人类白细胞抗原DRB1基因与肺结核的相关性研究

目的探讨HLA-DRB1基因多态性与肺结核(PTB)的遗传关联性及其与临床表现的关系。方法采用聚合酶链反应-序列特异性引物(PCR-SSP)方法,对74例PTB患者及90名正常人的HLA-DRB1等位基因进行分型。结果与对照组相比,PTB病例组的DRB1*15等位基因频率显著增高(34.3%比17.0%,Pc<0.05,RR=2.91),HLA-DRB1*12基因频率高(15.4%比7.5%),但统计学上无显著性差异(Pc>0.05);而DRB1*11基因频率显著低于对照组(1.4%比9.9%,Pc<0.05,RR=0.12)。HLA-DRB1*15阳性患者中复治病例数和耐药病例数均显著高于HLA-DRB1*15阴性组(P<0.05)。结论HLA-DRB1*15可能是PTB的易感基因,DRB1*11可能为保护基因,HLA-DRB1*15基因与PTB临床特征有一定相关性。     

The HLA–DQ associations with Graves' disease in Chinese children

OBJECTIVE: Graves' disease has been documented to be associated with different HLA genes in Caucasians and Chinese adults. The incidence of childhood Graves' disease has been reported to be high in Hong Kong Chinese. The aims of this study were to examine the HLA-DQA1 and DQB1 associations with Graves' disease in Chinese children. PATIENTS AND DESIGN: Sixty-seven Chinese children with Graves' disease (59 girls and 8 boys) and 51 racially matched healthy controls were recruited for the study. Genomic DNA was extracted from venous blood samples. HLA-DQ typings were determined by sequence-specific oligonucleotide probing of the respective enzymatically amplified gene. Frequencies of HLA-DQ alleles at each locus were compared between patients and controls using the chi 2-test. RESULTS: The frequency of HLA-DQB1.0303 was increased in the combined male and female patient group [53.7%; relative risk (RR) = 4.22; Pc = 0.005] and female patients (50.8%; RR = 3.76; Pc = 0.018) compared with that in the entire control group (21.2%). HLA-DQB1*201 was protective for Graves' disease (10.4%; RR = 0.20; Pc = 0.006). In contrast to studies in Caucasians, DQA1*0501 was not associated with susceptibility for Graves' disease in Chinese children. CONCLUSIONS: This study confirms that DQB1*0303 is a race-specific susceptible allele for Graves' disease in Chinese. Both susceptible and protective HLA-DQ alleles for Graves' disease in Chinese children are different from those in Caucasians.     

Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis

BACKGROUND & AIMS: In a recent study, we suggested that susceptibility to type 1 autoimmune hepatitis is associated with a six-amino acid motif, LLEQKR, within the DR beta polypeptide, but these data are in conflict with contemporary reports from Japan and Argentina. The purpose of the present study was to reexamine this question in a large independent cohort of patients. METHODS: Eighty-six North American white patients and 102 control subjects were studied. HLA class I antigens were determined serologically, and the DRB1, DQA1, DQB1, and DPB1 genes and the DRB3/4/5 subtypes were determined by high-resolution genotyping. RESULTS: The greatest risk was associated with DRB1*0301 (corrected probability [Pc] = 0.00003; relative risk [RR] = 4.58), and a secondary association with DRB1*0401 was identified (Pc = 0.000132; RR = 5.97). Protection from disease was associated with the DRB5*0101- DRB1*1501 haplotype (Pc = 0.021; RR = 0.3). However, further analysis indicated that a lysine residue at position 71 of the DR beta polypeptide may be the most important determinant of disease susceptibility (P = 0.0000003; RR = 8.6, increasing to RR = 16.38 with four lysine residues). CONCLUSIONS: DRB1*0301 and DRB1*0401 are confirmed as the principal susceptibility alleles for type 1 autoimmune hepatitis, and these data support the hypothesis that a lysine residue at position 71 of the DR beta-polypeptide chain may be the major risk factor. (Gastroenterology 1997 Jun;112(6):2028-35)     

Positive association of the HLA DMB1*0101-0101 genotype with rheumatoid arthritis.

