Association of HLA class I and class II alleles with susceptibility to endometriosis

Although the exact etiology of endometriosis is unclear, several lines of evidence support roles for both cell-mediated and humoral immunity in its pathogenesis. To assess the association between HLA genotypes and endometriosis, we investigated the frequencies of HLA-A, -B, -C, and -DRB1 antigens or alleles in 123 Japanese patients with endometriosis and 165 healthy women as controls. Significant positive association with endometriosis was observed for HLA-B7 (OR = 2.7, 95% CI = 1.5-5.1, p(u) = 0.0022, p(c) = 0.0440) and for Cw*0702 (OR = 2.1, 95% CI = 1.2-3.3, p(u) = 0.0026, p(c) = 0.0398). An increased frequency of DRB1*0101 was observed in endometriosis patients compared with control subjects (OR = 2.3, 95% CI = 1.2-4.4, p(u) = 0.0143), but was not statistically significant after correction for multiple comparisons. Two-locus analysis indicated that the susceptibility to endometriosis was primarily associated with B7, and that the increased frequencies of Cw*0702 and DRB1*0101 in patients reflected the linkage disequilibrium between B7 and Cw*0702 and DRB1*0101. Most of the B7 antigens were encoded by the B*0702 allele, which was in complete linkage disequilibrium with A24, Cw*0702, and DRB1*0101. Therefore, our results indicated that the HLA-A24-B*0702-Cw*0702-DRB1*0101 haplotype was associated with endometriosis susceptibility. Our findings may provide an important clue to elucidating the pathogenesis of endometriosis.     

Diversity of HLA-B17 alleles and haplotypes in East Asians and a novel Cw6 allele (Cw*0604) associated with B*5701

The distribution of HLA-B17 alleles and their association with HLA-A, -C and -DRB1 alleles were investigated in seven East Asian populations Japanese, South Korean, Chinese-Korean, Man, Northern Han, Mongolian and Buryat populations). The B17 alleles were identified from genomic DNA using group-specific polymerase chain reaction (PCR) followed by hybridization with sequence-specific oligonucleotide probes (SSOP). In all of these East Asian populations, except Japanese and Chinese-Koreans, B*5701 was detected and strongly associated with A*0101, Cw*0602 and DRB1*0701. In contrast, B*5801 was detected in all the seven populations and strongly associated with A*3303, Cw*0302, DRB1*0301 and DRB1*1302. The A*3303-Cw*0302-B*5801-DRB1*1302 haplotype was observed in South Korean, Chinese-Korean, Buryat and Japanese populations, while A*3303-Cw*0302-B*5801-DRB1*0301 was predominantly observed in the Mongolian population. A similar haplotype, A*0101-Cw*0302-B*5801-DRB1*1302, was observed in the Buryat population. A novel Cw6 allele, Cw*0604, was identified in the Man population. This Cw allele was observed on the haplotype A*0101-B*5701-DRB1*0701. Thus, we confirmed, at the sequence level, that the common haplotypes carrying B*5701 and B*5801 have been conserved and shared in East Asian populations.     

Novel HLA Class I Alleles Associated with Indian Leprosy Patients

Convincing results on HLA Class II associations have been reported, however data on HLA class I association are limited and inconsistent from studies in Leprosy. We present here the HLA A, B, and C allele distribution by molecular high resolution PCR-SSOP technique in 32 leprosy patients compared with the 67 controls, from the same ethnic background. The significant results from the present study were a significant increase in frequency of HLA A*0206, A*1102, B*4016, B*5110, Cw*0407, and Cw*0703 was observed when compared to controls. A striking decrease in the frequency of HLA A*0101, Cw*04011, and Cw*0602 leprosy patients was observed when compared to the controls. Further haplotype A*1102-B*4006-Cw*1502 was significantly increased among the lepromatous leprosy patients when compared to the controls. It seems that HLA class I alleles play vital roles in disease association/pathogenesis with leprosy among Indians.     

