The association between the genetic polymorphism of HLA-DQA1, DQB1, and DRB1 and serum alanine aminotransferase levels in chronic hepatitis C in the Chinese population

Background and Aim:  To investigate a possible association between HLA genes with serum alanine aminotransferase (ALT) levels and evaluate whether the HLA-DQA1, DQB1, and DRB1 genes could influence the development of liver damage in chronic hepatitis C.
Methods:  A total of 145 patients with chronic hepatitis C virus (HCV) infection (36 patients with persistently normal ALT values; 109 patients with elevated ALT levels) and 160 uninfected healthy controls were examined for HLA-DQA1, DQB1, and DRB1 molecules by using polymerase chain reaction–sequencing based typing (PCR-SBT).
Results:  Among the patients chronically infected with HCV, the frequencies of DQA1*0501, DQB1*0301, and DRB1*0401 alleles were significantly increased in the normal ALT group compared with those with abnormal ALT levels, whereas that of DQB1*0201 was significantly lower. As compared to uninfected healthy controls, DQA1*0501, DQB1*0301, and DRB1*0401 allele frequencies were also statistically higher in the normal ALT group, whereas that of DQB1*0201 was the inverse. The haplotype frequencies of DQA1*0301-DQB1*0301, DQA1*0501-DQB1*0301, and DRB1*1101-DQB1*0301 were found to be significantly higher in the normal ALT group. Multivariate logistic regression indicated that female sex, and the DQB1*0301 allele and DRB1*0401 allele were independently associated with normal ALT values, whereas DQB1*0201 allele was the inverse.
Conclusions:  These results suggest that particular HLA alleles may have an influence on the serum ALT level of chronic HCV infection as a host genetic factor in the Chinese population. The DQA1*0501, DQB1*0301, and DRB1*0401 alleles, and the DQA1*0301-DQB1*0301, DQA1*0501-DQB1*0301, and DRB1*1101-DQB1*0301 haplotypes seem to be associated with low hepatitis activity; whereas DQB1*0201 allele is closely correlated with the progression of liver injury in chronic HCV infection.     

中国人群1型糖尿病HLA-DQ基因多态性的Meta分析

目的　综合评价中国人群HLA DQ基因多态性与 1型糖尿病 (DM)的关联性。方法　以 1型DM组和健康对照组的各HLA DQ等位基因频数(基因型频数、单倍型频数 )分布的OR值为统计量,全面检索相关文献;应用Meta分析软件包REVMAN4. 2,在基因分型水平上,对各研究的结果进行一致性检验和数据合并,并评估发表偏倚。结果　等位基因DQA1* 0301、DQA1* 0501、DQB1* 0201、DQB1* 0303、DQB1* 0401和DQB1* 0604是中国人群 1型DM的危险基因 (均P<0. 05), 他们的合并OR值分别为2. 83、2. 90、4. 17、1. 65、2. 00和 3. 00;基因型 (或单倍型 )DQA1* 0301 /DQB1* 0201、DQA1* 0301 /DQB1*0302、DQA1* 0501 /DQB1* 0201、DQA1* 0301 /DQB1* 0201 /DRB1* 0301和DQB1* 0302 /DRB1* 0405是中国人群 1型DM的危险基因型(或单倍型,均P<0. 05),他们的合并OR值分别为 8. 95、3. 09、6. 01、6. 57和 14. 85。而等位基因DQA1* 0101、DQA1* 0102、DQA1* 0103、DQA1* 0104、DQA1* 0201、DQA1* 0401、DQA1* 0601、DQB1* 0301、DQB1* 0501、DQB1* 0503、DQB1* 0601和DQB1* 0602是中国人群 1型DM的保护等位基因(均P<0. 05),他们的合并OR值分别为 0. 47、0. 38、0. 21、0. 07、0. 44、0. 39、0. 44、0. 19、0. 33、0. 32、0. 42和 0. 28; 基因型     

Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population

AIMS: In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries.     

Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians

OBJECTIVE: To define the relative importance (RI) of class II major histocompatibility complex (MHC) alleles and peptide binding motifs as risk or protective factors for juvenile dermatomyositis (DM), and to compare these with HLA associations in adult DM. METHODS: DRB1 and DQA1 typing was performed in 142 Caucasian patients with juvenile DM, and the results were compared with HLA typing data from 193 patients with adult DM and 797 race-matched controls. Random Forests classification and multiple logistic regression were used to assess the RI of the HLA associations. RESULTS: The HLA-DRB1*0301 allele was a primary risk factor (odds ratio [OR] 3.9), while DQA1*0301 (OR 2.8), DQA1*0501 (OR 2.1), and homozygosity for DQA1*0501 (OR 3.2) were additional risk factors for juvenile DM. These risk factors were not present in patients with adult DM without defined autoantibodies. DQA1 alleles *0201 (OR 0.37), *0101 (OR 0.38), and *0102 (OR 0.51) were identified as novel protective factors for juvenile DM, the latter 2 also being protective factors in adult DM. The peptide binding motif DRB1 (9)EYSTS(13) was a risk factor, and DQA1 motifs F(25), S(26), and (45)(V/A)W(R/K)(47) were protective. Random Forests classification analysis revealed that among the identified risk factors for juvenile DM, DRB1*0301 had a higher RI (100%) than DQA1*0301 (RI 57%), DQA1*0501 (RI 42%), or the peptide binding motifs. In a logistic regression model, DRB1*0301 and DQA1*0201 were the strongest risk and protective factors, respectively, for juvenile DM. CONCLUSION: DRB1*0301 is ranked higher in RI than DQA1*0501 as a risk factor for juvenile DM. DQA1*0301 is a newly identified HLA risk factor for juvenile DM, while 3 of the DQA1 alleles studied are newly identified protective factors for juvenile DM.     

HLA-DRB3*0101 is associated with Graves' disease in Jamaicans

OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians.     

Association of HLA-DQA1*0101/2 and DQB1*0502 with Myasthenia Gravis in Southern Iranian Patients

Background: Myasthenia gravis is an autoimmune disorder of neuromuscular junction characterized by skeletal muscle weakness and fatigability. Different genes may control the induction and clinical presentation of this disease. Various HLA alleles are reported as predisposing or protective genetic elements in myasthenia gravis. Objective: The aim of this study was to investigate the probable association between HLA-DQ alleles and myasthenia gravis in southern Iranian patients. Methods: HLA-DQA1 and DQB1 alleles were determined in 104 sporadic patients with myasthenia gravis using polymerase chain reaction - restriction fragment length polymorphism method and the results were compared to 816 healthy controls. Results: HLA-DQA1*0101/2 (39.4%) and DQB1*0502 (21.6%) were the most frequent alleles in southern Iranian patients with myasthenia gravis. These alleles revealed positive associations with the disease with relative risks of 1.69 and 2.41, respectively. The most common haplotype was DQA1*0101/2-DQB1*0502 in these patients. Conclusion: According to the results of this study, DQA1*0101/2 and DQB1*0502 alleles might be considered as predisposing genetic factors to myasthenia gravis while DQA1*0501, DQB1*0301 and *0602/3 show protective roles against this disease.     

HLA-DRB1*15021 is the predominant allele in Japanese patients with juvenile dermatomyositis

OBJECTIVE: To investigate HLA molecules and genes in Japanese patients with juvenile dermatomyositis (JDM). METHODS: Twelve patients (8 girls and 4 boys) with ages of onset between 3 and 15 years were included. HLA class I antigen phenotypes were serologically typed by the Terasaki-NIH standard method. DNA was extracted from peripheral blood leukocytes using the phenol-chloroform extraction procedure, and stored at -70 degrees C until use. Genomic DNA for HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles in JDM patients and controls was determined by the direct sequence method. RESULTS: HLA-A24 and B52 were each detected in 7 cases (OR = 0.86, 5.02, p = 0.930, 0.006, respectively). HLA-DRB1*15021 was observed in 7 patients. This was significantly more frequent than occurred in the controls (OR = 5.72, p = 0.002). Seven patients out of 12 (58%) had the combination HLA-B52, DRB1*15021, DQA1*0103, and DQB1*0601. CONCLUSION: Our results suggest that the susceptibility gene for JDM either is HLA-DRB1*15021 or is present near the HLA-DRB1 locus. This differs from previous reports that describe the association with HLA-DQA1*0501 in Caucasian patients with JDM. The combination HLA-B52, DRB1*15021, DQA1*0103, and DQB1*0601 may contribute to the pathogenesis of JDM in Japanese patients.     

