HLA alleles associated with the adaptive immune response to smallpox vaccine: a replication study

We previously reported HLA allelic associations with vaccinia virus (VACV)-induced adaptive immune responses in a cohort of healthy individuals (n = 1,071 subjects) after a single dose of the licensed smallpox (Dryvax) vaccine. This study demonstrated that specific HLA alleles were significantly associated with VACV-induced neutralizing antibody (NA) titers (HLA-B*13:02, *38:02, *44:03, *48:01, and HLA-DQB1*03:02, *06:04) and cytokine (HLA-DRB1*01:03, *03:01, *10:01, *13:01, *15:01) immune responses. We undertook an independent study of 1,053 healthy individuals and examined associations between HLA alleles and measures of adaptive immunity after a single dose of Dryvax-derived ACAM2000 vaccine to evaluate previously discovered HLA allelic associations from the Dryvax study and determine if these associations are replicated with ACAM2000. Females had significantly higher NA titers than male subjects in both study cohorts [median ID50 discovery cohort 159 (93, 256) vs. 125 (75, 186), p < 0.001; replication cohort 144 (82, 204) vs. 110 (61, 189), p = 0.024]. The association between the DQB1*03:02 allele (median ID₅₀ discovery cohort 152, p = 0.015; replication cohort 134, p = 0.010) and higher NA titers was replicated. Two HLA associations of comparable magnitudes were consistently found between DRB1*04:03 and DRB1*08:01 alleles and IFN-γ ELISPOT responses. The association between the DRB1*15:01 allele with IFN-γ secretion was also replicated (median pg/mL discovery cohort 182, p = 0.052; replication cohort 203, p = 0.014). Our results suggest that smallpox vaccine-induced adaptive immune responses are significantly influenced by HLA gene polymorphisms. These data provide information for functional studies and design of novel candidate smallpox vaccines.     

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.     

Recent divergence of the<Emphasis Type="Italic"> HLA-DRB1*04</Emphasis> allelic lineage from the<Emphasis Type="Italic"> DRB1*0701</Emphasis> lineage after the separation of the human and chimpanzee species

Conventional phylogenetic trees for the human leukocyte antigen (HLA)-DRB1 alleles constructed by the neighbor-joining (Saitou and Nei 1987) and UPGMA (Sneath and Sokal 1973) methods using nucleotide sequences of the DRB1 alleles suggest that DRB1*0701 may have diverged from other DRB1 alleles before the separation of the human and chimpanzee species, because of a large number of nucleotide changes in DRB1*0701 compared with any of the other DRB1 alleles. Here we show new evidence that the haplotypes centering on DRB1*0701 and DRB1*04 alleles are the most homologous. This suggests that these haplotypes have derived from the common ancestral haplotype, and that they have likely retained complete linkage disequilibrium even after the divergence of the DRB1*0701 and DRB1*04 allelic lineages. Together with the corresponding haplotype carrying chimpanzee DRB1*0701, which has a high sequence homology to HLA-DRB1*0701, these haplotypes reveal that: (1) the DRB1*04 allelic lineage may have been generated from the DRB1*0701 lineage after the separation of the human and chimpanzee species; (2) the DRB1*04 allelic lineage possibly has a higher substitution rate of DRB1 compared with pseudogene and neutral region; (3) there could be a significant difference in the substitution rate of DRB1 between the DRB1*0701 and DRB1*04 allelic lineages. Based on the difference between the present and previous results, we would like to propose that phylogenetic studies using not only nucleotide sequences of the DRB1 alleles but also haplotypes centering on the alleles should be conducted for understanding detailed phylogenetic relationships of the DRB1 alleles.     

