HPV16 E6 variants and HLA class II polymorphism among Chinese women with cervical cancer

Infection with human papillomavirus type 16 (HPV16) confers a high risk for the development of cervical cancer. Variants of this virus may interact differentially with host genetic factors, possibly affecting the disease pathogenesis. This study was designed to investigate the association between HPV16 E6 variants and human leukocyte antigen (HLA) polymorphism within a Chinese population. Peripheral blood from HPV16 positive Chinese women with cervical carcinoma, who had previously been tested for HPV16 E6 variants, was used for HLA class II typing. It was found that there was a significant positive association between DQB1*060101 allele and HPV16 As variant-positive cervical cancers (OR, 4.47; Pc=0.0018). A negative relationship was found between DRB1*150101-DQB1*0602 haplotype and decreased risk for HPV16 As variant-positive cervical cancers (OR=0.31; P=0.037). Similar tendency was observed for the haplotype DRB1*070101-DQB1*0201 with HPV16 As variant-positive cervical cancers (OR=0.16, P=0.024). Additionally, as for the HPV16 E6 prototype-positive cervical cancers, a significant positive association was found in DQB1*060101 allele (OR=5.95; P=0.002; Pc=0.036), and similar trends were observed for DQB1*030201 (OR=10.87, P<0.0001; Pc=0.0018), and DPB1*1301(OR=7.40, P=0.002; Pc=0.04). It was found that there was no significant association between DRB1-DQB1 haplotype and HPV16 prototype-positive cervical cancers. These data indicate that host genetic factors, such as HLA polymorphism, may determine the potential oncogenicity of the HPV16 E6 variant. The results suggest that a specific match between E6 variant proteins and HLA class II alleles may contribute to HPV16-related cervical carcinogenesis in a certain Chinese population.     

Evidence for HLA class II susceptible and protective haplotypes for osteomyelitis in pediatric patients with sickle cell anemia

We investigated the association of human leukocyte antigen (HLA) class II alleles and haplotypes with the pathogenesis of sickle cell anemia (SCA) osteomyelitis. SCA patients comprised 42 patients with osteomyelitis and 150 patients without osteomyelitis; HLA-DRB1* and HLA-DQB1* genotyping was performed by polymerase chain reaction-sequence-specific priming (SSP). DRB1*100101 (P value corrected for the number of different alleles tested, Pc=0.003) was positively associated with osteomyelitis. At the haplotype level, DRB1*100101-DQB1*050101 (Pc=0.001) was more prevalent among patients, while DRB1*030101-DQB1*0201 (Pc=0.020) and DRB1*040101-DQB1*0302 (Pc=0.039) were more prevalent among SCA controls, thereby conferring disease susceptibility or protection to these haplotypes, respectively. These results show that specific HLA haplotypes influence SCA osteomyelitis risk and that specific HLA types may serve as markers for identifying SCA patients at high risk for osteomyelitis.     

Polymorphism of human leukocyte antigen-DRB1, -DQB1, and -DPB1 genes of Shandong Han population in China

In the present study, polymerase chain reaction-sequence-based typing (PCR-SBT) was used to analyze human leukocyte antigen (HLA)-DRB1, -DQB1, and -DPB1 alleles of 98 unrelated healthy Shandong Han individuals. A total of 60 alleles, in which 28 in DRB1, 15 in DQB1 and 17 in DPB1 were found. Among the 28 detected DRB1 alleles, DRB1*150101, DRB1*070101, DRB1*090102, DRB1*120201, and DRB1*080302 were commonly observed, with frequencies of 16.3%, 11.2%, 10.2%, 8.2%, and 5.6%, respectively. The most predominant DQB1 allele was DQB1*030101/0309 with the frequency of 20.4%, followed by DQB1*0201/0202 (14.8%), DQB1*0602 (14.3%), DQB1*030302 (12.2%), and DQB1*060101/060103 (10.7%). Of the 17 detected DPB1 alleles, DPB1*0501 was the most frequent allele with the frequency of 37.2%. DPB1*020102 (18.4%), DPB1*040101 (11.2%), DPB1*0402 (7.1%), and DPB1*1701 (6.6%) were also very frequent alleles. A total of 53 estimated DRB1-DQB1 two-locus haplotypes were observed in Shandong Han population, of which DRB1*150101-DQB1*0602 was the most predominant, followed by DRB1*090102-DQB1*030302, DRB1*070101-DQB1*0201/0202 DRB1*120201-DQB1*030101/0309, and DRB1*080302- DQB1*060101/060103. The distribution of the HLA class II alleles and haplotypes frequencies as well as the dendrogram showed that the Shandong Han population belongs to the northern group of Chinese. The data have implications for anthropological studies and disease associations.     