Class II HLA alleles and hepatitis B virus persistence in African Americans

Persistence of hepatitis B virus (HBV) infection is likely due to the interplay of the virus and host immune response. Given its critical role in antigen presentation, allelic differences in the HLA complex may affect HBV persistence. In a prospectively followed African American cohort, molecular class I and class II HLA typing was done on 31 subjects with persistent HBV infection and 60 controls who cleared the infection. HBV persistence was significantly associated with two class II alleles, DQA1 *0501 (odds ratio [OR], 2.6; P=.05) and DQB1 *0301 (OR, 3.9; P=.01), the two-locus haplotype consisting of these same two alleles (OR, 3; P=. 005) and the three-locus haplotype, DQA1 *0501, DQB1 *0301, and DRB1 *1102 (OR, 10.7; P=.01). In addition, HBV persistence was associated with class II allelic homozygosity. Several class I associations with persistence were also noted but were not statistically significant after correction for multiple comparisons. These results underscore the importance of the class II-mediated immune response in recovery from HBV infection.     

HLA-DRB1, DQA1, and DQB1 alleles associated with giant cell arteritis in northern Italy.

OBJECTIVE: To evaluate by molecular typing the possible associations of HLA-DRB1, DQA1, and DQB1 alleles with biopsy proven giant cell arteritis (GCA) in a Mediterranean country, and to examine possible relationships between these alleles and GCA clinical subsets. METHODS: Thirty-nine patients from the Reggio Emilia area diagnosed over a 12 year period with biopsy proven GCA were studied. The clinical findings at diagnosis and during the followup were evaluated through interviews and by reviewing the medical records. HLA-DRB1, DQA1, and DQB1 alleles were determined in the 39 patients and in 250 healthy controls from the same geographic area by polymerase chain reaction amplification using sequence-specific primers. RESULTS: No associations were found between GCA and the shared epitope, the DRYF epitope, or the DRB1*04 or DQA1 alleles. The only significant association was with DQB1*0302 allele (p = 0.03, RR = 2.2). However, the association was weak and the significance was lost when corrected for the number of antigens tested. The frequencies of DQB1*0301 and 0302 in DR4 patients were not significantly different from those observed in DR4 positive controls. Significant associations were found between DRB1*04 allele and the presence of systemic signs and/or symptoms (p = 0.04, RR = 1.5) and between DRB1*07 allele and the male patients (p = 0.04, RR = 2.6). CONCLUSION: Our data showed no associations of biopsy proven GCA with HLA-DRB1*04 and HLA-DRB1*01 alleles, rheumatoid epitope, or DRYF epitope. Discrepancies with other studies may be related to the different ethnic backgrounds of the populations studied and to differences in the referral patterns of patients with GCA.     

Associations of HLA-DRB1, DQB1 and DPB1 alleles with pulmonary tuberculosis in south India.

SETTING: Tuberculosis is endemic in south India: sputum positive pulmonary tuberculosis is predisposed by HLA-DR2 in south India and few other populations of the world. OBJECTIVE: To study HLA-DRB1, DQB1, DQA1 and DPB1 allelic polymorphism in pulmonary tuberculosis patients and endemic controls from south India. DESIGN: One hundred and twenty-six, sputum positive pulmonary tuberculosis patients and 87, endemic controls, from Madurai were studied for MHC class II allelic polymorphism by PCR-SSOP method. XI IHWC primers and probes and non-radioactive probing methods were employed. RESULTS: HLA DRB1*1501 and DQB1*0601 predisposed for pulmonary tuberculosis (DRB1*1501: odds ratio (OR) = 2.68, 95% confidence interval (CI) = 1.30-5.89, P value (P) = 0.013, aetiological fraction (EF) = 0.17; DQB1*0601: OR = 2.32, CI = 1.29-4.27, P = 0.008, EF = 0.26). Haplotype DRB1*1501-DQB1*0601 was higher in patients (1324 per 10,000, X2 = 27.07) than controls (F = 404/10,000, X2 = 8.84). In a subset of 63 caste matched samples, DPB1*04 was preventive (OR = 0.45, CI = 0.21-0.95, P = 0.036, PF = 0.26): the distributions of DRB1*1501-DQB1*0601-DPB1*04 phenotypes were different between patients and controls (P = 0.0092). These alleles were predominant in patients and controls of T5SU caste. CONCLUSION: HLA-DRB1*1501 and DQB1*0601 predisposed to sputum positive pulmonary tuberculosis, and DPB1*04 was preventive and epistatic to this risk. Caste T5SU is an ideal model to study immunology of tuberculosis.     