HLA-DRB1*1501 and HLA-DQB1*0301 alleles are positively associated with HPV16 infection–related Kazakh esophageal squamous cell carcinoma in Xinjiang China

Multiple determinant factors are involved in the occurrence and progression of esophageal squamous cell carcinoma (ESCC). Human papillomavirus (HPV) and human leukocyte antigen (HLA) polymorphism were identified as important factors. This study examined the associations between the development of Kazakh ESCC and the determinant factors including HLA-DRB1*0901, 1501; DQB1*0301, 0602; high-risk HPV infection in the area of Xinjiang, China. 200 Kazakh patients with ESCC and 150 controls were recruited, and polymerase chain reaction (PCR) was performed to detect HLA-DRB1*0901, 1501 and DQB1*0301,0602 using sequence-specific primers (SSPs). HPV16 was detected in esophageal specimens using PCR. HPV16 infection rate in Kazakh ESCC case group was 41 %, significantly higher than that of control group 14 % (OR = 3.62; 95 % CI, 2.15–6.09; P < 0.001). A positive association between ESCC and HLA-DRB1*1501 (OR = 2.46, P < 0.0125) or HLA-DQB1*0301 (OR = 3.34, P < 0.0125) alleles was observed. Similar tendencies were observed for HLA-DRB1*1501 (OR = 3.095, P < 0.0125) and HLA-DQB1*0301 (OR = 2.410, P < 0.0125) alleles with HPV16-positive ESCC. HLA-DRB1*1501, HLA-DQB1*0301 and DQB1*0602 were significantly associated with ESCC when the age was ≥55 years (P < 0.0125 for all), whereas only HLA-DQB1*0301 was significantly associated with ESCC when the age was <55 years (P < 0.0125). HLA-DRB1*1501 and HLA-DQB1*0301 were significantly associated with an increase in ESCC occurrence in females (P < 0.0125), whereas only HLA-DQB1*0301 was significantly associated with ESCC in males. Moreover, the occurrence of HLA-DQB1*0602 gene in poorly differentiated ESCC group (68.8 %) was slightly higher than that of well-differentiated squamous cell carcinoma group (31.2 %). The difference was not statistically significant (P > 0.0125). The study suggests that HLA-DRB1*1501 and HLA-DQB1*0301 may influence the immune response to specific tumor and HPV-encoded epitopes and affect the risk of Kazakh ESCC in XinJiang, China.     

Host genetics and viral load in primary HIV-1 infection: clear evidence for gene by sex interactions

Research in the past two decades has generated unequivocal evidence that host genetic variations substantially account for the heterogeneous outcomes following human immunodeficiency virus type 1 (HIV-1) infection. In particular, genes encoding human leukocyte antigens (HLA) have various alleles, haplotypes, or specific motifs that can dictate the set-point (a relatively steady state) of plasma viral load (VL), although rapid viral evolution driven by innate and acquired immune responses can obscure the long-term relationships between HLA genotypes and HIV-1-related outcomes. In our analyses of VL data from 521 recent HIV-1 seroconverters enrolled from eastern and southern Africa, HLA-A*03:01 was strongly and persistently associated with low VL in women (frequency = 11.3 %, P < 0.0001) but not in men (frequency = 7.7 %, P = 0.66). This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50). In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001). Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results. These findings can serve as a proof of principle that the gap of “missing heritability” in quantitative genetics can be partially bridged by a systematic evaluation of sex-specific associations.     

HLA-DPB1*04:01 allele is associated with non-obstructive azoospermia in Japanese patients

