检验分析病例组和对照组的等位基因频率、基因型频率及单倍型频率的差异。结果-455G／A、-148C／T、448G／A多态性的基因型频率、等位基因频率在病例组和对照组之间的差异有统计学意义（P〈0．01），其余6个核苷酸多态性的基因型频率、等位基因频率在病例和对照组间的差异无统计学意义（P〉0．05），A^-455、T^-148、A^448携带者患缺血性脑卒中的相对危险度比非携带者分别大2．46倍、2．30倍和2．08倍。连锁不平衡分析未发现所分析的区域内存在单倍型板块。9个位点构建的单倍型在病例组和对照组之间的差异无统计学意义，以4个位点构建的单倍型中，某些单倍型在病例组和对照组之间的差异有统计学意义，对照组中某些携带G^-455、C^148、G^448位点的单倍型的频率高于病例组，而病例组中某些携带A^-455、T^-148、A^448位点的单倍型的频率高于对照组。结论多个位点和单倍型分析的结果提示8纤维白原455G／A、-148C／T、448G／A可能是海南汉族人群中与缺血性脑卒中关联的危险因素。     

A powerful score test to detect positive selection in genome-wide scans

One of the surest signatures of recent positive selection is a local elevation of advantageous allele frequency and linkage disequilibrium (LD). We proposed to detect such hitchhiking effects by using extended stretches of homozygosity as a surrogate indicator of recent positive selection. An extended haplotype-based homozygosity score test (EHHST) was developed to detect excess homozygosity. The EHHST conditioned on existing LD and it tested the haplotype version of the Hardy–Weinberg equilibrium. Compared with existing popular tests, which usually lack clear distribution, the EHHST is asymptotically normal, which makes analysis and applications easier. In particular, the EHHST facilitates the computation of an asymptotic P-value instead of an empirical P-value, using simulations. We evaluated by simulation that the EHHST led to appropriate false-positive rates, and it had higher or similar power as the existing popular methods. The method was applied to HapMap Phase II data. We were able to replicate previous findings of strong positive selection in 17 autosome genomic regions out of 20 reported candidates. On the basis of high EHHST values and population differentiations, we identified 15 new candidate regions that could undergo recent selection.     

An additional susceptibility gene for juvenile idiopathic arthritis in the HLA class I region on several DR-DQ haplotypes

Juvenile idiopathic arthritis (JIA) is an HLA-associated rheumatic disease with onset in childhood. We recently reported that allele 5 at microsatellite D6S265 in the HLA class I region is associated with JIA, independent of linkage disequilibrium with the high risk DR8-DQ4 haplotype. In the present study, we investigated whether alleles at D6S265, or other markers in this region, also modify the risk for JIA on other haplotypes, i.e., DRB1*1301-DQB1*0603 or DRB1*1101/4-DQB1*0301. We observed a significant association with allele 6 at D6S265 on the DRB1*1301-DQB1*0603 haplotype. We also noted an association with allele 3 at D6S265, when carried on the DRB1*1101/4-DQB1*0301 haplotype. Our results further support an additional JIA susceptibility gene in the HLA class I region in linkage disequilibrium with alleles at D6S265.     

The distribution of HLA class II haplotypes reveals that the Sardinian population is genetically differentiated from the other Caucasian populations

In this study we have established the frequencies of the DRB1-DQA1-DQB1 haplotypes in a large cohort of Sardinian new-borns and found that the most frequent haplotypes were detected at frequencies unique to the Sardinians. Other haplotypes, common in other Caucasian populations, are rare or absent across the island. Next, the DRB1-DQA1-DQB1 haplotype frequencies obtained in Sardinians and those reported in other human populations were used to compute genetic distances and construct phylogenetic trees. A clear-cut pattern appeared with a split between the three major human groups: Caucasians, Asians and Blacks. Among the Caucasians there were three major clusters: a group representing the North-Africans, a group including most of the European-derived populations and a group encompassing Bulgaria, Greece and Sardinia. When we increased the resolution of the tree using the genetic distances calculated from both DRB1-DQA1-DQB1 haplotypes and class I HLA A, B, C allelic frequencies, the Sardinians clearly emerged as the major outlier among the various European populations considered in this study. These results indicate that the genetic structure of the present Sardinian population is the result of a fixation of haplotypes, which are very rare elsewhere, and are most likely to have originated from a relatively large group of founders.     

The HLA system in the population of Mongolia

The frequencies of HLA-A, B, C and DRB1 alleles and haplotype frequencies for HLA-A, B, C and A, B, DR loci were studied in 201 healthy unrelated Khalkha-Mongolians. The most common class I antigens were A24 (25.8%), A2 (23.4%), B61 (12.6%), B51 (8.5%), Cw10 (14.2%), Cw9 (14.1%), Cw7 (13.3%), Cwl (11.8%) and Cw6 (10.2%). A total of 35 DRB1 alleles were identified in this group of samples. The most frequent DRB1 allele was DRB1*0301 (11.1%), followed by DRB 1*0701 (9.7%) and DRBl*H01 (8.5%). One novel DRB1 allele (14MV) and three rare types, DRB1*1111, DRB 1*1504 and DRB 1*1412, recently described in Jews, the Dai minority of China and Japanese, respectively, were identified in Mongolians. The phylo-genetic tree constructed by UPG method put Mongolians in the Northeast Asian cluster. A comparison of three locus haplotype distributions with world populations, revealed that Mongolians share several characteristics in common with other Mongoloids as well as with Caucasoids and Amerindians. The most common A, B and DR haplotype in Mongolians, A33-B58-DR3, was shared with Thai, Thai Chinese and Singapore Chinese. These data support that unique genetic background of Mongolians played a major role in ethnic formation and differentiation of Mongoloid populations.