Specific HLA-DRB and -DQB alleles and haplotypes confer disease susceptibility or resistance in Bahraini type 1 diabetes patients

Insofar as genetic susceptibility to type 1 diabetes is associated with HLA class II genes, with certain allelic combinations conferring disease susceptibility or resistance, this study assessed the distributions of HLA-DR and -DQ among 107 unrelated patients with type 1 diabetes and 88 healthy controls from Bahrain, all of Arab origin. The HLA-DRB and -DQB genotypes were determined by PCR-sequence-specific priming. The following alleles showed the strongest association with type 1 diabetes among patients versus controls according to their frequencies: DRB1*030101 (0.430 versus 0.097; P < 0.001), DRB1*040101 (0.243 versus 0.034; P < 0.001), DQB1*0201 (0.467 versus 0.193; P < 0.001), and DQB1*0302 (0.229 versus 0.091; P < 0.001). When the frequencies of alleles in controls were compared to those in patients, negative associations were seen for DRB1*100101 (0.085 versus 0.014; P < 0.001), DRB1*110101 (0.210 versus 0.060; P < 0.001), DQB1*030101 (0.170 versus 0.075; P = 0.006), and DQB1*050101 (0.335 versus 0.121; P < 0.001). In addition, the DRB1*030101-DQB1*0201 (70.1 versus 22.7%; P < 0.001) and DRB1*030101-DQB1*0302 (21.5 versus 0.0%; P < 0.001) genotypes were more prevalent among patients, thereby conferring disease susceptibility, whereas the DRB1*100101-DQB1*050101 (20.5 versus 2.8%; P < 0.001), DRB1*110101-DQB1*030101 (28.4 versus 8.4%; P < 0.001), and DRB1*110101-DQB1*050101 (30.7 versus 0.9%; P < 0.001) genotypes were more prevalent among controls, thus assigning a protective role. These results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with type 1 diabetes and may underline several characteristics that distinguish Bahraini patients from other Caucasians patients.     

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.     

Influence of Common and Specific HLA-DRB1/DQB1 Haplotypes on Genetic Susceptibilities of Three Distinct Arab Populations to Type 1 Diabetes

The contribution of HLA DRB-DQB to type 1 diabetes (T1D) in Bahrainis, Lebanese, and Tunisians was investigated. DRB1*030101-DQB1*0201 was a locus that conferred susceptibility in three populations, while DRB1*040101-DQB1*0302 was a locus that conferred susceptibility only in Tunisians and Bahrainis. The DRB1*100101-DQB1*050101 (Bahrainis) and DRB1*150101-DQB1*060101 (Lebanese) loci were largely protective. The contribution of HLA to T1D must be evaluated with regard to ethnic background.     

Glutamic acid decarboxylase 65 and islet cell antigen 512/IA-2 autoantibodies in relation to human leukocyte antigen class II DR and DQ alleles and haplotypes in type 1 diabetes mellitus

The frequencies of autoantibodies against glutamic acid decarboxylase 65 (GAD65) and islet cell antigen (ICA) 512/IA-2 (512/IA-2) are functions of the specific human leukocyte antigen (HLA) in type 1 diabetes mellitus (T1D). We investigated the association of HLA class II (DR and DQ) alleles and haplotypes with the presence of GAD and IA-2 autoantibodies in T1D. Autoantibodies were tested in 88 Tunisian T1D patients and 112 age- and gender-matched normoglycemic control subjects by enzyme immunoassay. Among T1D patients, mean anti-GAD antibody titers were higher in the DRB1*030101 allele (P < 0.001), together with the DRB1*030101/DQB1*0201 (P < 0.001) and DRB1*040101/DQB1*0302 (P = 0.002) haplotypes, while lower anti-GAD titers were associated with the DRB1*070101 (P = 0.001) and DRB1*110101 (P < 0.001) alleles and DRB1*070101/DQB1*0201 (P = 0.001) and DRB1*110101/DQB1*030101 (P = 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in the DRB1*040101 allele (P = 0.007) and DRB1*040101/DQB1*0302 (P = 0.001) haplotypes but were lower in the DRB1*110101 allele (P = 0.010) and the DRB1*110101 (P < 0.001) and DRB1*110101/DQB1*030101 (P = 0.025) haplotypes. Multinomial regression analysis confirmed the positive association of DRB1*030101 and the negative association of DRB1*110101 and DQB1*030101, along with the DRB1*070101/DQB1*0201 and DRB1*110101/DQB1*030101 haplotypes, with anti-GAD levels. In contrast, only the DRB1*040101/DQB1*0302 haplotype was positively associated with altered anti-IA-2 titers. Increased GAD65 and IA-2 antibody positivity is differentially associated with select HLA class II alleles and haplotypes, confirming the heterogeneous nature of T1D.     