Sensitivity to bee venom antigen phospholipase A2: association with specific HLA class I and class II alleles and haplotypes in beekeepers and allergic patients

Bee venom hypersensitivity is a clinical entity of outstanding importance because bee stings are a leading cause of mortality worldwide. Individuals with immediate-type bee venom hypersensitivity, beekeepers, and healthy controls were examined for HLA-DRB1, DQB1, and DQA1 alleles by sequence-specific oligonucleotide probe typing. Defined hypersensitivity to bee venom antigen phospholipase A2 (vbPLA2) is significantly associated with the presence of susceptible HLA class II alleles: DRB1*0101 (RR = 2.7, p < 3 x 10(-3)), DRB1*0103 (RR = 21.2, p < 7.5 x 10(-11)), DQA1*0101 (RR = 1.2, p < 38.52 x 10(-10)), and DQB1*0501 (RR = 4, p < 2.18 x 10(-10)). Some HLA class I alleles were also associated with risk to bee venom allergy: A*01 (RR = 2.4, p < 7.5 x 10(-4)), B*57 (RR = 35.1, p < 3.5 x 10(-7)), and B*5901 (p < 3.5 x 10(-5)), but they are probably of secondary significance. Three- (DRB1*0103-DQA1*0101-DQB1*0501) (RR = 21.24, p < 7.5 x 10(-11)) and five-loci (A*01-B*59-DRB1*0103-DQA1*0101-DQB1*0501) (p < 2.3 x 10(-6)) extended haplotypes are also significantly carried by vbPLA2 allergic patients. When HLA allele frequencies from patients are compared with those from beekeepers, only HLA-DRB1*0103 (RR = 11.7, p < 8.5 x 10(-5)) and HLA-DQA1*0101 (p < 0.02) were significantly increased in the former. These observations emphasize the importance of the DRB1*0103-DQA1*0101-DQB1*0501 haplotype as a strong candidate for susceptibility to vbPLA2 hypersensitivity, at least in our region.     

HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in the Kinh population in Vietnam

Allele and haplotype frequencies of the human leukocyte antigens (HLA) were studied in the Kinh Vietnamese population. We analyzed 170 unrelated healthy individuals. DNA-based HLA typing was performed using a microsphere-based array genotyping platform with sequence-specific oligonucleotide probes to distinguish HLA-A, -B, -C, -DRB1 and -DQB1 alleles. A total of 21 HLA-A, 37 HLA-B, 18 HLA-C, 25 HLA-DRB1, and 14 HLA-DQB1 alleles were identified. HLA-A*1101, A*2402, A*3303, B*1502, B*4601, Cw*0102, Cw*0702, Cw*0801, DRB1*1202, DQB1*0301, DQB1*0303, and DQB1*0501 were found with frequencies higher than 10%. Two representative haplotypes bearing two to five HLA loci were A*1101-B*1502 and A*3303-B*5801 for HLA-A-B; Cw*0801-B*1502 and Cw*0102-B*4601 for HLA-C-B; B*1502-DRB1*1202 and B*4601-DRB1*0901 for HLA-B-DRB1; DRB1*1202-DQB1*0301 and DRB1*0901-DQB1*0303 for HLA-DRB1-DQB1; A*1101-Cw*0801-B*1502 and A*3303-Cw*0302-B*5801 for HLA-A-C-B; A*1101-B*1502-DRB1*1202 and A*2901-B*0705-DRB1*1001 for HLA-A-B-DRB1, A*1101-Cw*0801-B*1502-DRB1*1202-DQB1*0301 and A*2901-Cw*1505-B*0705-DRB1*1001-DQB1*0501 for HLA-A-C-B-DRB1-DQB1. Allele distribution and haplotype analysis demonstrated that the Vietnamese population shares HLA patterns with southern Chinese, Thai, Javanese and Micronesians, while it also retains unique characteristics.     

HLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish caucasian populations

Ulcerative colitis (UC) and Crohn's disease (CD) are the clinical entities comprising idiopathic inflammatory bowel disease (IBD). Previous studies on the association of IBD and human leukocyte antigen (HLA) class II genes suggested a role for HLA in this disease. Here we present HLA class II (DRB1, DQB1, DQA1, DPB1) allele and haplotype distributions determined using the polymerase chain reaction and sequence-specific oligonucleotide probe methods. A total of 578 UC and CD Caucasian patients and controls from Jewish (Ashkenazi) and non-Jewish populations was examined. Our previously reported association of DR1-DQ5 with CD was attributable to DRB1*0103. A dramatic association with IBD and the highly unusual DRB1*0103-DQA1*0501-DQB1*0301 haplotype (OR = 6.6, p = 0.036) was found. The more common DR1 haplotype, DRB1*0103-DQA1*0101-DQB1*0501, was also associated with IBD (OR = 3.1, p = 0.014), a result suggesting that interaction between DR and DQ may determine the extent of disease risk. Our previously reported association of DR2 with UC was attributable to DRB1*1502 (OR = 2.6, p = 0.006). At the DPB1 locus, a significant association of DPB1*0401 with CD was observed for the combined populations (OR = 1.85, p = 0.007). These observations indicate that some class II alleles and haplotypes confer susceptibility to both UC and CD, implying common immunogenetic mechanisms of pathogenesis, while others confer risk to only one of these diseases, and illustrate the value of DNA HLA typing in disease susceptibility analyses.     

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.     

Association of HLA-DR and -DQ genes with Graves disease in Koreans

Graves disease (GD) is an autoimmune thyroid disease and is associated with human leukocyte antigen (HLA)-DR3 and DQA1*0501 in Caucasians. However, the association of HLA with GD is less clear-cut in East Asian populations. We analyzed HLA-DRB1 and -DQB1 associations with GD in 198 Korean patients compared with 200 healthy controls. HLA-DRB1*0803 (27.8% vs. 14.5% in controls, OR = 2.27, corrected p [p(c)] = 0.03) and *1602 (5.1% vs. 0%, OR = 22.34, p(c) = 0.03) alleles and closely linked haplotypes, DRB1*0803-DQB1*0601 and DRB1*1602-DQB1*0502, conferred susceptibility to GD in Koreans. Weak association of DRB1*0301 with GD susceptibility was observed in male patients only (12.5% vs. 3.5%, OR = 3.57, p < 0.05). HLA-DRB1*0101, *0701, *1202, and *1302 alleles were weakly associated with resistance to the disease (OR < 0.5, p < 0.05). Some HLA alleles were weakly associated with clinical characteristics in GD patients. Patients with DRB1*1301-DQB1*0603 developed their diseases in younger ages and were more frequently associated with larger goiter (p < 0.05). Although HLA class II alleles associated with GD in Koreans were different from those in Caucasians, some associations are shared, such as association of DRB1*0301 in male patients and protective effect of DRB1*0701 to GD susceptibility.     

Type 1 diabetes risk for human leukocyte antigen (HLA)-DR3 haplotypes depends on genotypic context: association of DPB1 and HLA class I loci among DR3- and DR4-matched Italian patients and controls

Patients with high-risk human leukocyte antigen (HLA)-DR-DQ genotypes for type 1 diabetes (T1D) were compared with HLA-matched controls to evaluate T1D risk for other HLA loci, including HLA-A, -B, -Cw, and DPB1. Patients (n = 133) with high-risk genotypes (DR3/DR3, DR3/DR4, DR4/DR4) were selected from the Lazio (Rome) region of Italy. Screening of more than 9000 patients from the Lazio region and northern Italy yielded 162 controls with high-T1D-risk haplotypes. Although the overall distributions did not differ significantly, allele frequency differences were discovered between the controls from Lazio and controls from northern Italy for some alleles previously determined to affect T1D risk, such as A*3002, DPB1*0301, and DPB1*0402. Therefore, Lazio patient data were compared both with the Lazio subset of controls (n = 53) and with the entire group of controls for association analyses. Significant allele frequency differences between patients and DR-DQ-matched controls existed for specific alleles at all loci. Data for the DR3/DR3 subset of patients and controls demonstrated an increase of Cw*0702 in patients. Compared with controls, reduced patient frequencies were seen for several alleles, including A*0101, B*0801, and Cw*0701, all on the highly conserved, extended DR3 haplotype known as 8.1 in DR3/DR3, but not DR3/DR4, subgroup. DPB1*0101, often reported on 8.1 haplotypes, was also less frequent in DR3/DR3 patients than controls. Analysis of family-based data from the HBDI repository was consistent with the observed results from the Italian patients, indicating the presence of a T1D-protective locus at or near A*0101 and a second T1D-protective locus at or near DPB1*0101. These data indicate that T1D risk conferred by the 8.1 haplotype is genotype dependent.     