Association of selective HLA class II susceptibility-conferring and protective haplotypes with type 2 diabetes in patients from Bahrain and Lebanon

The association of HLA class II with type 2 diabetes (T2DM) was investigated in Bahraini and Lebanese subjects. DRB1*070101 (Lebanese and Bahraini) and DQB1*0201 (Lebanese) were susceptibility-conferring alleles, and unique susceptibility-conferring/protective haplotypes were found in both patient groups. Regression analysis confirmed that DRB1*070101-DQB1*0201 (Bahraini) and DRB1*110101-DQB1*0201 (Lebanese) were susceptibility-conferring haplotypes.     

Susceptible and protective human leukocyte antigen class II alleles and haplotypes in bahraini type 2 (non-insulin-dependent) diabetes mellitus patients

Whereas the genetic risk for type 1 diabetes is linked to human leukocyte antigen (HLA) class II genes, the HLA association in type 2 (non-insulin-dependent) diabetes is less clear. The association between HLA class II genotypes and type 2 diabetes was examined in adult Bahrainis, an Arab population with a high prevalence of type 2 diabetes. HLA-DRB1* and -DQB1* genotyping of 86 unrelated type 2 diabetes patients (age, 51.6+/-8.2 years; mean duration of diabetes, 7.7+/-7.1 years) who had a strong family history of diabetes (52 of 72 versus 0 of 89 for controls, P<0.001) and 89 healthy subjects was done by PCR-sequence-specific priming. DRB1*040101 (0.1221 versus 0.0562, P=0.019) and DRB1*070101 (0.2151 versus 0.0843, P<0.001) were positively associated, while DRB1*110101 (0.0698 versus 0.1461, P=0.014) and DRB1*160101 (0.0640 versus 0.1236, P=0.038) were negatively associated with type 2 diabetes. DRB1*040101-DQB1*0302 (0.069 versus 0.0007; P=0.004), DRB1*070101-DQB1*0201 (0.178 versus 0.0761, P=0.007), DRB1*070101-DQB1*050101 (0.125 versus 0.0310, P=0.002), and DRB1*150101-DQB1*060101 (0.0756 versus 0.0281, P=0.008) were more prevalent among patients, while DRB1*160101-DQB1*050101 (0.0702 versus 0.0349, P=0.05) was more prevalent among controls, conferring disease susceptibility or protection, respectively. In Bahrainis with type 2 diabetes, there is a significant association with select HLA class II genotypes, which were distinct from those in type 1 diabetes.     

Similar incidence of type 1 diabetes in two ethnically different populations (Italy and Slovenia) is sustained by similar HLA susceptible/protective haplotype frequencies