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.     

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.     

HLA-DPB1, -DRB1, and -DQB1 polymorphism defined in Ewenki ethnic minority of China Inner Mongolia Autonomous Region

In the present study, DNA typing for human leucocyte antigen (HLA)-DPB1, -DRB1, and -DQB1 was performed using polymerase chain reaction-sequence-based-typing (PCR-SBT) method on 94 randomly selected, healthy, unrelated individuals from the Ewenki ethnic population in Inner Mongolia Autonomous Region of China. A total of 64 alleles: 25 in DRB1, 19 in DQB1 and 20 in DPB1, were found. Among the 25 detected DRB1 alleles, DRB1*090102, DRB1*030101, DRB1*040101, DRB1*070101, and DRB1*120101/1206 were commonly observed, with frequencies of 16.0%, 13.3%, 10.1%, 7.4%, and 7.4%, respectively. The most predominant DQB1 allele was DQB1*030101/0309 with the frequency of 27.7%, followed by DQB1*0201/0202 (19.7%), DQB1*030302 (12.8%), DQB1*060101/060103 (6.4%), and DQB1*050201 (5.9%). Of the 20 detected DPB1 alleles, DPB1*020102 was the most frequent allele with the frequency of 25.5%. DPB1*0402 (21.3%), DPB1*0401 (20.2%), DPB1*0501 (10.6%) and DPB1*4101 (3.7%) were also very frequent alleles. The most frequent two-locus haplotypes observed in the Ewenki were: DRB1*030101-DQB1*0201/0202(10.7%), DRB1*090102-DQB1*03032(9.8%), DRB1*070101-DQB1*0201/0202 (5.5%), DRB1*070101-DQB1*030302 (5.2%) and DRB1*120101/1206-DQB1*030101/0309 (4.6%). The distribution of the HLA class II alleles and haplotypes frequencies as well as the dendrogram showed that the Ewenki population belongs to the northern group of Chinese.     

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.     

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.     

Molecular analyses of HLA-DRB1, -DPB1, and -DQB1 in Jing ethnic minority of Southwest China

In the present study, DNA typing for HLA-DRB1, DQB1 and DPB1 was performed using polymerase chain reaction-sequencing based typing (PCR-SBT) method in 144 random selected Jing ethnic individuals inhabiting in South China. Allele frequencies and two-locus haplotypes (DRB1-DQB1) were statistically analyzed and 20 DPB1 alleles, 27 DRB1 and 20 DQB1 were detected. The most frequent DPB1 allele was DPB1*0501 with the percentage of 36.9% followed by DPB1*1301 (15.7%), DPB1*0401 (11.0%) and DPB1*020102 (9.8%). Among the 27 detected DRB1 alleles, DRB1*120201 (13.8%) was most commonly observed followed by DRB1*150201, *030101 and *090102 alleles with the frequencies of 9.4%, 9.1% and 8.3%, respectively. Among the 20 detected DQB1 alleles the most predominant one was DQB1*030101/0309 (19.9%). DQB1*050201 (19.1%), DQB1*0201/0202 (16.1%) and DQB1*050101 (12.3%) were also frequently observed in Jing population. Statistical analysis of two-locus haplotypes showed that DRB1*120201-DQB1*030101/DRB1*120201-DQB1*0309 (HF = 9.4%, D = 6.65x10(-2)) was most predominant followed by DRB1*030101-DQB1*0201/DRB1*030101-DQB1*0202 (HF = 8.1%, D = 6.66 x 10(-2)). The comparison of HLA class II allele and haplotype frequencies in Jing with those in other populations all over the world and a dendrogram based on the DRB1, DQB1 and DPB1 genes suggested that Jing ethnic population has an origin of Southeast Asia and is belonged to the southern group of Chinese populations.     