Azoospermia is defined by absence of sperm in the semen and can either be caused by obstruction of the seminal tract (obstructive azoospermia) or by defects in spermatogenesis (non-obstructive azoospermia, NOA). Previous studies reported that specific alleles and single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region were associated with NOA in East Asians. We attempt to expand upon previous findings by genotyping more HLA genes and to replicate SNP associations by focusing on Japanese NOA patients. HLA typing of six genes (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) was done on 355 NOA patients using SSO-Luminex assay while genotyping of two previously reported SNPs (rs498422 and rs3129878) was done on 443 patients and 544 fertile males using TaqMan assay. Association between the HLA alleles and SNP with NOA was assessed with Chi squared and logistic regression tests. We found that HLA-DPB1*04:01 [corrected p value, P _c 7.13 × 10^?6; odds ratio (OR) 2.52], DRB1*13:02 (P _c 4.93 × 10^?4, OR 1.97), DQB1*06:04 (P _c 8.94 × 10^?4, OR 1.91) and rs3129878 (p value 3.98 × 10^?4; OR 1.32) showed significant association with NOA, however, these loci are in linkage disequilibrium with each other. The conditional logistic regression tests showed that DPB1*04:01 is independently associated with NOA, confirming the involvement of the HLA region in the etiology of NOA in Japanese patients.     

Search for schizophrenia susceptibility variants at the HLA-DRB1 locus among a British population

Schizophrenia is a complex mental disorder with unknown aetiology. Both candidate gene and genome-wide association (GWA) studies suggest that the human leukocyte antigen (HLA) system may play a part in development of the illness, but the causal HLA variant(s) remain(s) unclear. Previous studies showed that the DRB1*0101 and DRB1*13 alleles might be associated with a high risk of schizophrenia. Therefore, the present study was undertaken to test their association with the disease by genotyping seven DRB1-tagging single nucleotide polymorphisms (SNPs) in a British population. The results showed that, of the previously reported variants that were associated with schizophrenia, the DRB1*1303 allele was the only one marginally associated with a protective effect on the illness in our sample set (χ ²?=?4.138, P?=?0.042, odds ratio (OR)?=?0.42, 95 % confidence interval (CI) 0.27–0.66). Interestingly, a significant association was found for rs424232 (χ ²?=?9.404, P?=?0.002, OR?=?0.69, 95 % CI 0.54–0.88), which is a tag SNP for the DRB1*1303 allele and located near to the NOTCH4 gene that is a schizophrenia susceptibility locus confirmed by GWA studies. Analysis with the Haploview program demonstrated that rs424232 was in complete linkage disequilibrium with rs3130297 and rs3131296 present in the NOTCH4 locus. While we have failed to confirm association of the candidate alleles in the DRB1 gene with a high risk of schizophrenia, the present work suggests that the association signal detected in the HLA class II locus may extend a relatively long distance, and more work is needed in order to identify the true causal variants within this region or nearby.     

HLA-DRBl and susceptibility to kidney allograft rejection in Southern Iranian patients

Kidney transplantation is the best treatment option for the patients with end-stage renal disease. Viral infections and genetic factors such as HLA-II antigens may affect the kidney transplant outcome. The compatibility of HLA-DRB1 molecules in the survival of kidney transplant is important. Also, the correlation between these molecules and viral infections is significant. The current study investigates the allele frequency of HLA-DRB1 in 41 recipient kidney transplant and 203 normal healthy controls by polymerase chain reaction using sequence specific primers. Moreover the relation between HLA-DRB1 allelic groups and hepatitis B, hepatitis C and cytomegalovirus viral infections was also studied. However statistical analysis of the allele frequencies didn’t show any significant association between HLA-DRB1 allelic group distributions or sharing and susceptibility to acute kidney transplant rejection (P > 0.05). Comparing the allele frequencies between HLA-DRB1*14 and DRB1*04 allelic showed a significant difference in controls and patients (P = 0.03 and P = 0.05 respectively). The results of the present study also showed a significant association between possession of HLA-DRB1*07 allele in kidney transplant recipients and hepatitis C virus infection (P = 0.009). In conclusion however the results of the present study did not showed relation between HLA-DRB1 allele’s frequencies or sharing and kidney transplantation outcome, the results indicated that HLA-DRB1 alleles may susceptible individuals to renal disease or play a role in susceptibility to viral infection in kidney transplant patients.     