应用SBT直接测序分型法研究中国南方汉族人群HLA五个基因座单倍型

目的 研究中国南方汉族人群HLA-A、B、Cw、DRBl、DQBl等位基因多态性及单倍型的分布特征.方法 应用聚合酶链反应-直接测序分型(polymerase chain reaction sequence-based typing,PCR-SBT)法对186名中国南方汉族健康人群HLA-A、B、Cw、DRBl、DQBl进行基因分型.结果 检出的HLA-A、B、Cw、DRBl、DQBl等位基因分别有28、49、24、29、20种.经统计分析A*0207-B*4601(10.81%),A*3303-B*5801(6.14%),B*4601-DRBl*0901(6.22%),B*4001*DRBl*0901(3.78%),DRBl*0901-DQBl*0303(12.16%)和DRBl*1202-DQBl*0301(8.38%)单倍型呈强连锁不平衡单倍型(RLF≥0.5,X<'2>>3.84,P<0.05);A*0207-B*4601-Cw*0102(10.75%),A*3303-B*5801-Cw*0302(5.14%),A*0207-B*4601-DR*0901(5.07%),A*3303-B*5801-DRBl*0301(2.96%),A*0207-B*4601-Cw*0102-DRBl*0901-DQBl*0303(4.87%)和A*1101-B*1301-Cw*0304-DRBl*1501-DQBl*0601(2.43%)单倍型分别是中国南方汉族人群常见单倍型.结论 中国南方汉族人群HLA 5个基因座单倍型分布具有高度的遗传多态性且有其自身分布特点.本研究获得的较完整的HLA 5个基因座单倍型分布数据,将为人类学、HLA疾病相关性和器官移植等研究提供遗传学参考数据.     

Association of HLA-A*3303-B*4403-DRB1*1302 haplotype,but not of TNFA promoter and NKp30 polymorphism,with postherpetic neuralgia (PHN) in the Japanese population

Herpes zoster is a common disease caused by reactivation of the varicella zoster virus (VZV). In a small number of herpes zoster patients, pain persists beyond 4 weeks or more after healing of vesicular eruptions; this condition is termed postherpetic neuralgia (PHN). Positive associations of human histocompatibility leukocyte antigens (HLA) class I antigens, A33 and B44, with PHN in the Japanese population have been reported. Our hypothesis is that susceptibility genes to PHN might exist in the HLA region and the study objective is to further examine possible associations of genes in HLA class I, II and III regions, HLA-A, -B, -DRB1, tumor necrosis factor alpha (TNFA) promoter, and a natural killer cell activating receptor, NKp30 polymorphisms with PHN. Although TNFA or NKp30 in the class III region had been considered as a candidate locus, we found no associations of TNFA promoter or NKp30 polymorphisms with PHN in this study. We demonstrated that HLA-A*3303, -B*4403 and -DRB1*1302 alleles were significantly associated with PHN (P = 0.0007 for A*3303, P = 0.001 for B*4403 and P = 0.001 for DRB1*1302). The frequency of the HLA-A*3303-B*4403-DRB1*1302 haplotype was also significantly higher in the PHN patients than in the healthy controls (P = 0.0039). Our results suggest that this haplotype might be related to the pathogenesis of PHN.     

Association of HLA class I and leukemia in mestizo patients of the state of Zulia, Venezuela

The Human Leukocyte Allele (HLA) Class I (A, B, C) and Acute Lymphoid Leukemia and Myeloid Leukemia association, was determined by polymerase chain reaction--sequence specific primers (PCR-SSP) in 60 patients and 30 healthy controls. The results were reported as allelic frequencies and haplotype. The Chi-square corrected, Fisher's Test, Relative risk and etiologic fraction were calculated. A significant positive association was showed between HLA-B*39 (RR = 16.184; p = 0.0237) and HLA C*03 (RR = 5.0; p = 0.0127) alleles and Mycloid Leukaemia. Positive associations between haplotypes 2 loci: HLA-A*02-C*03 (RR = 6.0; p = 0.0153), A*24-C*03 (RR = 16.184; p = 0.0237), B*40-C*03 (RR = 10.706; p = 0.0021) and haplotype 3 loci: HLA-A*02-B*40-C*03 (RR = 8.11; p = 0.0102) and Myeloid Leukemia were found. No association was evident in Acute Lymphoid Leukemia. No negative association with Leukemias were observed.     