The incidence of type 1 diabetes (T1DM) seems to depend in part on the population frequencies of susceptible and protective HLA haplotypes. The present study aimed to (i): characterize the genetic susceptibility to T1DM in the Slovenian population, (ii) test the general hypothesis that T1DM incidence is related to the frequencies of susceptible/protective haplotypes, (iii) compare allele, haplotype and genotype frequencies in Slovenians and Italians that represent two white populations with a similar incidence of T1DM (7.9/100,000/year and 8.1/100,000/year, respectively). The haplotype found most frequently among Slovenian T1DM patients was DRB1*0301-DQA1*0501-DQB1*0201 (53%). The DR4-DQA1*0301-DQB1*0302 haplotypes conferring susceptibility to T1DM were those bearing DRB1*0401 (OR = 12), DRB1*0404 (OR = 4.7) and DRB1*0402 (OR = 4.5). Negative associations with the disease were found for the following haplotypes: DRB1*1501-DQA1*0102-DQB1*0602, DRB1*1301-DQA1*0102-DQB1*0603, DRB1*1101/1104-DQA1*0501-DQB1*0301, and DRB1*1401-DQA1*0101-DQB1*0503. Our findings indicate that the low frequencies of susceptible genotypes, in particular, DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302, together with a high frequency of protective haplotypes, could in part explain the low incidence of T1DM in the Slovenian population. The combined frequencies of susceptible genotypes were similar in the two populations (Slovenia = 19.2%, Italy = 17.6%), and the 95% confidence limits of the OR values for each genotype in the two populations overlapped, indicating no significant differences between the values. We conclude that the similar incidences of T1DM in Italian and Slovenian populations are in part a reflection of similar frequencies of HLA susceptible/protective haplotypes.     

The distribution of HLA class II susceptible/protective haplotypes could partially explain the low incidence of type 1 diabetes in continental Italy (Lazio region)

HLA class II is the primary susceptibility gene to type 1 diabetes and the analysis of HLA class II association could help to clarify the relative weight of genetic contribution to the incidence of the disease. Here we present an extensive typing for HLA class II alleles and their haplotypes in a homogenous population of type 1 diabetic patients (n=134) and controls (n=128) and in simplex (n=100) and multiplex families (n=50) from continental Italy (Lazio region). Among the various haplotypes tested, the DRB1*0301-DQA1*0501-DQB1*0201 was the most frequent found in type 1 diabetic patients and was transmitted in 82% of affected siblings, whereas DRB1*0402-DQA1*0301-DQB1*0302 appeared to have the highest odds ratio (10.4), this haplotype was transmitted in 96.3% of affected siblings, followed by DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0405-DQA1*0301-DQB1*0201, DRB1*0401-DQA1*0301-DQB1*0302 and DRB1*0404-DQA1*0301-DQB1*0302. The following haplotypes showed a significant decreased transmission to diabetic siblings: DRB1*0701-DQA1*0201-DQB1*0303, DR2-DQA1*01-DQB1*0602, DR5-DQA1*0501-DQB1*0301. We suggest that the HLA DR/DQ haplotype/genotype frequencies observed could in part explain the low incidence of type 1 diabetes registered in Lazio region (8.1/100.000/year), for a number of reasons: i) the low frequency, in the general control population, of the most susceptible haplotypes and genotype for type 1 diabetes DRB1*0301-DQA1*0501-DQB1*0201 (14%), and DR4-DQA1*0301-DQB1*0302 (9%) and DRB1*0301-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302 (0.8%) compared to other countries characterised by high incidence rate of the disease, Sardinia and Finland, respectively; ii) a significant lower ratio, in the control population, between the susceptible DRB1*0301-DQA1*0501-DQB1*0201 and the neutral DRB1*0701-DQA1*0501-DQB1*0201 haplotypes compared to the Sardinian population; iii) the high frequency of protection haplotypes/genotypes as the DR5-DQA1*0501-DQB1*0301, and DR5-DQA1*0501-DQB1*0301/DR5-DQA1*0501-DQB1*0301 very common in the control population of Lazio region and the DRB1*1401-DQA1*0101-DQB1*0503 haplotype.     