HLA class II haplotypic association and DQCAR microsatellite polymorphisms in Croatian patients with psoriasis

The purpose of the present study was to investigate polymorphism of HLA class II haplotypic associations (HLA-DRB1, -DQA1, -DQB1) and DQCAR alleles in 78 Croatian patients with psoriasis. Patients were divided into two groups according to a family history of disease and age of onset: type I (positive family history and early onset) and type II (negative family history and late onset). The difference in frequency of HLA class II haplotypic associations between type I patients and controls was observed for the following combinations: HLA-DRB1*0701, -DQA1*0201, -DQB1*02 (23.6% vs. 7.2%; p < 0.001), HLA-DRB1*0701, -DQA1*0201, -DQB1*0303 (8.5% vs. 1.3%; p = 0.0018) and HLA-DRB1*1601, -DQA1*0102, -DQB1*0502 (2.8% vs. 9.3%; p = 0.06). The difference between type II psoriasis and controls for association: HLA-DRB1*1501, -DQA1*0102, -DQB1*0602 is not significant (20.0% vs. 8.9%; p = 0.06). The significantly higher frequency of DQCAR 113bp and 119bp alleles in patients with type Ipsoriasis is a result of linkage disequlibrium of these alleles with both HLA-DRB1*0701 haplotypic associations. Analysis ofDQCAR alleles in the HLA-DRB1*0701 haplotypic associations in patients with psoriasis vulgaris and matched controls did not reveal any difference in polymorphism of DQCAR alleles. These data suggest that HLA-DRB*0701 haplotypic combinations are associated with type I but not for type II psoriasis in the Croatian population. DQCAR polymorphism is not useful genetic marker to distinguish susceptible HLA class II haplotypic association.     

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.     

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.     

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 HLA-DRB1 and DQB1 alleles with red blood cell alloimmunization in Chinese

Few systematic investigations have assessed the correlations between red blood cell (RBC) antibodies and human leukocyte antigen (HLA)-DRB1 alleles in the Chinese population. In this case-control study, we investigated whether specific HLA-DRB1 alleles were associated with RBC alloimmunization by calculating the odds ratios for the frequencies of HLA alleles associated with alloimmunization to different RBC antigens. Three hundred and eight patients harboring RBC alloantibodies were analyzed as the case group, and the frequencies of the HLA-DRB1and HLA-DQB1 alleles in control individuals were analyzed by collecting data from the China Marrow Donor Program (including more than 1.6 million healthy people). HLA alleles were genotyped by single specific primer-polymerase chain reaction. The development of anti-C was associated with DRB1*07, DQB1*06, and DQB1*08; anti-C,e was associated with DRB1*07 and DQB1*06; and anti-E and anti-M were associated with DQB1. Other associations were identified between anti-E and DRB1*09 and between anti-Le^a and DRB1*01. Thus, our findings confirmed that HLA-DRB1 and DQB1 restriction played an important role in the generation of RBC alloantibodies in Chinese individuals.     

Correlation Between HLA-A,B and DRB1 Alleles and Severe Fever with Thrombocytopenia Syndrome