Class II HLA allele polymorphism: DRB1, DQB1 and DPB1 alleles and haplotypes in the New Zealand Maori population

Class II alleles of interest to transplantation comprise the DRB1, DQB1 and DPB1 loci. Sequence-based typing was used to determine the class II allelic variability present in New Zealand Maori, a population with close genetic ties to Polynesia and known anthropological and linguistic connections to mainland Asia. The most common DRB1 alleles identified were DRB1*1201, DRB1*110101, DRB1*0403 and DRB1*080302, with frequencies of 21.5%, 14%, 11.25% and 9.25%, respectively. Standard linkages between the DRB1 locus and the DRB3, 4 and 5 loci were maintained, with no novel patterns identified. The most common DQB1 alleles identified were DQB1*030101, DQB1*060101, DQB1*020101, DQB1*0602 and DQB1*050201, with frequencies of 29.5%, 8%, 7.8%, 6.4% and 6.2%, respectively. The most common DPB1 alleles identified were DPB1*0501, DPB1*040101 and DPB1*020102, with frequencies of 40.2%, 28.89% and 15.83%, respectively. A total of 80 estimated DRB1-DQB1 two-locus haplotypes were detected. DRB1*1201-DQB1*030101 was the most frequent (15.40%) haplotype, followed by DRB1*110101-DQB1*030101 (9.97%), DRB1*0403-DQB1*030201 (7.37%) and DRB1*080302-DQB1*060101 (5.96%). The allelic variation determined is being used in further analysis of the requirement for bone marrow transplantation in the New Zealand Maori population and has implications for optimal ethnic donor distribution on the New Zealand Bone Marrow Donor Registry, anthropological studies and disease association.     

Molecular analysis of HLA allelic frequencies and haplotypes in Jordanians and comparison with other related populations.

Twenty alleles for the locus human leukocyte antigen (HLA-A) and 46 for the HLA-B locus were detected in Jordanians. This indicates the existence of high polymorphism in this area. The most frequent HLA class I alleles found were A*0201 (0.1344), B*0713 (0.1724), and C*0502 (0.1793). Twenty-six different alleles in the Jordanian population were identified for the DRB1 locus being the DRB1*0704 (0.2552), DRB1*0401 (0.1965), and DRB1*1501 (0.0896) the most frequent. Common DQA1 alleles were DQA1*0201 (0.2690), DQA1*0301 (0.2414), and DQA1*0501 (0.1724). Three-loci haplotype heterogeneity was common: 38 HLA class II haplotypes were identified, of which the most frequently observed was DRB1*0401-DQA1*0301-DQB1*0302 (0.1793). In addition, as expected, 220 different five-loci haplotypes with several unusual allelic combinations were observed, although many of them are pan-European haplotypes. The most frequent five-loci haplotype was the A30-B7-DRB1*03-DQA1*0501-DQB1*0201 (0.0138). It seems that the specific Jordanian haplotypes are the following: the A31-B7-DRB1*04/07-DQA1*0301/0201-DQB1*0302/0202 haplotypes (0.0103) and the A1-B7-DRB1*07-DQA1*0201-DQB1*0202, A2-B7-DRB1*04-DQA1*0301-DQB1*0302, A11-B7-DRB1*07-DQA1*0201-DQB1*0201 haplotypes but at lower frequencies (0.007). A tree analysis of HLA class I and class II alleles were made for several Caucasian populations and individual genetic distances calculated. The haplotype frequencies, genetic distances, and dendrograms do not reveal great differences as compared with those in other Mediterranean countries and Western Europeans populations. Our results suggest that both HLA class I and class II polymorphism (but especially the former) of the Jordanian population demonstrates considerable heterogeneity, which reflects ancient and recent admixture with neighboring populations, and important human migratory trends throughout the history.     