Molecular diversity of HLA-A, -B and -C alleles in a North Indian population as determined by PCR-SSOP

We have used molecular methods to determine the frequencies of human leukocyte antigen (HLA)-A, -B and -C alleles in normal, healthy, unrelated individuals from North India using polymerase chain reaction and hybridization with sequence-specific oligonucleotide probes as there is no comprehensive report showing molecular diversity of all the class-I alleles present in North Indians. A*0101, A*0206, A*0301, A*1101, A*6801, A*2401 and A*3101 were the most prevalent alleles of the A locus with 91.11% of the samples showing heterozygosity. At the HLA-B locus a total of 47 B locus alleles were observed and the only allele found with an allele frequency of 15% was B*5801. Other frequent B-locus alleles observed were B*5101, B*3503 and B*4006 with relatively less frequent alleles like B*5201, B*3501, B*0702, B*4403, B*5701, B*1801 and B*5501. Of the samples studied 92.31% were heterozygous for B-locus alleles. Cw*0602 and Cw*0401 were the most frequent C-locus alleles. Other frequent C-locus alleles were Cw*0102, Cw*0302, Cw*0701, Cw*0702, Cw*1202, Cw*1203, Cw*1502 and Cw*1503. HLA alleles common in Africans like B*5801, A*68012, B*5301, B*44032, B*4006 and Cw*1701 were observed in the North Indians besides oriental alleles like B*1301, B*1502 and B*4001 confirming that the genetic make-up of North Indians is Caucasoid with elements of Mongoloid and Negrito races. Some new/rare alleles like B*1802, described as a new allele from Thailand and B*8101, described earlier in a Bubi population were also observed although with low frequencies, showing the diversity of HLA class-I alleles present in the North Indians.     

Allelic and haplotypic diversity of HLA-A, -B, -C, -DRB1, and -DQB1 genes in the Korean population

High-resolution human leukocyte antigen (HLA) typing exposes the unique patterns of HLA allele and haplotype frequencies in each population. In this study, HLA-A, -B, -C, -DRB1, and -DQB1 genotypes were analyzed in 485 apparently unrelated healthy Korean individuals. A total of 20 HLA-A, 43 HLA-B, 21 HLA-C, 31 HLA-DRB1, and 14 HLA-DQB1 alleles were identified. Eleven alleles (A*0201, A*1101, A*2402, A*3303, B*1501, Cw*0102, Cw*0302, Cw*0303, DQB1*0301, DQB1*0302, and DQB1*0303) were found in more than 10% of the population. In each serologic group, a maximum of three alleles were found with several exceptions (A2, B62, DR4, DR14, and DQ6). In each serologic group exhibiting multiple alleles, two major alleles were present at 62-96% (i.e. A*0201 and A*0206 comprise 85% of A2-positive alleles). Multiple-locus haplotypes estimated by the maximum likelihood method revealed 51 A-C, 43 C-B, 52 B-DRB1, 34 DRB1-DQB1, 48 A-C-B, 42 C-B-DRB1, 46 B-DRB1-DQB1, and 30 A-C-B-DRB1-DQB1 haplotypes with frequencies of more than 0.5%. In spite of their high polymorphism in B and DRB1, identification of relatively small numbers of two-locus (B-C and DRB1-DQB1) haplotypes suggested strong associations of those two loci, respectively. Five-locus haplotypes defined by high-resolution DNA typing correlated well with previously identified serology-based haplotypes in the population. The five most frequent haplotypes were: A*3303-Cw*1403-B*4403-DRB1*1302-DQB1*0604 (4.2%), A*3303-Cw*0701/6-B*4403-DRB1*0701-DQB1*0201/2 (3.0%), A*3303-Cw*0302-B*5801-DRB1*1302-DQB1*0609 (3.0%), A*2402-Cw*0702-B*0702-DRB1*0101-DQB1*0501 (2.9%), and A*3001-Cw*0602-B*1302-DRB1*0701-DQB1*0201/2 (2.7%). Several sets of allele level haplotypes that could not be discriminated by routine HLA-A, -B, and -DRB1 low-resolution typing originated from allelic diversity of A2, B61, DR4, and DR8 serologic groups. Information obtained in this study will be useful for medical and forensic applications as well as in anthropology.     