Ⅱ类人白细胞抗原等位基因与晚期肝脾型日本血吸虫病的相关性研究

目的　探讨Ⅱ类人白细胞抗原 (HLA-Ⅱ)基因多态性与晚期肝脾型日本血吸虫病的相关性。　方法　用聚合酶链反应-序列特异性引物 (PCR-SSP)技术对 46例晚期肝脾型日本血吸虫病患者 (实验组 )和 43例慢性日本血吸虫病患者 (对照组 )HLA-DRB1、DPA1、DQA1和DQB14个基因位点的等位基因进行分型。对两组间等位基因频率的差异进行 χ² 检验。　结果　实验组HLA-DRB1*04、DPA1*0103、DQA1*0601和DQB1*020 1等位基因频率明显高于对照组 ,而HLA-DQA1*0501和DQB1*0601等位基因频率明显低于对照组。　结论　HLA-DRB1*04、DPA1*0103、DQA1*0601和DQB1*0201等位基因 ,因其与晚期肝脾型日本血吸虫病呈显著的正相关 (P <0.0 5 )而可能是该病的遗传易感基因 ,而HLA-DQA1*0501和DQB1*0601等位基因与对该病存在抵抗性有关。     

HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus

The objective of this study was to determine the HLA class II associations of the anticardiolipin (aCL) and anti-beta2GPI (abeta2GPI) antibodies in a large series of European patients with systemic lupus erythematosus (SLE). A cohort of 577 European SLE patients was enrolled. aCL and abeta2GPI were measured by ELISA methods. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1 loci was performed by the polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) method. aCL of IgG, IgM and IgA isotypes were detected in 22.8%, 14% and 13.9% of patients, respectively. IgG and IgM abeta2GPI were detected in 20% of patients. aCL showed positive association with HLA DRB1*04, DRB1*0402, DRB1*0403, DRB1*07, DRB3*0301, DQA1*0201, DQA1*0301, DQB1*0302, and negative association with DQA1*0501, DRB3*0202. abeta2GPI showed positive association with DRB1*0402, DRB1*0403, DQB1*0302. DRB1*0402 carried the highest relative risk for the presence of both aCL (RR=8. 1) and abeta2GPI (RR=4.6). Our results confirm the already described associations of aCL with HLA DR4 and DR7, but also demonstrate that, among the alleles at the DRB1*04 locus, the *0402 was most represented both in aCL and in abeta2GPI positive patients. In addition, HLA class II associations of abeta2GPI are for the first time extensively examined in a large cohort of European SLE patients.     

Association of the HLA-DRB1*0301 and HLA-DQA1*0501 alleles with Graves' disease in a population representing the gene contribution from several ethnic backgrounds.

Graves' disease (GD) is the most frequent cause of hyperthyroidism. Although the etiology is not completely elucidated, there are several lines of evidence suggesting multifactorial mechanisms. Genetic, constitutional, and environmental factors are involved in its pathogenesis. Major histocompatibility complex (MHC) class II alleles have been associated with GD in several populations of distinct ethnic backgrounds and there is increasing evidence supporting an association between GD and HLA-DR3 in Caucasian populations. The MHC class II alleles were evaluated in 75 Brazilian patients presenting with GD and in 166 control individuals from the same geographic area. HLA-DRB, DQB, and DQA alleles were identified using polymerase chain reaction (PCR)-amplified DNA hybridized with sequence-specific probes. The HLA-DRB1*0301 allele was significantly increased in patients (34/75, 45.3%) as compared with controls (37/166, 22.3%, p = 0.009), conferring a relative risk (RR) of 2.8 and an etiologic fraction (EF) of 0.287. The HLA-DQA1*0501 allele was also overrepresented in patients (48/71, 67.6%) in relation to controls (24/71, 33.8%; p = 0.004), conferring an RR of 3.74 and an EF of 0.351. The susceptibility conferred by HLA-DQA1*0501 was independent of the HLA-DRB1*0301 allele. On the other hand, the HLA-DQB1*0602 allele was significantly decreased in patients (6/75, 8.0%) in relation to controls (53/166, 31.9%, p = 0.0008), conferring an RR of 0.18 and a preventive fraction of 0.267. Although the Brazilian population comprises individuals of several ethnic backgrounds, these results corroborate the participation of the HLA-DRB1*0301 and HLA-DQA1*0501 alleles as susceptibility markers for GD, and emphasize the participation of the HLA-DQB1*0602 allele as conferring protection against the development of the disease.     

