HLA Class II Antigens and Their Interactive Effect on Perinatal Mother-To-Child HIV-1 Transmission

HLA class II antigens are central in initiating antigen-specific CD4+ T cell responses to HIV-1. Specific alleles have been associated with differential responses to HIV-1 infection and disease among adults. This study aims to determine the influence of HLA class II genes and their interactive effect on mother-child perinatal transmission in a drug naïve, Mother-Child HIV transmission cohort established in Kenya, Africa in 1986. Our study showed that DRB concordance between mother and child increased risk of perinatal HIV transmission by three fold (P = 0.00035/Pc = 0.0014, OR: 3.09, 95%CI, 1.64-5.83). Whereas, DPA1, DPB1 and DQB1 concordance between mother and child had no significant influence on perinatal HIV transmission. In addition, stratified analysis showed that DRB1*15:03+ phenotype (mother or child) significantly increases the risk of perinatal HIV-1 transmission. Without DRB1*15:03, DRB1 discordance between mother and child provided 5 fold protection (P = 0.00008, OR: 0.186, 95%CI: 0.081-0.427). However, the protective effect of DRB discordance was diminished if either the mother or the child was DRB1*15:03+ phenotype (P = 0.49-0.98, OR: 0.7-0.99, 95%CI: 0.246-2.956). DRB3+ children were less likely to be infected perinatally (P = 0.0006, Pc = 0.014; OR:0.343, 95%CI:0.183-0.642). However, there is a 4 fold increase in risk of being infected at birth if DRB3+ children were born to DRB1*15:03+ mother compared to those with DRB1*15:03- mother. Our study showed that DRB concordance/discordance, DRB1*15:03, children’s DRB3 phenotype and their interactions play an important role in perinatal HIV transmission. Identification of genetic factors associated with protection or increased risk in perinatal transmission will help develop alternative prevention and treatment methods in the event of increases in drug resistance of ARV.     

Study of the HLA class II allele polymorphism and phylogenetic analysis in Vojvodina population

The polymorphism at the HLA DRB1 and DQB1 loci in the population of Vojvodina was studied by PCR-SSP method. A total of 13 DRB1 and 5 DQB1 specificities displaying population-specific frequency distribution pattern were described. The most frequent HLA Class II alleles in Vojvodina population were: HLA-DRB1*11 (af = 0.30), −DRB1*04 (af = 0.28), −DRB1*07 (af = 0.21), −DRB1*13 and −DRB1*16 (af = 0.18), −DQB1*03 (af = 0.64), −DQB1*05 (af = 0.39) and −DQB1*02 (af = 0.35). The haplotypes with high frequencies (≥0.02) included HLA DRB1*11 DQB1*03 (0.0825), DRB1*04DQB1*03 (0.0725), DRB1*07DQB1*02 (0.0475). The allele DRB1*07 showed the strongest association with DQB1*02 (Δ = 0.0261, gC² = 4.437) and DRB1*13 allele with DQB1*06 (Δ = 0.0222, gC² = 4.247). The allelic frequencies and populations distance dendrogram revealed the closest relationship of Vojvodina population with Hungarians, Croat, and Greeks which can be the result of turbulent migration within this region and admixture with neighbour populations during the history.     

HLA polymorphisms are associated with Helicobacter pylori infected gastric cancer in a high risk population, China