Human leukocyte antigen non-class II determinants for type 1 diabetes in the Finnish population

We explored the contribution of non-class II HLA loci to type 1 diabetes genetic susceptibility in the Finnish population. We analyzed 11 markers covering a 4-Mb region telomeric to the DQB1 gene in Finnish nuclear families with parents carrying either the DR8-DQB1*04 (n=188) or the DRB1*0404-DQB1*0302 haplotypes (n=135). On the DRB1*0404-DQB1*0302 haplotype we found independent disease association of the D6S273 and C125 markers (p(corr) = 10(-4) and 0.0095, respectively). The C125*200 alleles on this haplotype conferred an increased disease risk (OR = 3.6; p = 0.003). The B*39 allele also showed disease association (OR = 2.6; p = 0.054). The C125*200 allele appeared at an increased frequency also on transmitted B39 positive DRB1*0404-DQB1*0302 haplotypes, suggesting an independent effect. In addition, the C143*417 allele on the DRB1*08-DQB1*04 haplotype was associated with decreased disease risk (OR = 0.48, p = 0.003). Our data confirm that non-class II HLA loci affect genetic susceptibility to type 1 diabetes. In addition to HLA B*39 the C125 locus contributes to disease risk on the Finnish DRB1*0404-DQB1*0302 haplotypes. Another locus close to D6S273 may also have an effect. For the first time we report that a locus near the C143 marker appear to affect disease association of the DRB1*08-DQB1*04 haplotype.     

HLA class II haplotypes distinctly associated with vaso-occlusion in children with sickle cell disease

We investigated the association of HLA class II alleles and haplotypes with sickle cell anemia vaso-occlusive crisis (VOC). DRB1*100101 was positively associated, while DRB1*140101, DRB1*150101, and DQB1*060101 were negatively associated, with VOC. Both susceptible (DRB1*100101-DQB1*050101) and protective (DRB1*110101-DQB1*030101 and DRB1*150101-DQB1*060101) haplotypes were identified, indicating that HLA class II haplotypes influence VOC risk.     

HLA-associated genetic resistance and susceptibility to type I diabetes in French North Africans and French natives

The distribution of human leukocyte antigen (HLA)-DRB1-DQA1-DQB1 haplotypes was analyzed separately in two distinct French ethnic groups with type I diabetes (T1D), i.e. French North African migrants (n= 64, mean age at diagnosis = 8.25 years) and ancient French natives (n= 60, mean age at diagnosis = 7.42 years). HLA associations were determined by calculating odds ratios (ORs) between patients and two ethnic-matched control populations. Results show highly similar ORs for the conservative DRB1*0301-DQA1*0501-DQB1*0201 haplotype of susceptibility (OR: 3.22 and 3.93 in migrants and natives, respectively) and the DRB1*1501-DQA1*0102-DQB1*0602 haplotype of resistance (OR: 0.05 and 0.03, respectively). In contrast, among the more variable DRB1*04-DQB1*0302 haplotypes of susceptibility, the DRB1*0402 (OR: 3.10 and 32.84) and 0405 (OR: 5.90 and 16.25, respectively) were associated with T1D in migrants and natives, whereas an increase of DRB1*0401, a rare allele in migrants, was significant in natives only. Also, among the DRB1*11-DQA1*0505-DQB1*0301 haplotypes of resistance, the OR observed for DRB1*1104-DQA1*0505-DQB1*0301, common in migrants, was lower (OR: 0.08) than for DRB1*1101-DQA1*0505-DQB1*0301 (OR: 0.32), common in natives. How DRB1*11 subtypes might affect differently the risk conferred by DQA1*0505-DQB1*0301 will be discussed.     

HLA class II profile and distribution of HLA-DRB1 and HLA-DQB1 alleles and haplotypes among Lebanese and Bahraini Arabs