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.     

Polymorphism of HLA-DRB1, -DQB1 and -DPB1 genes in Bai ethnic group in southwestern China

In this work, polymorphism of human leukocyte antigen (HLA)-DRB1, -DQB1 and -DPB1 genes was detected using polymerase chain reaction-sequence-based typing method in 128 healthy unrelated volunteers from the Bai ethnic group of Yunnan province of southwest China. Among all the 28 alleles detected for the DRB1 gene, the most common allele was DRB1*120201 with a frequency of 16.41%, followed by DRB1*090102, DRB1*080302, DRB1*1404, DRB1*150101, DRB1*140101 and DRB1*160201, with frequencies of 10.16%, 9.77%, 9.38%, 8.98%, 8.59% and 8.21%, respectively. Among 19 DQB1 alleles detected, the most frequent allele was DQB1*030101/0309 (35.94%), followed by DQB1*050201 (11.33%), DQB1*060101/060103 (10.54%) and DQB1*0401 (10.16%). For the DPB1 locus, the most common alleles were DPB1*0501 (42.19%), DPB1*1301 (13.28%), DPB1*020102 (10.93%) and DPB1*040101 (9.77%). The comparison of HLA class II allele frequencies of Bais with those of other Chinese populations suggested that the Bai ethnic group belonged to the southern group of Chinese.     

Molecular analysis of HLA-DRB1, DQA1, DQB1, DQ promoter polymorphism and extended class I/class II haplotypes in the Seri Indians from Northwest Mexico

The study of the genetics of the Major Histocompatibility Complex (MHC) in Amerindians is of great value in understanding the origins and migrations of these native groups, as well as the impact of immunogenetics on the epidemiology of diseases affecting these populations. We analyzed, using Polymerase Chain Reaction and Sequence Specific Oligonucleotide Probes (PCR-SSOP), DRB1, DQA1, DQB1 alleles and the promoter regions of DQA1 and DQB1 genes in 31 unrelated and 24 related Seri, a Mexican Indian group, from the state of Sonora (Northwest Mexico). The class II genotypes of this population were found to be in genetic equilibrium. The allele frequency (AF) of the prevalent DRB1 alleles were DRB1*0407 (48.4%), DRB1*0802 (33.9%) and DRB1*1402 (16.1%). The most frequent DQA1 and DQB1 alleles were DQA1*03011 (AF = 50.00%), DQA1*0401 (AF = 33.87%) and DQA1*0501 (AF = 16.13%); DQB1*0302 (AF = 50.00%), DQB1*0402 (33.87%) and DQB1*0301 (16.13%); which were in combination with DRB1*0407, DRB1*0802 and DRB1*1402, respectively. Three QAP and three QBP alleles were present (QAP 3.1, 4.1, 4.2; QBP 3.1, 3.21, 4.1) associated with the typical published DQA1 and DQB1 alleles. Four class II haplotypes were present in family members: DRB1*0407-QAP-3.1-DQA1*03011-QBP-3.21-DQB1*0302; DRB1*0802-QAP-4.2-DQA1*0401-QBP-4.1-DQB1*0402; DRB1*1402-QAP-4.1-DQA1*0501-QBP-3.1-DQB1*0301 and DRB1*0701-QAP-2.1-DQA1*0201-QBP-2.1-DQB1*0201. The family data were used to confirm extended haplotypes. A total of 21 haplotypes were found when A* and B* loci were also considered. The three most frequent combinations included A*0201-B*3501-DRB1*0407, A*3101-B*5101-DRB1*0802, and A*0201-B*40-DRB1*1402.     

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.     