Helicobacter pylori is one of the most common bacterial infections associated with an increased risk of gastric cancer, but its association with host factors, particularly polymorphisms of the immune response genes, such as human leukocyte antigen (HLA) genes, is still unclear. To investigate the role of HLA polymorphisms in the risk of gastric cancer among subjects with H. pylori infection, a case-control study involving 52 gastric cancer patients and 139 non-cancer controls was conducted in Linqu County, China, an area with a high incidence of gastric cancer. Polymorphisms of HLA class I and class II alleles were determined by PCR with sequence-specific primers (PCR-SSP). The information about H. pylori infection was obtained from previous records. Among 48 class I and 19 class II HLA alleles detected in this study, two alleles, CW*03 and DRB1*01, were found to be distributed significantly differently between patients and controls [odds ratio(OR)=1.95, 95% confidence interval (CI)=1.13–3.35, P=0.017 and OR=4.39, 95% CI=1.39–13.84, P=0.012, respectively). The OR of gastric cancer risk in individuals carrying CW*03/CW*03 or CW*03/CW*N was 2.06, 95% CI=1.05–4.02, P=0.035, while the OR was 3.49, 95% CI=1.0–12.4, P=0.04 for DRB1*01/DRB1*01 or DRB1*01/DRB1*N carriers. The analysis of the interaction between H. pylori infection and HLA risk genotypes of CW*03 or DRB1*01 revealed that the effect of CW*03 and DRB1*01 genotypes on gastric cancer risk was manifested stronger in H. pylori-positive individuals (OR=5.30, 95% CI=1.73–16.29, P=0.004 and OR=13.38, 95% CI=2.52–70.98, P=0.002, respectively) than in H. pylori-negative ones (OR=1.25, 95% CI=0.25–6.12, P=0.785 and OR=2.26, 95% CI=0.18–28.88, P=0.531, respectively). The combined effect of the two risk HLA genotypes on gastric cancer risk was also analysed. The result showed that the individuals carrying both the CW*03 and DRB1*01 alleles could only be found in cancer patients (5/52), and not in controls (0/139), further suggesting that CW*03 and DRB1*01 are risk alleles advancing the progression of tumorigenesis. These observations demonstrate that host HLA genotypes may play an important role in the risk of gastric cancer, especially among persons with H. pylori infection.     

Alleles of HLA-DRB1*04 Associated with Pulmonary Tuberculosis in Amazon Brazilian Population

Immunogenetic host factors are associated with susceptibility or protection to tuberculosis (TB). Strong associations of HLA class II genes with TB are reported. We analyzed the HLA-DRB1*04 alleles to identify subtypes associated with pulmonary TB and their interaction with risk factors such as alcohol, smoking, and gender in 316 pulmonary TB patients and 306 healthy individuals from the Brazilian Amazon. The HLA-DRB1*04 was prevalent in patients with pulmonary TB (p<0.0001; OR = 2.94; 95% CI = 2.12 to 4.08). Direct nucleotide sequencing of DRB1 exon 2 identified nine subtypes of HLA-DRB1*04. The subtype HLA-DRB1*04:11:01 (p = 0.0019; OR = 2.23; 95% CI = 1.34 to 3.70) was associated with susceptibility to pulmonary TB while DRB1*04:07:01 (p<0.0001; OR = 0.02; 95% CI = 0.001 to 0.33) to protection. Notably, the interaction between alcohol and HLA-DRB1*04:11:01 increased the risk for developing pulmonary TB (p = 0.0001; OR = 51.3; 95% CI = 6.81 to 386). Multibacillary pulmonary TB, the clinical presentation of disease transmission, was strongly associated with interaction to alcohol (p = 0.0026; OR = 11.1; 95% CI = 3.99 to 30.9), HLA-DRB1*04:11:01 (p = 0.0442; OR = 2.01; 95% CI = 1.03 to 3.93) and DRB1*04:92 (p = 0.0112; OR = 8.62; 95% CI = 1.63 to 45.5). These results show that HLA-DRB1*04 are associated with pulmonary TB. Interestingly, three subtypes, DRB1*04:07:01, DRB1*04:11:01 and DRB1*04:92 of the HLA-DRB1*04 could be potential immunogenetic markers that may help to explain mechanisms involved in disease development.     

HLA class II alleles with susceptibility of leprosy in the Mexican Mestizo population

Leprosy is a chronic, infectious disease, caused by Mycobacterium leprae, Mycobacterium lepromatosis or both, which affects the peripheral nervous system and the skin. Activation of cellular immunity in infected individuals depends on antigen recognition, which involves relevant HLA-Class II alleles. Therefore, the objective of this study was to determine HLA-Class II allele frequencies (HLA-DRB1and-DQB1)in Mexican Mestizo leprosy patients and compare themwith healthy controls, in order to define their role in the genetic susceptibility to this infection.The genomic DNA of each participant was obtained from peripheral blood, using the salting-out method. PCR amplification and hybridization ofHLA-class II alleleswas made by PCR-SSO. The results showed that frequencies of HLA-DRB1*15(Pc =0.003, OR=3.3 95%CI=1.53-7.33), HLA-DQB1*05(Pc =0.00003, OR=6.03 95%CI=2.49-14.61) and HLA-DQB1*06 (Pc =0.007, OR=2.89, 95%CI=1.38-6.04)were significantly higher among leprosypatients than those of healthy controls. The study suggests that HLA-DRB1*15, HLA-DQB1*05, and HLA-DQB1*06 are associated with leprosy susceptibility in the Mexican Mestizo population.     