The human leukocyte antigen HLA DRB3*020/DQA1*0501 haplotype is associated with Graves' disease in African Americans

Information on genetic susceptibility to Graves' disease in African Americans is limited. We studied DRB1, DQB1, DRB3 subtypes, DQA1*0501, DQA1*0201, and CTLA-4 polymorphisms in 49 African American patients with adult onset Graves' disease and 47 racially-matched controls using PCR-based sequence-specific priming methods. There were no significant differences in DRB1 or DQB1 allelic frequencies or CTLA-4 polymorphisms between patients and controls. However, we found that the frequency of DRB3 was significantly increased in the patients (75.5% vs. 57.4%, P = 0.006, X2 = 3.52), especially for the DRB3*0202 subtype (53.1% vs. 23.4, P = 0.003, X2 = 8.91). In this one respect, the finding was in concordance with our previous observations in Caucasian patients with adult-onset Graves' disease. In addition, whereas the frequency of DQA1*0501 was increased (P = 0.018, X2 = 5.63) in our patients, the haplotype of DRB3/DQA1*0501, or DRB3*0202/DQA1*0501 was found to be more strongly associated (P = 0.008, X2 = 7.0; P = 0.0008, X2 = 11.34, respectively). These data suggest that DRB3*0202, particularly when found with DQA1*0501 in a haplotype is a susceptible gene(s) for Graves' disease in adult African Americans. Considering these data with those in Caucasian patients, our results would suggest that the primary Graves susceptible locus is likely DRB3 and not DRB1.     

Respective weight of genotypes DQA1 and DQB1 associated with insulin-dependent diabetes in French children]

Genetic susceptibility alleles have been identified at the DQ HLA region. The aim of the present study was to confirm the value of these markers, and to evaluate the respective weight in the risk of the different alleles at the DQA1 and DQB1 levels, identified by restriction mapping after polymerase chain reaction on exon 2. A significant enrichment in DQB1 alleles encoding for an aminoacid different from Aspartic acid at position 57 (NA) was observed in diabetic (n = 213) in comparison to control (n = 93) children (94% vs 52%; p < 10(-8)). Not all the given NA/NA allelic combinations were equally and positively associated to the disease. Homozygous "Ala/Ala" combinations carried the highest relative risk (OR = 12.3; p < 10(-8)), and among them, the *0201/*0302 genotype was more positively associated to type 1 diabetes (OR = 66; p < 10(-8)). A significant enrichment in DQA1 alleles encoding for Arginine at position 52 in diabetic children was also observed (82% vs 40%; p < 10(-8)). The *0301/*0501 (Arg/Arg) genotype was significantly associated to Type 1 diabetes (OR = 16.2; p < 10(-4)). The highest risk was carried by the whole genotype, a result which could be expected from the known linkage desequilibrium between HLA-DQA1 and DQB1, DRB1 loci. The frequency of Ala DQB1 alleles was low in the background non-at-risk population, although the incidence of the disease is low in our country.     

Common major histocompatibility complex class II markers in clinical variants of cicatricial pemphigoid.

Cicatricial pemphigoid (CP) is a chronic autoimmune blistering disease affecting multiple mucous membranes derived from stratified squamous epithelium and occasionally the skin. CP has a wide spectrum of disease manifestations. Patients with oral pemphigoid (OP) have a benign self-limited disease in which pathological changes are restricted to the oral mucosa. On the other hand, patients with ocular cicatricial pemphigoid (OCP), a chronic condition marked with relapses and remissions, have ocular involvement and also perhaps involvement of other mucous membranes. All clinical subsets are characterized by the presence of a similar anti-basement zone autoantibody. The factors that determine the development of one form of CP or the other are not known. In a previous study, we described the association between OCP and the DQB1*0301 allele (P = 0.006). In this study, we have analyzed 22 Caucasian patients with OP and their family members for major histocompatibility complex DRB generic, DQA1, and DQB1 allele associations by PCR-sequence-specific oligonucleotide probe hybridization. The results were compared to those obtained from 17 Caucasian patients with OCP and to control Caucasian alleles and haplotypes. The DQB1*0301 allele frequency was 38.6% in OP, 52.9% in OCP, and 17.8% in controls. Statistically significant associations were detected between the DQB1*0301 allele and both OP (P = 0.0047) and OCP (P < 0.0001). In addition, DRB1*04 showed a statistically significant association (P = 0.005) with OCP when compared to controls. Analysis of major histocompatibility complex class II haplotypes showed significant statistical associations between both OCP and OP and the HLA-DRB1*04, DRB4*0101, DQA1*03, DQB1*0301 haplotype (P < 0.0001 and P = 0.0012, respectively). Our results indicate that DQB1*0301 is a marker of both oral and ocular forms of CP. The analysis of the amino acid sequence of the DQB1 alleles present in both OP and OCP suggested that amino acid residues at position 57 and positions 71-77 may also be markers of CP.     