HLA Class II (DRB,DQA1 and DQB1) Allele and Haplotype Frequencies in the Patients with Pemphigus Vulgaris

Introduction  Pemphigus vulgaris (PV), an autoimmune disease affecting the skin and mucous membranes, is associated with some human leukocyte antigen (HLA) class II alleles and haplotypes. Materials and Methods  In order to evaluate the association of HLA-DR and DQ alleles and haplotypes in Iranian non-Jewish patients with PV, 52 patients with PV and 180 normal subjects as control group were investigated in this study. Results and Discussion  HLA-DRB1*04, -DRB1*1401, -DRB4, -DQA1*0104, -DQA1*03011, -DQB1*0302, and -DQB1*0502 alleles have been significantly increased in our patients group. Moreover, the haplotypes HLA-DRB1*04/-DQA1*03011/-DQB1*0302 and HLA-DRB1*1401/-DQA1*0104/-DQB1*0502 increased significantly in our patients. In contrast, the following alleles decreased significantly in our patients: HLA-DRB1*15, -DRB1*0301, -DRB1*07, -DRB1*11, -DRB5, -DQA1*0101, -DQA1*0103, -DQA1*201, -DQA1*05, -DQB1*0201, -DQB1*0301, -DQB1*06011, and -DQB1*0602. In addition, HLA-DRB1*15/-DQA1*0103/-DQB1*06011, HLA-DRB1*0301/-DQA1*05011/-DQB1*0201, HLA-DRB1*07/-DQA1*0201/-DQB1*0201, and HLA-DRB1*11/-DQA1*05/-DQB1*03011 decreased significantly in our patients. Genetic factors are involved in the occurrence of PV; HLA-DRB1*04 and -DRB1*1401 alleles and the related haplotypes are suggestive to be two major PV susceptibility factors in our population study.     

Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia

Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility to type 1 diabetes (T1D), and susceptible alleles and haplotypes were implicated in the pathogenesis of T1D. This study investigated the heterogeneity in HLA class II haplotype distribution among Tunisian patients with T1D. This was a retrospective case control study done in Monastir in central Tunisia. The subjects comprised 88 T1D patients and 112 healthy controls. HLA-DRB1 and -DQB1 genotyping was done by PCR-sequence-specific priming. Significant DRB1 and DQB1 allelic differences were seen between T1D patients and controls; these differences comprised DRB1*030101 and DQB1*0302, which were higher in T1D patients than in control subjects, and DRB1*070101, DRB1*110101, DQB1*030101, and DQB1*060101, which were lower in T1D patients than in control subjects. In addition, the frequencies of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were higher in T1D patients than in control subjects, and the frequencies of DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 haplotypes were lower in T1D patients than in control subjects. Multiple logistic regression analysis revealed the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 and the negative association of only DRB1*070101-DQB1*0201 haplotypes with T1D. Furthermore, a significantly increased prevalence of DRB1*030101-DQB1*0201 homozygotes was seen for T1D subjects than for control subjects. Our results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with T1D in Tunisians. The identification of similar and unique haplotypes in Tunisians compared to other Caucasians highlights the need for evaluating the contribution of HLA class II to the genetic susceptibility to T1D with regard to haplotype usage and also to ethnic origin and racial background.Type 1 (insulin-dependent) diabetes (T1D) is the most prevalent form of diabetes in children and young adults (12, 17) and results from autoimmune CD4⁺ and CD8⁺ T-cell-directed destruction of insulin-producing pancreatic ß islet cells, leading to irreversible hyperglycemia and related complications (4, 22). In addition to environmental factors, there is a strong genetic component to T1D pathogenesis, of which the human leukocyte antigen (HLA) locus, in particular the class II region (DR and DQ), account for 40 to 50% of T1D familial clustering (13, 30). This was evidenced by the enrichment of DR3, DR4, DQ2, and DQ8, and the lower prevalence of DR15 or DQ6.2 alleles among T1D patients, thereby assigning a susceptible or protective role for these alleles in T1D pathogenesis, respectively (3, 16, 21).The fact that not all carriers of a specific high-risk DR or DQ variant develop the disease and the strong linkage disequilibrium between select DRB1 and DQB1 alleles (28) indicate that the pathogenesis of T1D results from the complex interaction between several genes within the class II region, in which specific DRB1-DQB1 haplotypes contribute to disease susceptibility. Accordingly, the enrichment or decreased prevalence of select DRB1-DQB1 haplotypes in T1D patients imparts disease susceptibility or protection, respectively (3, 18, 24). This susceptibility or protection effect disappears when a different DRB1 or DQB1 allele replaces the specific allele in the haplotype (29). The contribution of specific HLA haplotypes toward T1D susceptibility depends on the ethnic/racial background (26), which was highlighted by the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 haplotypes with T1D among Caucasians (3, 16) compared to DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 haplotypes and T1D in Japanese (18), while DRB1*1501-DQB1*0602 appeared to be protective of T1D in all populations (3, 16, 18). This indicates that association of a specific class II allele and DRB1-DQB1 haplotype with T1D must be evaluated in the context of the specific ethnic/racial background (26).We previously reported an association between HLA DRB1 and DQB1 alleles and haplotypes in Tunisian T1D patients (n = 50) and control subjects (n = 50) and identified two susceptible haplotypes (DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302), but no protective haplotypes (27). Using haplotype estimation and regression analysis, here, we extend our investigation of HLA class II and T1D risk on a large sample size by confirming the association of these haplotypes and identified an additional T1D-protective haplotype.     