A WT1 protein‐derived,naturally processed 16‐mer peptide,WT1332, is a promiscuous helper peptide for induction of WT1‐specific Th1‐type CD4+ T cells

The Wilms' tumor gene WT1 is overexpressed in various tumors, and the WT1 protein has been demonstrated to be an attractive target antigen for cancer immunotherapy. A WT1 protein‐derived 16‐mer peptide, WT1₃₃₂ (KRYFKLSHLQMHSRKH), which was naturally generated through processing in cells and could elicit Th1‐type CD4⁺ helper T cell responses with an HLA‐DRB1*0405‐restriction has previously been identified by us. In the present study, it has been demonstrated that WT1₃₃₂ can induce WT1₃₃₂‐specific CD4⁺ T cell responses with the restriction of not only HLA‐DRB1*0405 but also HLA‐DRB1*1501, ‐DRB1*1502, or ‐DPB1*0901. These HLA class II‐restricted WT1₃₃₂‐specific CD4⁺ T cell lines produced IFN‐γ but neither IL‐4 nor IL‐10 with WT1₃₃₂ stimulation, thus showing a Th1‐type cytokine profile. Furthermore, HLA‐DRB1*1501 or ‐DRB1*1502‐restricted WT1₃₃₂‐specific CD4⁺ T cell lines responded to WT1‐expressing transformed cells in an HLA‐DRB1‐restricted manner, which is consistent with our previous finding that WT1₃₃₂ is a naturally processed peptide. These results indicate that the natural peptide, WT1₃₃₂, is a promiscuous WT1‐specific helper epitope. WT1₃₃₂ is expected to apply to cancer patients with various types of HLA class II as a WT1‐specific helper peptide in combination with HLA class I‐restricted WT1 peptides.     

Association between polymorphisms in the promoter region of miR‐17‐92 cluster and systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association of genetic polymorphisms in the promoter region of miR‐17‐92 with systemic lupus erythematosus (SLE). The gene polymorphism was analysed using SNaPshot in 312 SLE patients and 396 controls. Relative expression of miR‐17‐92 was measured by quantitative real‐time PCR. Association was found between rs9515692 and a decreased risk of SLE (CT vs CC: OR = 0.65, 95%CI, 0.46‐0.92, P = .014; CT+TT vs CC: OR = 0.64, 95%CI, 0.46‐0.90, P = .009; T vs C: OR = 0.69, 95%CI, 0.52‐0.92, P = .010, respectively). Haplotype analysis showed that C‐G‐G, C‐A‐A haplotypes were associated with an increased SLE risk (OR=4.46, 95%CI, 2.17‐9.17, P < 0.001; OR=2.33, 95%CI, 1.44‐3.76, P < 0.001, respectively). T allele and CT+TT genotypes in rs9515692 were associated with decreased risk of anti‐dsDNA in SLE (CT+TT vs CC: OR = 0.42, 95%CI = 0.24‐0.72, P = .002; T vs A: OR = 0.49, 95%CI = 0.31‐0.79, P = .003). Moreover, rs9515692 CT+TT genotypes had a higher level of miR‐17 as compared to CC genotype (P = .017). These findings suggest that the rs9515692 CT+TT genotypes were a protective factor for the susceptibility of SLE, probably by increasing the expression of miR‐17.     

Human Leukocyte Antigen and Systemic Sclerosis in Japanese: The Sign of the Four Independent Protective Alleles,DRB1*13:02, DRB1*14:06, DQB1*03:01, and DPB1*02:01