The gene frequencies of HLA class II alleles were studied in 95 healthy Lebanese Arab and 72 healthy Bahraini Arab subjects. Our aim was to establish the genetic relationship between Bahraini and Lebanese Arabs in terms of HLA class II gene and haplotype frequencies and to compare these results with frequencies for other countries with populations of Caucasian and non-Caucasian descent. Subjects were unrelated and of both sexes, and HLA-DRB1 and -DQB1 genotyping was done by the PCR sequence-specific primer technique. Comparative analysis of the HLA-DR and -DQ alleles revealed differences in the allelic distribution among Bahraini and Lebanese subjects. Analysis of the 25 HLA-DRB1 alleles that have been investigated showed that the DRB1*040101 and DRB1*110101 alleles were more frequent among Lebanese, whereas DRB1*030101 and DRB1*160101 alleles were more frequent among Bahrainis. Similarly, of the seven HLA-DQB1 alleles analyzed, the presence of DQB1*0201 was more frequent among Bahrainis, whereas DQB1*030101 was more frequent among Lebanese. The DRB1*160101-DQB1*050101 (0.1318 versus 0.0379%) and DRB1*030101-DQB1*0201 (0.1202 versus 0.0321%) haplotypes were more frequent among Bahrainis, while the DRB1*110101-DQB1*030101 (0.3142 versus 0.1198%) and DRB1*040101-DQB1*0302 (0.1416 versus 0.0278%) haplotypes were more frequent in Lebanese subjects. Furthermore, a high prevalence of the DRB1*040101-DRB1*110101-DQB1*0302-DQB1*030101 (12.63 versus 1.35%, P = 0.015) and the homozygous DRB1*110101-DRB1*110101-DQB1*030101-DQB1*030101 (7.37 versus 0.00%, P = 0.046) genotypes was seen among Lebanese, and DRB1*070101-DRB1*160101-DQB1*0201-DQB1*050101 (6.76 versus 0.00%, P = 0.034) was seen more frequently among Bahraini subjects. Our results underline significant differences between these two populations in HLA class II distribution, provide basic information for further studies of major histocompatibility complex heterogeneity among Arabic-speaking countries, and serve as a reference for further anthropological studies.     

Polymorphism of HLA-A, -B, -DRB1, -DQA1 and -DQB1 haplotypes in a Croatian population.

We describe for the first time extended haplotypes in a Croatian population. The present study gives the HLA-A, -B, -DRB1, -DQA1 and -DQB1 allele and haplotype frequencies in 105 families with at least two offspring. All individuals were studied by conventional serology for HLA class I antigens (A and B), while class II alleles (DRB1, DQA1, DQB1) were typed using the PCR-SSOP method. HLA genotyping was performed by segregation in all 105 families. For extended haplotype analysis, 420 independent parental haplotypes were included. Fourteen HLA-A, 18 HLA-B, 28 DRB1, 9 DQA1 and 11 DQB1 alleles were found in the studied population. Most of the DRB1 alleles in our population had an exclusive association with one specific DQA1-DQB1 combination. This strong linkage disequilibrium within the HLA class II region is often extended to the HLA-B locus. A total of 10 HLA-A, -B, -DRB1, -DQA1, -DQB1 haplotypes were observed with a frequency 相似文献   

The HLA-DRB, -DQB polymorphism and anti-insulin antibody response in Slovenian patients with type 1 diabetes.

A combination of specific HLA class II antigens and the presence of type 1 diabetes (T1D)-related antibodies has a high positive predictive value for T1D but low sensitivity. The aim of the present study was to determine the frequencies of HLA-DRB-DQB deduced haplotypes associated with susceptibility and protection in Slovenian patients with established T1D, to evaluate the relationship between the HLA-DRB1-QBP-DQB1 haplotypes and the presence of insulin autoantibodies (IAA) and glutamic acid decarboxylase antibodies (GADA), and to access the possible impact of polymorphic QBP promoters on this relationship. A cohort of 135 patients with T1D (age 17.5 +/- 7.0 years, duration of T1D 9.14 +/- 6.3 years) was investigated. HLA-DRB1 and DQB1 alleles were typed using the polymerase chain reaction (PCR)-reverse line blot method. QBP promoter region alleles were determined using PCR-sequence-specific oligonucleotide hybridization (SSO) and PCR-sequence-specific primers (SSP). IAA and GADA antibodies were determined by enzyme-linked immunosorbent assay (ELISA). The chi-square test with Yates' correction was used for statistical analysis. Deduced haplotypes DRB1*0301-DQB1*0201 (P = 0.0001, OR = 3.4), DRB1*0401-DQB1*0302 (P = 0.0001, OR = 29.8), and DRB1*0402-DQB1*0302 (P = 0.008, OR = 4.7) were significantly more common, and DRB1*1501-DQB1*0602 (P = 0.0001, OR = 0.03) significantly less common in the investigated cohort than in a Slovenian control group. The highest risk and the strongest protective HLA-DR-DQ haplotypes found in Slovenian patients with T1D did not differ from those found in other Caucasian populations. While the DRB1*0301-QBP2.1-DQB1*0201 haplotype, where QBP2.1 did not help to further distinguish DQB1*0201-possessing haplotypes in IAA-positive and IAA-negative patients, was strongly associated with the presence of IAA, the DRB1*0101-QBP5.12-DQB1*0501 haplotype, although not protective compared to the control population, was associated with an absence of IAA in the investigated cohort. It is suggested that there may be a combined influence of the QBP5.12 promoter and the DQB1*0501 functional molecule on reduced IAA production.     