Molecular analysis of HLA class II polymorphism in Croatians

Abstract: HLA-class II polymorphisms have been studied in a population of 141 unrelated healthy Croatians using PCR amplification, followed by non-radioactive oligonucleotide hybridization. Thirty one DRB1, 8 DQA1, 13 DQB1 and 16 DPB1 alleles were found in the tested population. DRB1*1601, 0701, 1501, 0101 and 1104 are the most frequent alleles at the DRB1 locus. At the DQA1 locus two alleles predominate: DQA1*0501 and 0102, while the most frequent DQB1 allele is *0301. Analysis of HLA-DPB1 polymorphism showed that, as in other Europeans, DPB1* 0401 is the most frequent allele. Four different two locus haplotypic associations (DRB1-DRB3, DRB1-DRB5, DRB1-DQB1 and DQA1-DQB1) as well as three locus DRB1-DQA1-DQB1 haplotypic associations were assigned on the basis of known linkage disequilibria. Several unusual two-locus associations have been observed: DRB1*0301-DRB3* 0202, DRB1*1501-DRB5*02, DRB1*1601-DRB5*0101, DRB1*1502-DRB5*0101, DQA1*0103-DQB1*0503 and DQA1*0501-DQB1*0302. Among 236 examined DRB1-DQA1-DQB1 haplotypic combinations, the most frequent was DRB1*1601-DQA1*0102-DQB1*0502 that was found with statistically significant higher frequency than in other Europeans. Twenty-eight distinct probable haplotypes were observed just once, suggesting that the main characteristic of Croatian population is great heterogeneity of haplotypes. This study will serve as a reference for further anthropology studies, HLA and disease associations studies and for donor/recipient matching in organ and bone marrow transplantation.     

HLA class II antigens in South African Blacks with type I diabetes

Type 1 diabetes mellitus is poorly characterised in many African communities, including South Africa, where little is known of the disease epidemiology. This study aimed to identify the HLA class II alleles associated with type 1 diabetes in a group of Zulu subjects in Durban, KwaZulu-Natal by PCR-SSP. The HLA alleles associated with type 1 diabetes included HLA-DQB*0302 (P<0.0001), DRB1*O9 (P<0.0001), DRB1*04 (P=0.002), DRB1*0301 (P=0.003), DQB*02 (P=0.004) and DQA*03 (P=0.035). Estimated haplotypes positively associated with type 1 diabetes included HLA-DRB1 *0301-DQA*0501, DRB1*04-DQA*03, DRB1*04-DQB*0302, DRB1*0301-DQB*0201, DQA*0501-DQB*0201 and DQA*03-DQB*0302. These findings are similar to those reported from Zimbabwe and other populations with type 1 diabetes.