ObjectiveSeveral studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic sclerosis (SSc) have been reported. Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are found in SSc patients. Here, we sought to identify HLA alleles associated with SSc in Japanese, and explored their associations with SSc phenotypes including the presence of autoantibodies.MethodsAssociations of HLA-DRB1, DQB1, and DPB1 were analyzed in 463 Japanese SSc patients and 413 controls.ResultsWe found that DRB1*13:02 (P = 0.0011, Pc = 0.0319, odds ratio [OR] 0.46, 95% confidence interval [CI] 0.29–0.73), DRB1*14:06 (P = 6.60X10^-5, Pc = 0.0020, OR 0.05, 95%CI 0.01–0.41), DQB1*03:01 (P = 0.0009, Pc = 0.0150, OR 0.56, 95%CI 0.40–0.79), and DPB1*02:01 (P = 5.16X10^-6, Pc = 8.77X10^-5, OR 0.52, 95%CI 0.39–0.69) were protectively associated with SSc. In addition, these four alleles seemed to be independently associated with the protection against the susceptibility of SSc. On the other hand, we could not find predisposing alleles for overall SSc. With respect to SSc subsets, a tendency for these four alleles to be protectively associated was observed. However, there was a significant association between DRB1*01:01, DRB1*10:01, DQB1*05:01, and DPB1*04:02 and the susceptibility to SSc with ACA. On the other hand, the presence of DRB1*15:02, DQB1*06:01, DPB1*03:01, and DPB1*09:01 was associated with SSc with ATA.ConclusionThus, the present study has identified protective associations of the four HLA class II alleles with overall Japanese SSc and predisposing associations of HLA class II alleles with Japanese SSc subsets.     

HLA association with nasopharyngeal carcinoma in southern Tunisia

In order to study the association of HLA-A, -B and/or DRB1, DQB1 and the nasopharyngeal carcinoma (NPC), 141 patients affected with NPC were typed for the HLA class I by serology method of microlymphocytotoxicity. Among these patients 101 were genotyped for HLA class II system by the PCR-SSP technique. HLA typing results were compared to those of 116 controls. We found that the HLA-A31 and -A33 antigens were significantly more expressed in patients than in the controls (P = 0.016 and 0.010, respectively) and the HLA-A19 antigen, was significantly more frequent in patients when compared to the controls (P = 0.007). The HLA-DRB1*03 and DRB1*13 alleles were significantly more frequent in patients as compared to the controls. The DRB1*01 allele was expressed with a frequency of 20.69% in the controls whereas it was only detected in 3.96% of the NPC patients. Furthermore, the DQB1*05 allele was expressed at a frequency which was significantly less important in affected patient (P = 0.03), whereas, the DQB1*02 allele was more frequent in patients (P = 0.643 × 10⁻⁴). Thus our study revealed a significant increase of HLA-A31, A33, A19, B16, B53 and DRB1*03, DRB1*13 and DQB1*02 alleles in our patients. These markers could play a predisposing role in the development of NPC. In contrast, a decrease of HLA-B14, -B35 and DRB1*01 and DQB1*05 alleles was found suggesting a likely protective effect.     

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

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

CYP1B1 (4326C > G), CYP2F1 (c.14_15insC), CYP2J2 (?76G > T), and CYP2S1 (13106C > T and 13255A > G) polymorphisms and genetic predisposition to chronic respiratory diseases induced by smoking and occupational factors

The contribution of the polymorphic markers of cytochrome P450 genes to respiratory diseases caused by smoking and occupational factors has been assessed. For this purpose, PCR-RFLP analysis of the CYP1B1 (rs1056836, 4326C > G), CYP2F1 (rs11399890, c.14_15insC), CYP2J2 (rs890293, -76G > T), and CYP2S1 (rs34971233, 13106C > T and rs338583, 13255A > G) gene polymorphisms has been performed. The analysis has shown that CYP1B1 (rs1056836, 4326C > G) and CYP2F1 (rs11399890, c.14_15insC) polymorphisms may contribute to the development of occupational chronic bronchitis. The proportion of CYP1B1*1*3 heterozygotes in the group of patients with occupational chronic bronchitis is considerably greater than in the group of healthy workers (69.16% versus 53.29%; χ² = 5.94, p = 0.02, p _cur = 0.04, OR = 1.97, the 95% CI is 1.13–3.42). Patients with occupational chronic bronchitis and healthy workers significantly differed from each other in the CYP2F1 genotypes frequency distribution (rs11399890, c.14_15insC) (χ² = 6.18, d.f. = 2, p = 0.05). CYP2F1 wild type/ins heterozygous genotype frequency is higher in healthy workers (36.08%) than in patients (22.22%) (χ² = 5.48, p = 0.02, p _cur = 0.04, OR = 0.51, the 95% CI is 0.28–0.90). No association has been found between the CYP2J2 (rs890293, −76G > T) or CYP2S1 (rs34971233, 13106C > T, and rs338583, 13255A > G) gene polymorphisms and respiratory diseases.     

HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity

Background and Aim

The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases.

Methods

High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls.

Results

The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07).

Conclusions

HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.     

IL-10R1 S138G loss-of-function polymorphism is associated with extrapulmonary tuberculosis risk development in Tunisia

There is considerable evidence that host genetic factors are important in determining susceptibility to mycobacterial infections. More recently, functional genetic mutations affecting IL-10 receptor 1 (IL-10R1) were described. In this study, we investigated the relationship of IL-10R1 S138G loss-of-function polymorphism (A536G: rs3135932) with susceptibility to active tuberculosis (TB) in Tunisian patients. A total of 168 patients with pulmonary TB, 55 with extrapulmonary TB, and 150 control subjects were studied. Genomic DNA samples were extracted from leukocytes and used to investigate S138G polymorphism in IL-10R1 gene by multiplex allele-specific polymerase chain reaction. Associations between G allele [odds ratio OR = 5.01; 95% confidence intervals CI = 2.58–9.77; P = 10⁻⁷], GG genotypes [OR=9.06; 95% CI (1.58–67.33); correcting P-values using the Bonferroni method for multiple tests Pc=0.015] and AG genotype [OR=3.75; 95% CI (1.62–8.7); Pc=0.0012] with the risk development of active extrapulmonary TB were found. In contrast, the AA genotype was found to be associated with resistance to extrapulmonary TB [OR=0.19; 95% CI (0.09–0.42); Pc=6.10⁻⁶]. No association was found between S138G SNP and pulmonary TB. In conclusion, our study suggested the possible role of IL-10R1 S138G loss-of-function polymorphism in extrapulmonary TB susceptibility-resistance in Tunisia.     

Beh?et’s disease in HLA-B*51 negative Germans and Turks shows association with HLA-Bw4-80I

Introduction

Behçet’s disease (BD) as systemic vasculitis of unknown etiology is associated with HLA-B*51 in European and Asian populations. HLA-A*26 was claimed as an additional BD susceptibility marker in Japanese and Greek patients. This study was performed to test for HLA associations in HLA-B*51 negative German and Turkish BD populations.

Methods

In total, 65 German and 46 Turkish patients lacking HLA-B*51 were analyzed in comparison to healthy HLA-B*51 negative Germans (n = 1500) and Turks (n = 130). HLA-A/B genotypes were determined by SSOP. P-values with correction for multiple testing (p_c), χ2-test and odds ratio (OR) were used for statistical evaluation.

Results

HLA-A*26 was significantly more frequent in HLA-B*51⁻ German patients [p_c = 0.0076, OR = 3.23, 95% CI 1.63 to 6.39] than in respective controls. HLA-A*26 was also elevated in a smaller group of Turkish patients versus the controls. Significant association of HLA-Bw4 with isoleucine at amino-acid position 80 (HLA-Bw4-80I) was found in the HLA-B*51⁻ German cohort of BD patients [p_c = 0.0042, OR = 2.35, 95% CI 1.41 to 3.93) and in the Turkish patients in comparison to the respective controls [p = 0.025, OR = 2.17, 95% CI 1.09 to 4.31]. On the contrary, HLA-Bw4-80 T was reduced in both HLA-B*51⁻ BD patient cohorts.

Conclusions

The study shows a significant association of HLA-Bw4-80I present on HLA-B*51 as well as on other B-locus molecules with BD. This indicates that distinctive Bw4 epitopes on HLA-B locus molecules could play a role in BD pathogenesis. The study also indicates an association with HLA-A*26 in German and Turkish BD patients as a genetic risk factor independent of HLA-B*51.     

Association of Increased Frequencies of HLA-DPB1*05∶01 with the Presence of Anti-Ro/SS-A and Anti-La/SS-B Antibodies in Japanese Rheumatoid Arthritis and Systemic Lupus Erythematosus Patients

Introduction

Autoantibodies to ribonucleoprotein are associated with a variety of autoimmune diseases, including rheumatoid arthritis (RA). Many studies on associations between human leukocyte antigen (HLA) alleles and RA have been reported, but few have been validated in RA subpopulations with anti-La/SS-B or anti-Ro/SS-A antibodies. Here, we investigated associations of HLA class II alleles with the presence of anti-Ro/SS-A or anti-La/SS-B antibodies in RA.