人类白细胞抗原与风湿热和风湿性心瓣膜病易感性研究

为探讨人类白细胞抗原（ＨＬＡ）－ＤＱＡ１基因与风湿热（ＲＦ）和风湿性心脏病（ＲＨＤ）患者发病中宿主的遗传关联，选择无亲缘关系的广东籍汉族健康人１０６例和５４例ＲＦ／ＲＨＤ患者，应用聚合酶链反应－聚丙烯酰胺凝胶电泳（ＰＣＲ－ＰＡＧＥ）法，结合高灵敏的银染色作ＨＬＡ－ＤＱＡ１等位基因分型。发现本方法检测的６种ＤＱＡ１等位基因中，ＲＦ／ＲＨＤ组ＤＱＡ１＊０１０１（３１．４８％，相对危险率ＲＲ＝２．８９，Ｐ＜０．００５，病因系数ＥＦ＝０．２０６）明显增高，而ＤＱＡ１＊０１０２（１．８５％，ＲＲ＝０．１０６，Ｐ＜０．００５，预防分数ＰＦ＝０．１３４）显著下降；ＤＱＡ１的两种基因型（＊０１０１／０３０１和＊０１０１／０４０１）在病人组显著增高，而ＤＱＡ１的＊０１０２／０３０１基因型比健康人组明显下降（Ｐ＜０．００５）。上述结果显示：ＨＬＡ－ＤＱＡ１＊０１０１对ＲＦ／ＲＨＤ有遗传易感作用，而ＤＱＡ１＊０１０２有遗传抵抗作用；ＤＱＡ１基因型检测可能为预测ＲＦ／ＲＨＤ易感者提供理论依据。     

Human leukocyte antigen-associated susceptibility to pulmonary tuberculosis: molecular analysis of class II alleles by DNA amplification and oligonucleotide hybridization in Mexican patients

BACKGROUND: Pulmonary tuberculosis (PTB) develops by a complex combination of environmental factors with genetic susceptibility. In this context, an association between human leukocyte antigens (HLAs) and tuberculosis has been examined in several populations, but results have been controversial. DESIGN AND MEASUREMENTS: A prospective evaluation of class II HLA genotypes was completed by the polymerase chain reaction (PCR) sequence-specific primer technique and PCR sequence-specific oligonucleotide hybridization in a Mexican population. SETTING: This study was conducted at the Clinical Service of Tuberculosis and the Department of Immunology, National Institute of Respiratory Diseases, Mexico City, Mexico. PATIENTS: Four groups were examined: 95 healthy subjects; 50 nonimmunosuppressed PTB patients; 15 HIV-infected patients (stage IVc in the Centers for Disease Control and Prevention [CDC] classification system for AIDS) with PTB; and 37 HIV-infected patients in the asymptomatic stage (CDC stage II). RESULTS: The frequencies of alleles DQA1*0101 (odds ratio [OR], 6.18; 95% confidence interval [CI], 2.38 to 16.08), DQB1*0501 (OR, 6.16; 95% CI, 2.44 to 17.71), and DRB1*1501 (OR, 7.92; 95% CI, 2.71 to 23.14) were significantly increased in nonimmunosuppressed patients with PTB when compared with healthy subjects. By contrast, frequencies of allele DQB1*0402 and antigens DR4 and DR8 were significantly decreased in patients with PTB. Additionally, a significantly higher frequency of the DRB1*1101 allele was found in HIV-positive subjects (OR, 6.67; 95% CI, 2.13 to 20.83). CONCLUSION: The genetic influence associated with the HLA system appears to have an important role in the development of PTB, although this susceptibility may not be relevant in patients with severe immunodeficiency diseases such as AIDS.     