ObjectiveSevere fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever caused by a tick-borne bunyavirus (SFTSV) in East Asian countries. The role of human leukocyte antigen (HLA) in resistance and susceptibility to SFTSV is not known. We investigated the correlation of HLA locus A, B and DRB1 alleles with the occurrence of SFTS.MethodsA total of 84 confirmed SFTS patients (patient group) and 501 unrelated non-SFTS patients (healthy individuals as control group) from Shandong Province were genotyped by PCR-sequence specific oligonucleotide probe (PCR-SSOP) for HLA-A, B and DRB1 loci.Allele frequency was calculated and compared using χ² test or the Fisher''s exact test. A corrected P value was calculated with a bonferronis correction. Odds Ratio (OR) and 95% confidence intervals (CI) were calculated by Woolf’s method.ResultsA total of 11 HLA-A, 23 HLA-B and 12 HLA-DRB1 alleles were identified in the patient group, whereas 15 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles were detected in the control group. The frequencies of A*30 and B*13 in the SFTS patient group were lower than that in the control group (P = 0.0341 and 0.0085, Pc = 0.5115 and 0.252). The ORs of A*30 and B*13 in the SFTS patient group were 0.54 and 0.49, respectively. The frequency of two-locus haplotype A*30-B*13 was lower in the patient group than in the control group(5.59% versus 12.27%, P = 0.037,OR = 0.41, 95%CI = 0.18–0.96) without significance(Pc>0.05). A*30-B*13-DRB1*07 and A*02-B*15-DRB1*04 had strong associations with SFTS resistance and susceptibility respectively (Pc = 0.0412 and 0.0001,OR = 0.43 and 5.07).ConclusionThe host HLA class I polymorphism might play an important role with the occurrence of SFTS. Negative associations were observed with HLA-A*30, HLA-B*13 and Haplotype A*30-B*13, although the associations were not statistically significant. A*30-B*13-DRB1*07 had negative correlation with the occurrence of SFTS; in contrast, haplotype A*02-B*15-DRB1*04 was positively correlated with SFTS.     

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.     

Associations of <Emphasis Type="Italic">CTLA4</Emphasis> +49 A/G Dimorphism and HLA-DRB1*/DQB1* Alleles With Type 1 Diabetes from South India

The aim of present study was to elucidate the association of CTLA4 +49 A/G and HLA-DRB1*/DQB1* gene polymorphism in south Indian T1DM patients. The patients and controls (n?=?196 each) were enrolled for CTLA4 and HLA-DRB1*/DQB1* genotyping by RFLP/PCR-SSP methods. The increased frequencies of CTLA4 ‘AG’ (OR?=?1.99; p?=?0.001), ‘GG’ (OR?=?3.94; p?=?0.001) genotypes, and ‘G’ allele (OR?=?2.42; p?=?9.26?×?10^?8) were observed in patients. Reduced frequencies of ‘AA’ (OR?=?0.35; p?=?7.19?×?10^?7) and ‘A’ (OR?=?0.41; p?=?9.26?×?10^?8) in patients revealed protective association. Among HLA-DRB1*/DQB1* alleles, DRB1*04 (OR?=?3.29; p?=?1.0?×?10^?5), DRB1*03 (OR?=?2.81; p?=?1.9?×?10^?6), DQB1*02:01 (OR?=?2.93; p?=?1.65?×?10^?5), DQB1*02:02 (OR?=?3.38; p?=?0.0003), and DQB1*03:02 (OR?=?7.72; p?=?0.0003) were in susceptible association. Decreased frequencies of alleles, DRB1*15 (OR?=?0.32; p?=?2.55?×?10^?7), DRB1*10 (OR?=?0.45; p?=?0.002), DQB1*06:01 (OR?=?0.43; p?=?0.0001), and DQB1*05:02 (OR?=?0.28; p?=?2.1?×?10^?4) in patients were suggested protective association. The combination of DRB1*03+AG (OR?=?5.21; p?=?1.4?×?10^?6), DRB1*04+AG (OR?=?2.14; p?=?0.053), DRB1*04+GG (OR?=?5.21; p?=?0.036), DQB1*02:01+AG (OR?=?4.44; p?=?3.6?×?10^?5), DQB1*02:02+AG (OR?=?20.9; p?=?9.5?×?10^?4), and DQB1*02:02+GG (OR?=?4.06; p?=?0.036) revealed susceptible association. However, the combination of DRB1*10+AA (OR?=?0.35; p?=?0.003), DRB1*15+AA (OR?=?0.22; p?=?5.3?×?10^?7), DQB1*05:01+AA (OR?=?0.45; p?=?0.007), DQB1*05:02+AA (OR?=?0.17; p?=?1.7?×?10^?4), DQB1*06:01+AA (OR?=?0.40; p?=?0.002), and DQB1*06:02+AG (OR?=?0.34; p?=?0.001) showed decreased frequency in patients, suggesting protective association. In conclusion, CTLA4/HLA-DR/DQ genotypic combinations revealed strong susceptible/protective association toward T1DM in south India. A female preponderance in disease associations was also documented.     