Methods

An association study was conducted for HLA-DRB1, DQB1, and DPB1 in Japanese RA and systemic lupus erythematosus (SLE) patients that were positive or negative for anti-Ro/SS-A and/or anti-La/SS-B antibodies.

Results

An increased prevalence of certain class II alleles was associated with the presence of anti-Ro/SS-A antibodies as follows: DRB1*08∶03 (Pc = 3.79×10⁻⁵, odds ratio [OR] 3.06, 95% confidence interval [CI] 1.98–4.73), DQB1*06∶01 (Pc = 0.0106, OR 1.70, 95%CI 1.26–2.31), and DPB1*05∶01 (Pc = 0.0040, OR 1.55, 95%CI 1.23–1.96). On the other hand, DRB1*15∶01 (Pc = 0.0470, OR 3.14, 95%CI 1.63–6.05), DQB1*06∶02 (Pc = 0.0252, OR 3.14, 95%CI 1.63–6.05), and DPB1*05∶01 (Pc = 0.0069, OR 2.27, 95% CI 1.44–3.57) were associated with anti-La/SS-B antibodies. The DPB1*05∶01 allele was associated with anti-Ro/SS-A (Pc = 0.0408, OR 1.69, 95% CI 1.19–2.41) and anti-La/SS-B antibodies (Pc = 2.48×10⁻⁵, OR 3.31, 95%CI 2.02–5.43) in SLE patients.

Conclusion

HLA-DPB1*05∶01 was the only allele associated with the presence of both anti-Ro/SS-A and anti-La/SS-B antibodies in Japanese RA and SLE patients.     

Characterization of the major histocompatibility complex locus association with Beh?et’s disease in Iran

IntroductionThe aim of this study was to characterize the association of human leukocyte antigen (HLA) B alleles and major histocompatibility complex (MHC) single nucleotide polymorphisms (SNPs) with Behçet’s disease (BD) in an Iranian dataset.MethodsThe association of three SNPs in the MHC region previously identified as the most associated in high-density genotyping studies was tested in a case–control study on 973 BD patients and 825 controls from Iran, and the association of HLA-B alleles was tested in a subset of 681 patients and 414 controls.ResultsWe found that HLA-B*51 (P = 4.11 × 10⁻⁴¹, OR [95% CI] = 4.63[3.66-5.85]) and B*15 confer risk for BD (P = 2.83 × 10⁻², OR [95% CI] = 1.75[1.08-2.84]) in Iranian, and in B*51 negative individuals, only the B*15 allele is significantly associated with BD (P = 2.51 × 10⁻³, OR [95% CI] = 2.40[1.37-4.20]). rs76546355, formerly known as rs116799036, located between HLA-B and MICA (MHC class I polypeptide-related sequence A), demonstrated the same level of association with BD as HLA-B*51 (P_adj = 1.78 × 10⁻⁴⁶, OR [95% CI] = 5.46[4.21-7.09], and P_adj = 8.34 × 10⁻⁴⁸, OR [95% CI] = 5.44[4.20-7.05], respectively) in the HLA-B allelotyped subset, while rs2848713 was less associated (P_adj = 7.14 × 10⁻³⁵, OR [95% CI] = 3.73[2.97-4.69]) and rs9260997 was not associated (P_adj = 1.00 × 10⁻¹). Additionally, we found that B*51 genotype-phenotype correlations do not survive Bonferroni correction, while carriers of the rs76546355 risk allele predominate in BD cases with genital ulcers, positive pathergy test and positive BD family history (2.31 × 10⁻⁴ ≤ P ≤ 1.59 × 10⁻³).ConclusionsWe found that the HLA-B*51 allele and the rs76546355/rs116799036 MHC SNP are independent genetic risk factors for BD in Iranian, and that positivity for the rs76546355/rs116799036 risk allele, but not for B*51, does correlate with specific demographic characteristics or clinical manifestations in BD patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0585-6) contains supplementary material, which is available to authorized users.     

Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP,DQA1, DQB1 haplotypes in systemic lupus erythematosus

We have investigated the DNA polymorphism for the DQA1 promoter region (QAP) and HLA-class II DRB1, DQA1, and DQB1 genes in 178 central European patients with Systemic lupus erythematosus (SLE) using polymerase chain reaction and Dig-ddUTP labeled oligonucleotides. Increased frequencies of DRB1*02 and *03 are confirmed by DNA typing. In addition, the frequencies of DQA1*0501, *0102 and DQB1*0201, *0602 alleles are increased in the patients as compared to controls. The strongest association to SLE is found with DRB1*03 and DQB1*0201 alleles (p<10^–7, p corr. <10^–5 and p<10^–6, p corr. <10^–4, respectively). By investigating the DQA1 promoter region in the SLE patients we have detected nine different QAP variants. Increased frequencies of QAP1.2 and QAP4.1 are observed in patients as compared to controls (p <0.05, p corr. = n. s.). Analysis of linkage disquilibria demonstrates a very strong association between QAP variants and DQA1, DRB1 alleles. Certain QAP variants are completely associated with DQA1 and DRB1 alleles, whereas others can combine with different DQA1 and DRB1 alleles. All DRB1*02-positive patients and controls carry QAP1.2, and all DRB1*03-positive patients and controls carry QAP4.1. Conversely, the QAP1.2 variant appears only in DRB1*02 haplotypes, while the QAP4.1 variant can be observed in DRB1*03, *11, and *1303 haplotypes. Based on the strong linkage disequilibria between DRB1-DQA1-DQB1 genes and between DRB1-QAP-DQA1, we have deduced the four-point haplotypes for DRB1-QAP-DQA1-DQB1 in patients and controls. Two haplotypes DRB1*02-QAP1.2-DQA1*0102-DQB1*0602-and DRB1*03-QAP4.1-DQA1*0501-DQB1*0201 are significantly increased in patient as compared to controls (p<0.01, p corr. = n.s., RR = 1.8 and p <10^–7, p corr. <10^–5, RR = 3.1, respectively). The analysis of relative risks attributed to the various alleles of QAP, DQA1, and DQB1 as well as the investigation of the deduced DRB1-QAP-DQA1-DQB1 haplotypes leads to the conclusion that QAP4.1 and DQA1*0501 on the DR3 haplotypes are probably not involved in SLE susceptibility. There is no evidence for the involvement of DQ2 / dimers coded in transposition. Thus, susceptibility to SLE is on the DR3 haplotype most probably localized at DRB1 or telomeric of DRB1, while for the DR2 haplotype such orientation cannot be given. SLE study group members: M. Baur, A. Corvetta, H. Ehrfeld, J. Frey, J. R. Kalden, F. Krapf, B. Lang, G. G. Lange, K. Pirner, C. Rittner, E. Röther, P. Schneider, H. P. Seelig, S. Seuchter, W. Stangel, C. Specker, P. Späth, H. Deicher. Correspondence to: Z. Yao.     

云南汉族HLA-DRB1多态性分析及与9个汉族群体的比较

主要应用聚合酶链反应—微孔板杂交(Polymerase Chain Reaction and Microtitre Plate Hybridization,PCR-MPH)的方法对云南129个无亲缘关系的汉族样品进行了HLA-DRB1的遗传多态性分析,对MPH初分出的DRB1*15组的样品进行了单链构象多态（Single-Strand Conformation Polymorphism, SSCP）检测。共发现36种等位基因,其中等位基因频率大于0.05的有DRB1*1501(0.1240),DRB1*09012(0.0969),DRB1*08032(0.0930),DRB1*1202(0.0891),DRB1*1201(0.0814),DRB1 *1401(0.0775),DRB1 *0701(0.0620)。云南汉族HLA-DRB1等位基因频率与中国其他9个汉族群体进行χ²检验,结果显示与云南汉族比较χ²>10的有西安汉族（DR8,χ²=13.9712）、上海汉族（DR4,χ²=10.1632）、广东汉族（DR9,χ²=12.6121）和南京汉族（DR4,χ²=10.5796）。从遗传距离分析发现,在9个国内汉族群体中云南汉族与辽宁汉族有最近的距离（0.0541）,而与广东汉族最远（0.1851）。云南汉族在构成上可能与辽宁汉族更为接近,尽管地处南方,但已不属典型的南方汉族。这也可能因云南汉族与当地的少数民族存在基因交流,从而形成了一个较为特殊的群体。     

Association of Human Leukocyte Antigen Class II with Susceptibility to Primary Biliary Cirrhosis: A Systematic Review and Meta-Analysis

Purpose

Several previous studies suggested that HLA-Class II may be associated with susceptibility to primary biliary cirrhosis (PBC), but data from individual studies remain controversial. Therefore, a systematic review and meta-analysis is needed to comprehensively evaluate the association between HLA-Class II and PBC risk.