HLA class II DRB1, DQB1, DPB1 polymorphism and cardiomyopathy due to Trypanosoma cruzi chronic infection

Trypanosomiasis is an important cause of cardiomyopathy in endemic rural areas of Latin America. Previous studies have suggested participation of HLA molecules in the immune response regulation of T. cruzi infection, and association of HLA antigens with heart damage.One hundred and eleven unrelated T. cruzi antigen-seropositive individuals were tested for HLA class II alleles by the polymerase chain reaction and sequence specific oligonucleotide (PCR-SSO) method. Patients were classified in 3 groups according to clinical and electrocardiographic characteristics: asymptomatics (group A), with arrhythmia (group B), and with overt congestive heart failure (group C). Statistical analysis confirmed the significant increment of the DRB1*01 DQB1*0501 haplotype (p = 0.03) previously reported by our laboratory in patients with cardiomyopathy. The DPB1*0401 allele frequency is also significantly increased in patients with heart disease (groups B + C) (p = 0.009) while DPB1*0101 frequency is higher among the asymptomatic group (p = 0.04) compared with individuals of group C. The DPB1*0401 allele in homozygous form or in combination with allele DPB1*2301 or 3901, was found present more often in patients of groups B and C. Thus, the combination of two of these three alleles, sharing specific sequence motifs in positions 8, 9, 76, and 84-87 confers a relative risk of 6.55 to develop cardiomyopathy in seropositive patients (p = 0.041). Furthermore, 32% of the cardiomyopathics have either DRB1*01 DQB1*0501 and/or DPB1*0401/*0401, 0401/*2301, or* 0401/*3901 compared with 9% of the seropositive asymptomatics (OR = 5.0; p = 0.006).     

The association of HLA -A, -B,and -DRB1 genotypes with Graves' disease in Taiwanese people

Graves' disease has been associated with different human leukocyte antigen (HLA) genes in different races. To evaluate the association of HLA type in Taiwanese with Graves' disease, the HLA-A, -B, and -DRB1 alleles in a total of 236 Taiwanese adults with Graves' disease and 533 racially matched normal control subjects were examined using the PCR-SSOP (sequence specific oligonucleotide probe) technique. The prevalence of HLA-A*0207, -B*2704, -B*4601, and -DRB1*0901 among patients with Graves' disease was found to be increased, with odds ratios (OR) of 2.21, 3.82, 1.76 and 1.62, respectively. However, after correction for multiple comparisons, the relative risk of HLA-A*0207 susceptibility to Graves' disease remained statistically significant and the haplotype HLA-A*3303 -B*5801 -DRB1*0301 had a significantly protective effect. None of the other 2- or 3-locus haplotypes showed any significantly increased risk. Although HLA-DRB1*1405 showed an increased relative risk in patients with GO (Graves' opthalmopathy) (OR 4.61) when compared with patients without GO, the relative risk after adjusting for the number of comparisons was not significant. Taiwanese patients with Graves' disease have HLA-associated susceptibility genes which are similar to those found in Chinese patients in Hong Kong and Singapore. However, the finding in this study of a higher frequency of HLA-A*0207 in Taiwanese with Graves' disease has not been documented in any other ethnic group.     

Association and interaction of the TNF-alpha gene with other pro- and anti-inflammatory cytokine genes and HLA genes in patients with type 1 diabetes from North India

Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where major histocompatibility complex (MHC) genes and the insulin-linked polymorphic region have been shown to play major roles. We report here an integrated effect of tumor necrosis factor (TNF) alpha with other cytokine genes. The TNF-alpha-308 GA and AA (high secretor) polymorphisms were significantly increased in the patients with T1D (n = 235) [P < 7 x 10(-6), odds ratio (OR) = 3.04, 95% confidence interval (CI) = 1.8-5.3] compared with the controls (n= 128). The variants of interferon-gamma (IFN-gamma) (A(+874)T), interleukin (IL)-6 (G(-174)C), IL-10 (A(-1082)G, T(-819)C, C(-592)A) and transforming growth factor (TGF) beta1 (T(cdn10)C, G(cdn25)C) did not show a significant difference between patients and controls. However, simultaneous presence of TNF-alpha-308 GA+AA along with both high and low secretor genotypes of IFN-gamma (P < 0.003) was significantly increased in patients. Simultaneous presence of TNF-alpha-308 GA + AA along with high secretor genotypes of IL-6 (P < 0.0001, OR = 2.61, 95% CI = 1.5-4.56), IL-10 (P < 0.0001, OR = 4.26, 95% CI = 1.9-10.1) and TGF-beta1 (P < 0.00004, OR = 2.8, 95% CI = 1.6-4.86) was also significantly increased in patients with T1D. Low secretor genotype of TNF-alpha-308 GG along with low secretor genotypes of IFN-gamma (P < 0.001, OR = 0.465, 95% CI = 0.28-0.77), high secretor genotypes of IL-6 (P < 0.000004, OR = 0.76, 95% CI = 0.227-0.621) and TGF-beta1 (P < 0.000006, OR = 0.336, 95% CI = 0.198-0.568) was protective. The TNF-alpha-308 G allele was in linkage disequilibrium (LD) with the human leukocyte antigen (HLA)-B*0801-DRB1*0301 haplotype, while TNF-alpha-308 A allele was in LD with the HLA-B*5001-DRB1*0301 and B*5801-DRB1*0301 haplotypes, suggesting that the effect of TNF-alpha -308 A allele is not because of its being in LD with any HLA alleles, but because of its functional role and its integrated effect with other cytokines.     

Human leukocyte antigen class II alleles and risk of cervical cancer in China

Human leukocyte antigen (HLA) class II alleles have been associated with an increased or decreased risk of developing cervical cancer through infection with oncogenic forms of human papillomavirus (HPV). To verify whether HLA class II allelic polymorphism is related to cervical cancer in China, 133 cervical cancers and 98 healthy controls were analyzed for HLA typing. Our results showed that DPB1*1301 allele frequency was significantly higher in the cervical cancers compared with healthy controls (OR, 3.793; p = 0.002; Pc = 0.04). A significant relationship was found between DRB1*150101-DQB1*0602 haplotype (OR, 0.180; p < 0.0001; Pc < 0.003), DRB1*070101-DQB1*0201 haplotype (OR, 0.110; p = 0.001; Pc = 0.03), and decreased risk for cervical cancer. Similar tendencies were observed for DRB1*150101-DQB1*0602 haplotype with HPV16 positive cervical cancers (OR, 0.182; p = 0.001; Pc = 0.021), and for DRB1*070101-DQB1*0201 haplotype (OR, 0.144; p =0.003; Pc = 0.063). These results indicate that HLA-DPB1*1301 may confer susceptibility to cervical cancer, and the haplotypes DRB1*150101-DQB1*0602 and DRB1*070101-DQB1*0201 may contribute to the resistance to the development of cervical cancer among Chinese women. The study suggests that specific HLA class II alleles and haplotypes may influence the immune response to specific HPV-encoded epitopes and affect the risk of cervical cancer in a Chinese population from an area with a high incidence of this neoplasia.     

DRB1-TNF-alpha-TNF-beta haplotype is strongly associated with severe aortoiliac occlusive disease, a clinical form of atherosclerosis