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.     

Tumor necrosis factor A and MHC class I chain related gene A (MIC-A) polymorphisms in Swedish patients with cervical cancer

Human papillomaviruses type 16 and 18 are the major cause of cervical cancer. However, genetic factors contribute to the propensity of persistent HPV infection and cervical carcinoma. Allelic variants of the human leukocyte genes have shown to be associated with cervical neoplasia. The strongest associations have been found with the genes in the HLA class II region. The aim of this study was to analyze the association of two non-HLA class II markers with invasive cervical cancer. Microsatellite polymorphism of the TNFA gene located in the class III region and a short tandem repeat polymorphism of the MICA gene located in the centromeric end of the HLA class I region were analyzed. Eighty-five patients and 120 matched control individuals from a population-based cohort from Northern Sweden participated in this nested case-control study. MICA was not associated with cervical carcinoma. TNFa-11 frequency was increased in the HPV18 DNA positive patients (OR = 2.84, p = 0.0481, CI = 1.04-7.78, pc = NS). TNFa-11 was not associated with susceptibility to HPV16 infection, but it increased the risk for cervical cancer with the HLA DQ6 (DQA 1*0102-DQB 1*0602) haplotype. Our findings indicate that the association of TNFA with cervical cancer is different with CIN. The extended HLA DQ6-TNFa-11 haplotype is increasing the risk for development of cervical cancer significantly (OR = 3.08, p = 0.0104, CI = 1.30-7.31).     

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.     

Human leucocyte antigen class II DRB1 and DQB1 associations in human immunodeficiency virus-infected patients of Mumbai,India

The pathogenesis of human immunodeficiency virus (HIV) infection clearly involves immunoregulatory host factors and products of major histocompatibility complex class II genes, which present antigenic peptides to the T-cell receptor on CD4+ cells, which in turn increase the production of specific antibodies and cytotoxic T lymphocytes. The main objective of this study was to determine the associations of human leucocyte antigen (HLA) DRB1 and DQB1 alleles and their haplotypes in 210 HIV-1-infected patients and compare them with 129 healthy normal individuals with same ethnic background. The HLA DRB1 and DQB1 alleles were genotyped using polymerase chain reaction product and sequence-specific probes for reverse line hybridization, analysed with the Invitrogen Dynal PMP software. Our results revealed a highly significant increase of HLA DRB1*0902 [odds ratio (OR) = 17.12; P = 0.004], DQB1*030103 (OR = 53.53; P = 4.61E-07) and DQB1*050201 (OR = 16.26; P = 0.0002) alleles while in contrast highly significant decrease in frequency of HLA DQB1*030101 (OR = 0.36; P = 0.0002), DQB1*050301 (OR = 0.22; P < 0.0001) and DQB1*060101 (OR = 0.43; P < 0.0001) among the HIV-1-infected patients when compared with the controls. The haplotype DRB1*0902-DQB1*030103 (OR = 10.65; P = 0.06) was significantly increased in HIV1 patients, while haplotypes DRB1*150101–DQB1*060101 (OR = 0.386, P < 0.0001), DRB1*030101–DQB1*020101 (OR = 0.197, P = 0.004) and DRB1*070101–DQB1*0202 (OR = 0.167, P = 0.001) were significantly decreased. Our results indicate clearly that there are HLA class II alleles involved in the susceptibility to and protection from HIV-1 infection in our study group and further they vary in different ethnic groups reported in literature.     