Diversity of Extended HLA-DRB1 Haplotypes in the Finnish Population

The Major Histocompatibility Complex (MHC, 6p21) codes for traditional HLA and other host response related genes. The polymorphic HLA-DRB1 gene in MHC Class II has been associated with several complex diseases. In this study we focus on MHC haplotype structures in the Finnish population. We explore the variability of extended HLA-DRB1 haplotypes in relation to the other traditional HLA genes and a selected group of MHC class III genes. A total of 150 healthy Finnish individuals were included in the study. Subjects were genotyped for HLA alleles (HLA-A, -B, -DRB1, -DQB1, and -DPB1). The polymorphism of TNF, LTA, C4, BTNL2 and HLA-DRA genes was studied with 74 SNPs (single nucleotide polymorphism). The C4A and C4B gene copy numbers and a 2-bp silencing insertion at exon 29 in C4A gene were analysed with quantitative genomic realtime-PCR. The allele frequencies for each locus were calculated and haplotypes were constructed using both the traditional HLA alleles and SNP blocks. The most frequent Finnish A∼B∼DR -haplotype, uncommon in elsewhere in Europe, was A*03∼B*35∼DRB1*01∶01. The second most common haplotype was a common European ancestral haplotype AH 8.1 (A*01∼B*08∼DRB1*03∶01). Extended haplotypes containing HLA-B, TNF block, C4 and HLA-DPB1 strongly increased the number of HLA-DRB1 haplotypes showing variability in the extended HLA-DRB1 haplotype structures. On the contrary, BTNL2 block and HLA-DQB1 were more conserved showing linkage with the HLA-DRB1 alleles. We show that the use of HLA-DRB1 haplotypes rather than single HLA-DRB1 alleles is advantageous when studying the polymorphisms and LD patters of the MHC region. For disease association studies the HLA-DRB1 haplotypes with various MHC markers allows us to cluster haplotypes with functionally important gene variants such as C4 deficiency and cytokines TNF and LTA, and provides hypotheses for further assessment. Our study corroborates the importance of studying population-specific MHC haplotypes.     

HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites

Sarcoidosis is a granulomatous disorder of unknown etiology, associated with an accumulation of CD4+ T cells and a TH1 immune response. Since previous studies of HLA associations with sarcoidosis were limited by serologic or low-resolution molecular identification, we performed high-resolution typing for the HLA-DPB1, HLA-DQB1, HLA-DRB1, and HLA-DRB3 loci and the presence of the DRB4 or DRB5 locus, to define HLA class II associations with sarcoidosis. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled biopsy-confirmed cases (736 total) from 10 centers in the United States. Seven hundred six (706) controls were case matched for age, race, sex, and geographic area. We studied the first 474 ACCESS patients and case-matched controls. The HLA-DRB1 alleles were differentially distributed between cases and controls (P<.0001). The HLA-DRB1*1101 allele was associated (P<.01) with sarcoidosis in blacks and whites and had a population attributable risk of 16% in blacks and 9% in whites. HLA-DRB1-F(47) was the amino acid residue most associated with sarcoidosis and independently associated with sarcoidosis in whites. The HLA-DPB1 locus also contributed to susceptibility for sarcoidosis and, in contrast to chronic beryllium disease, a non-E(69)-containing allele, HLA-DPB1*0101, conveyed most of the risk. Although significant differences were observed in the distribution of HLA class II alleles between blacks and whites, only HLA-DRB1*1501 was differentially associated with sarcoidosis (P<.003). In addition to being susceptibility markers, HLA class II alleles may be markers for different phenotypes of sarcoidosis (DRB1*0401 for eye in blacks and whites, DRB3 for bone marrow in blacks, and DPB1*0101 for hypercalcemia in whites). These studies confirm a genetic predisposition for sarcoidosis and present evidence for the allelic variation at the HLA-DRB1 locus as a major contributor.     