Methods

All published reports of an association between HLA class II and PBC risk were searched in PubMed, EMBASE (updated to 22 May 2012). ORs with 95% confidence intervals (CIs) were extracted from each included study and the meta-analysis was performed using the fixed- or random-effects model.

Results

A total of 3,732 PBC patients and 11,031 controls from 34 studies were included in the meta-analysis. An assessment of study quality revealed that the majority of studies included (18 studies) were of high quality. The serological group DR8 was found to be a risk factor for PBC (OR = 2.82, 95%CI: 1.84–4.30). At the allelic level, HLA-DR*08 and HLA-DR*0801 were identified as risk factors for PBC (OR = 2.30, 95%CI: 1.76-3.00; OR = 3.23, 95%CI: 2.22–4.70, respectively), whereas HLA-DR*11 and HLA-DR*13 were potent protective factors (OR = 0.31, 95%CI: 0.27-0.38; OR = 0.62, 95%CI: 0.48-0.81, respectively). HLA-DQB1 and HLA-DQB1*0402 conferred a predisposition to PBC development (OR = 3.47, 95%CI: 2.35–5.13), whereas HLA-DQB1*0604 was protective against PBC (OR = 0.3, 95%CI: 0.18–0.58). No HLA-DPB1 allele was observed to be associated with PBC susceptibility (P > 0.05).

Conclusions

The present study revealed that HLA-Class II components are closely associated with the development of PBC.     

Association of HLA and post-schistosomal hepatic disorder: a systematic review and meta-analysis

Several human genetic variants, HLA antigens and alleles are reportedly linked to post-schistosomal hepatic disorder (PSHD), but the results from these reports are highly inconclusive. In order to estimate overall associations between human genetic variants, HLA antigens, HLA alleles and PSHD, we systematically reviewed and performed a meta-analysis of relevant studies in both post-schistosomal hepatic disorder and post-schistosomal non-hepatic disorder patients. PubMed, Scopus, Google Scholar, The HuGE Published Literature database, Cochrane Library, and manual search of reference lists of articles published before July 2009 were used to retrieve relevant studies. Two reviewers independently selected articles and extracted data on study characteristics and data regarding the association between genetic variants, HLA antigens, HLA alleles and PSHD in the form of 2×2 tables. A meta-analysis using fixed-effects or random-effects models to pooled odds ratios (OR) with corresponding 95% confidence intervals were calculated only if more than one study had investigated particular variation. We found 17 articles that met our eligibility criteria. Schistosoma mansoni and Schistosoma japonicum were reported as the species causing PSHD. Since human genetic variants were only investigated in one study, these markers were not assessed by meta-analysis. Thus, only HLA-genes (a total of 66 HLA markers) were conducted in the meta-analysis. Our meta-analysis showed that human leucocyte antigens HLA-DQB1*0201 (OR=2.64, P=0.018), DQB1*0303 (OR=1.93, P=0.008), and DRB1*0901 (OR=2.14, P=0.002) alleles and HLA-A1 (OR=5.10, P=0.001), A2 (OR=2.17, P=0.005), B5 (OR=4.63, P=0.001), B8 (OR=2.99, P=0.02), and B12 (OR=5.49, P=0.005) serotypes enhanced susceptibility to PSHD, whereas HLA-DQA1*0501 (OR=0.29, P≤0.001) and DQB1*0301 (OR=0.58, P=0.007) were protective factors against the disease. We further suggested that the DRB1*0901-DQB1*0201, DRB1*0901-DQB1*0303 and A1-B8 haplotypes enhanced susceptibility to PSHD, whereas DQA1*0501-DQB1*0301 linkage decreased the risk of PSHD. The result improved our understanding of the association between the HLA loci and PSHD with regard to pathogenic or protective T-cells and provided novel evidence that HLA alleles may influence disease severity.