HLA class IIDRB, DQA1 and DQB1 polymorphisms in the Polish population from Wielkopolska

HLA DRB1, DQA1 and DQB1 alleles were determined by DNA PCR-SSO typing in a sample of 99 individuals originating from Wielkopolska (midwestern Poland). A high number of alleles (38 DRB1, 8 DQA1 and 14 DQB1) was detected at each locus, many of them presenting notable frequencies in this population. The three HLA loci are thus characterized by very high heterozygosity levels (93% for DRB1, 85% for DQA1, and 88% for DQB1), which confirms the results found for other European populations. A total of 6 DRB1-DQA1-DQB1 haplotypes are detected with an estimated frequency higher than 5%, namely, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*0701-DQA1*0201-DQB1*0201, DRB1*0101-DQA1*0101-DQB1*0501, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*03011-DQA1*0501-DQB1*0201, and DRB1*1301-DQA1*0103-DQB1*0603. A genetic distance analysis between the Polish and other world populations tested for HLA class II indicates that the Wielkopolska community is close to geographically close, rather than linguistically related populations from Europe. More generally, a good agreement between genetics and geography is found for DRB1 and DQB1 polymorphisms in Europe, suggesting that these two loci are highly informative for assessing historical relationships among humans.     

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.     

HLA class II allele and haplotype frequencies in Koreans based on 107 families

We have investigated the distribution of HLA class II alleles and haplotypes in 107 Korean families (207 parents and 291 children) for the HLA-DRB1, DRB3/B4/B5, DQA1, DQB1 and DPB1 loci. Numbers of alleles observed for each locus were DRB1: 25, DQA1: 14, DQB1: 15, and DPB1: 13. Only two to three alleles were observed for the DRB3 (*0101, *0202, *0301), DRB4 (*0103, * 0103102 N), and DRB5 (*0101, *0102) loci. These alleles showed strong associations with DRB1 alleles: DRB3*0101 with DRB1*1201, *1301 and *1403; DRB3*0301 with DRB1*1202 and *1302; DRB3*0202 with DRB1*0301, *1101, *1401 and *1405; DRB5*0101 and *0102 were exclusively associated with DRB1*1501 and *1502, respectively. The seven most common DRB1-DQB1 haplotypes of frequencies > 0.06 accounted for 52% of the total haplotypes. These haplotypes were exclusively related with the seven most common DRB1-DRB3/B4/B5-DQA1-DQB1 haplotypes: DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 (0.085), DRB1*0405-DRB4*0103-DQA1*0303-DQB1*0401 (0.082), DRB1*09012-DRB4*0103-DQA1*0302-DQB1*03032 (0.082), DRB1*0101-DQA1*0101-DQB1*0501 (0.075), DRB1*0701-DRB4*0103-DQA1*0201-DQB1*0202 (0.065), DRB1*0803-DQA1*0103-DQB1*0601 (0.065), and DRB1*1302-DRB3*0301-DQA1*0102-DQB1*0604 (0.065). When these haplotypes were extended to the DPB1 locus, much diversification of haplotypes was observed and only one haplotype remained with a frequency of > 0.06: DRB1*0405-DRB4*0103-DQA1*0303-DQB1*0401-DPB1*0501 (0.062). Such diversification would have resulted from cumulated events of recombination within the HLA class II region, and the actual recombination rate observed between the HLA-DQB1 and DPB1 loci was 2.3% (10/438 informative meioses, including 2 recombinants informative by analysis of TAP genes). Comparison of the distribution of DRB1-DQB1 haplotypes with other populations revealed that Koreans are closest to Japanese people. However, Koreans share a few haplotypes with white people and Africans, which are rare in Japanese: DRB1*0701-DQB1*0202 and DRB1*1302-DQB1*0609. The results obtained in this study will provide useful information for anthropology, organ transplantation and disease association studies.