HLA-DRB1 Shared Epitope-Dependent DR-DQ Haplotypes Are Associated with Both Anti-CCP–Positive and –Negative Rheumatoid Arthritis in Chinese Han

The association between Human Leukocyte Antigen (HLA) class II and rheumatoid arthritis (RA) has been extensively studied, but few reported DR-DQ haplotype. Here we investigated the association of HLA-DRB1, DQA1, DQB1, and DR-DQ haplotypes with RA susceptibility and with anti-CCP antibodies in 281 RA patients and 297 control in Han population. High-resolution genotyping were performed. The HLA-DRB1 shared epitope (SE)-encoding allele *0405 displayed the most significant RA association (P = 1.35×10⁻⁶). The grouped DRB1 SE alleles showed great association with RA (P = 3.88×10⁻¹³). The DRB1 DRRAA alleles displayed significant protective effects (P = 0.021). The SE-dependent DR-DQ haplotype SE-DQ3/4/5 remained strong association with both anti-CCP -positive (P = 3.71×10⁻¹³) and -negative RA (P = 3.89×10⁻⁵). Our study revealed that SE alleles and its haplotypes SE-DQ3/4/5 were highly associated with RA susceptibility in Han population. The SE-DQ3/4/5 haplotypes were associated with both anti-CCP positive RA and -negative RA.     

Polymorphism of human HLA-DRB1 leukocyte antigen alleles and its association to juvenile rheumatoid arthritis in a sample of Colombian mestizo children

Oligotypes of the human leukocyte antigen HLA Class II, DRB1 alleles were characterized at the molecular level in a group of Colombian children suffering juvenile rheumatoid arthritis (JRA). The distribution of these alleles was examined in a group of Colombian mestizo children (genetic admixture of Amerindians, Europeans and Africans) suffering from clinically distinct JRA subsets in order to detect HLA allele frequency differences in patients with different JRA subsets. A group of 65 patients with JRA and 65 controls were characterized for the subtypes of the HLA-DRB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide probes (PCR-SSOP). The oligotyping protocol recommended by the 12th International Histocompatibility Workshop held in St. Malo, Paris, in 1996, was used. Subtype HLA-DRB1*1104 was the allele most strongly associated with susceptibility to JRA (Fisher's p = 0.013, odds ratio (OR) = 16.79, etiologic fraction (EF) = 0.93). HLA-DRB1*1602 was also associated with susceptibility to a lesser degree (Fisher's p = 0.016, OR = 8.98, EF = 0.88). HLA-DRB1 alleles participating in JRA protection were HLA-DRB1*1501 (preventive fraction (PF) = 0.466, p = 0.005) and HLA DRB1*1402 (PF = 0.49, p = 0.009). The relationship between some HLA-DRB1 alleles and clinical features was also compared. The presence of rheumatic factor was associated with the alleles HLA-DRB1*0407 (p = 0.05, OR = 11.2, EF = 0.45) and HLA-DRB1*1302 (p = 0.02, OR = 22.8, EF = 0.63). There was also an association between HLA-DRB1*0701 (p = 0.001, OR = 58, EF = 0.73) with expressing ANA +. We found that in the oligoarticular subset, the allele HLA-DRB1*1104 (p = 0.0034, OR = 41.53, EF = 0.97) was the one expressed most commonly. In the poliarticular group, the alleles most frequently expressed were HLA-DRB1*0404 (Fisher's p = 0.012, OR = 8.75, EF = 0.88). In patients with systemic JRA, the HLA-DRB1*1602 allele (p = 0.005, OR = 21.33, EF = 0.95) was most frequent. These results suggested that the MHC genes of mestizo children influence not only the clinical expression of the disease, but also the susceptibility to its development.