Autoantibodies to islet antigen-2 are associated with HLA-DRB1*07 and DRB1*09 haplotypes as well as DRB1*04 at onset of type 1 diabetes: the possible role of HLA-DQA in autoimmunity to IA-2

AIMS/HYPOTHESIS: To further our understanding of antigen presentation by HLA class II molecules, we have examined the influence of HLA class II genotype on expression of autoantibodies to islet antigen-2 (IA-2A). METHODS: HLA class II genotype and IA-2A were determined within 3 months of diagnosis in 618 patients with type 1 diabetes (median age 11 years [range 0.7-20.9]). Antibodies to the juxtamembrane region of IA-2 were measured by a radiobinding assay in 481 of 484 IA-2A-positive patients. RESULTS: IA-2A prevalence was highest in patients carrying at least one HLA-DRB1*04-DQA1*0301 (385 of 450; 86%), DRB1*07-DQA1*(0201 or 0301) (58 of 64; 91%) or DRB1*09-DQA1*0301 haplotype (18 of 19; 95%). Multiple regression showed that IA-2A were strongly associated with the number of these haplotypes carried; only 69 of 132 (52%) patients carrying none of these haplotypes had IA-2A, compared with 322 of 391 (82%) patients with one and 93 of 95 (98%) with two of these haplotypes (p < 0.001). IA-2 juxtamembrane antibodies were less frequent in IA-2A-positive patients with one (35%) or two (36%) DRB1*03-DQB1*02 or DRB1*07-DQB1*02 haplotypes than in those negative for these haplotypes (52%) (p = 0.002), but showed an independent positive association with IA-2A level (p < 0.001). CONCLUSIONS/INTERPRETATION: HLA class II alleles strongly influence the prevalence of IA-2A. The high IA-2A prevalence in patients carrying DRB1*04, DRB1*07 and DRB1*09 alleles in linkage disequilibrium with DQA1*0301 or the closely related DQA1*0201 suggests the humoral response to IA-2 may be driven by HLA-DQA1 genes.     

Weak associations between human leucocyte antigen genotype and acute myocardial infarction

Abstract. Björkbacka H, Lavant EH, Fredrikson GN, Melander O, Berglund G, Carlson JA, Nilsson J (Lund University, Malmö University Hospital, Malmö; and Lund University, Lund University Hospital, Lund; Sweden). Weak associations between human leucocyte antigen genotype and acute myocardial infarction. J Intern Med 2010; 268 :50–58. Objectives. Human leucocyte antigens (HLAs) are polymorphic molecules involved in antigen presentation. Associations between HLA type and autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, are well established but the potential association of genetic variation affecting antigen presentation with cardiovascular disease has not been systematically investigated in large cohorts. The importance of such studies is stressed by recent experimental findings of an involvement of autoimmunity in the atherosclerotic disease process. Results. An SSP‐PCR method was used for HLA genotyping to determine associations of HLA‐DRB1, ‐DQA1 and ‐DQB1 with cardiovascular disease in a population‐based cohort of 1188 acute myocardial infarction (AMI) patients and 1191 matched healthy controls. The HLA‐DRB1*0101 allele, as well as the HLA‐DRB1*0101‐DQA1*01‐DQB1*05 haplotype, was found to be associated with increased risk for AMI (OR 1.24; 95% CI 1.00–1.54 for both). In contrast, the DRB1*07 and DQA*02 alleles (OR 0.78; 95% CI 0.65–0.95 for both), as well as the DRB1*07‐DQA*02‐DQB*02 haplotype, conferred protection (OR 0.79; 95% CI 0.63–0.98). An HLA risk score taking each individual’s both haplotypes into account was higher amongst cases (2.43 ± 0.92 vs. 2.29 ± 0.95, P = 0.001). The association between HLA risk score and AMI was independent of other cardiovascular risk factors assessed. Conclusions. This study demonstrates that the associations between HLA‐DRB1 and DQA1 loci and cardiovascular disease exists but that they are considerably weaker than those previously reported for other diseases with an established autoimmune aetiology such as type 1 diabetes, systemic lupus erythematosus and rheumatoid arthritis.