Severe aortoiliac occlusive disease (AOD) is a clinical manifestation of peripheral arteriosclerosis. Atherosclerosis has been associated with some human leukocyte antigen (HLA)-DRB1 alleles, stressing its relationship with autoimmune or inflammatory disorders. Additionally, in rheumatoid arthritis patients, the DRB1*0404 allele is specifically associated with endothelial dysfunction. Our objective was to assess the role of class II HLA alleles in the susceptibility to AOD; a combined study of the nearby tumor necrosis factor (TNF) locus was also performed. We included 104 AOD patients and 504 healthy controls from Madrid. DRB1 typing and DRB1*04 subtyping was done by polymerase chain reaction amplification followed by hybridization with specific oligonucleotides. TNF-alpha and TNF-beta microsatellites were studied by polymerase chain reaction and capillary electrophoresis. None of the markers was associated with AOD, although a trend was observed for DRB1*0404 (OR = 2.18; p = 0.05). However, among DRB1*0404 individuals, the TNFa11-b4 pair was present more frequently in patients than in controls (OR = 16.0; p = 0.007). The combined appearance of TNFa11-b4 and DRB1*0404 was much more frequent in patients than in controls (OR = 5.92; p = 0.0013), a result enhanced by haplotypic estimates (OR = 10.0; p = 0.00017). Our results show that the HLA region modulates the predisposition to AOD. More specifically, they suggest that an extended haplotype encompassing DRB1*0404 and TNFa11-b4 carries a genetic factor conferring susceptibility to AOD.     

HLA-C disparity between patients and unrelated donors matched for HLA-A, -B, and -DRB1 alleles: impact of serological vs. DNA typing for HLA-A and -B loci.

High incidences of graft failure, graft-vs.-host disease (GVHD), and serious infections following unrelated donor (URD) marrow transplantation, despite apparent human leukocyte antigen (HLA) identity, may reflect the presence of molecular disparities, including those for HLA-C alleles between the patient and the URD. The level of these disparities could be significant, because as many as 42 alleles are currently known for HLA-C locus. We studied 84 patients and 251 potential URDs to evaluate 1) the extent of HLA-C disparity between the patient and the URD identified by serology for HLA-A and -B and by DNA typing for -DRB1 and 2) the level of HLA-C disparity between patients and URDs matched by high-resolution DNA typing for HLA-A, -B, and -DRB1. The DNA typing was performed at the Memorial Sloan Kettering Cancer Center, and the serotyping was provided by the registries. Of 251 URDs matched by HLA-A and -B serology and -DRB1 (sA_sB_dnaDRB1 ); 94, 75, and 82 were 6/6, 5/6, and 4/6 matches, respectively. Of 94 sA_sB_dnaDRB1 6/6 URDs, 51 (54.3%) were matched for both HLA-C alleles. In contrast, 31 (41.3%) 5/6 (p=0.12) and 15 (18.3%) 4/6 (p < 0.01) sA_sB_dnaDRB1 URDs were matched for both HLA-C alleles. Following DNA typing for HLA-A and -B, 52 (55.3%) of 94 6/6, 30 (40%) of 75 5/6, and 25 (30.5%) of 82 4/6 sA_sB_dnaDRB1 URDs remained 6/6, 5/6, and 4/6 matches at the DNA level (dnaA_B_DRB1). HLA-C disparities continued to exist in the dnaA_B_DRB1 URD group. Of 54 dnaA_B_DRB1 6/6 URDs, 41 (75.9%) were matched for both HLA-C alleles. Only 45.3% of the 5/6 (p=0.01) and 22.2% of the 4/6 (p < 0.01) dnaA_B_DRB1 URDs were matched for both HLA-C alleles. In the 6/6 category, the frequency of HLA-C matching improved (75.9 vs. 54.3%; p=0.01) following DNA matching for HLA-A and -B. In comparison to mismatching for HLA-B locus, mismatching for either HLA-DRB1 or -A resulted in a lower odds ratio for HLA-C disparity. The presence of a common haplotype in the sA_sB_dnaDRBl (p=0.06) URD category improved the level of HLA-C matching. We identified alleles that are associated with high (B*1501, B*4402, B*5101, DRB1*0101, A*0201, A*1101, A*2301, and A*3201) or low (B*0702, B*0801, B*1302, B*3502, DRB1*0301, DRB1*1104, A*0101, A*3001, and A*6801) probability of HLA-C disparity. Overall, sA_sB_dnaDRB1 as well as dnaA_B_DRB1 matched URDs for non-Caucasian patients were more likely to have HLA-C disparity in comparison to the matched URDs of Caucasian patients. However, a high incidence of HLA-C disparities was identified even in the URDs for Caucasian patients. Whether the disparities demonstrated by this study contribute to the higher immunological complications noted following URD bone marrow transplantation is unclear. Outcome analysis and studies aimed at understanding the functional role of HLA-C may provide an answer.