OBJECTIVE: HLA DM is a non-classical major histocompatibility complex (MHC) class II molecule that has been shown to facilitate peptide loading with classical class II molecules. METHODS: In this study, we analysed the polymorphism in exon 3 of HLA DMA and DMB genes by a polymerase chain reaction-sequence-specific oligonucleotide probe method in 163 rheumatoid arthritis (RA) patients and 146 ethnically matched controls. The HLA-DRB1 genotype was also analysed by a reverse-dot blot method. RESULTS: Our results show in RA patients a significant increase in the HLA DMB*0101 allele frequency (83% vs 72.3% of the controls, P < 1.6 x 10(-3), significance at P < 0.0125) and in the HLA DMB*0101-0101 homozygote genotype frequency [70.8% vs 50% of the controls, P < 4.2 x 10(-4), significance at P < 0.00625, odds ratio (OR) = 2.4, 95% confidence interval (CI): 1.43-4]. The increase in DMB*0101 allele and homozygote genotype frequencies was independent of a linkage disequilibrium between DMB and DRB1 alleles. The analysis of non-random associations between the HLA-DM and DRB1 alleles only revealed a significant association in controls between DMB*0104 and DRB1*07 alleles (delta = 0.01, P < 7 x 10(-4), significance at P < 9.6 x 10(-4)). On the other hand, the DMB*0101-0102 genotype frequency was increased in DRB1*0401-negative RA patients as compared to controls (11% vs 2%, P < 0.011, significance at P < 0.015, OR = 6.2, 95% CI: 1.2-30). CONCLUSION: Our data suggest that HLA-DM alleles could play a role in the genetic susceptibility to RA.     

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.     

HLA DQA1*0501 and DRB1*0301 antigens do not independently convey susceptibility to Graves' disease

Genes of, or closely associated to, the HLA complex are assumed to contribute to the genetic predisposition of Graves' disease. The aim of this study was to investigate the presence of the HLA DQA1*0501 and DRB1*0301 antigens in Greek patients with Graves' disease. In addition, we tried to establish if there is any association between these antigens and any of the clinical manifestations of the disease. We examined 117 patients with Graves' disease and 104 healthy controls. DNA was extracted from peripheral lymphocytes and the HLA DQA1*0501 and DRB1*0301 genomic regions were amplified by PCR and characterized by hybridization with sequence specific oligonucleotides (SSO). Two of the patients had a positive family history for Graves' disease and 46 had clinical thyroid eye disease (TED). The frequencies of both DQA1*0501 and DRB1*0301 antigens were significantly increased in patients compared to controls (relative risk [RR] 4.2 and 4.5 for each antigen respectively). Neither of these two antigens was an independent risk factor for Graves' disease. However, the combination of both these HLA antigens resulted in a striking increase in the RR for development of Graves' disease especially in females (RR/F=27, RR/M=8.4). No association was found between these antigens and positive family history or the presence of TED. These data suggest that HLA DQA1*0501 and DRB1*0301 antigens are not independent risk factors for the development of Graves' disease. On the contrary, the presence of both these alleles results in a significant increase in the RR for the development of Graves' disease in the Greek population, particularly in females.     

Histocompatibility leucocyte antigens and closely linked immunomodulatory genes in autoimmune thyroid disease

OBJECTIVES: Associations between autoimmune thyroid disease and antigens of the major histocompatibility complex (MHC) have long been recognized. Graves' disease (GD) is associated with the histocompatibility leucocyte antigen (HLA) haplotype A*01-B*0801-DRB1*0301-DQA1*0501-DQB1*0201 (or B8/DR3) whereas autoimmune hypothyroidism (AIH) has been weakly associated with HLA DRB1*03, *04 and *11/*12 alleles (or DR3, DR4 and DR5). However, the presence of important immunoregulatory genes within the HLA Class II and III regions raises the possibility that these genes harbour the primary susceptibility locus. This study examines genetic variation across the MHC in UK Caucasoid subjects with autoimmune thyroid disease. PATIENTS AND METHODS: DNA extracted from venous blood samples from 215 patients with autoimmune thyroid disease (GD 135, AIH 77) and 267 control subjects was analysed. Genotyping was performed using polymerase chain reaction and sequence specific primers for HLA Class I and II alleles and polymorphisms within the TAP1, TAP2, tumour necrosis factor (TNF), lymphotoxin alpha (LTalpha), heat shock protein (HSP)70-1, HSP70-2 and HSP70-Hom genes. RESULTS: For GD, the strongest association was with DRB1*03 [56% patients positive vs. 24% controls, P = 2 x 10(-10), odds ratio (OR) 4.0]. Positive associations were also seen for DRB1*03 linked alleles, B*0801, DRB3*01/02, DQA1*05, DQB1*02 and DPB1*0101 (OR 2.3-3.4). Specific TNF and LTalpha alleles were strongly associated with GD (Pc = 3 x 10(-5) and 0.001) and weak associations were seen for HSP70-1 + 190C and HSP70-2 + 1267G polymorphisms (Pc = 0.05 and 0.01). These associations were not significant when DRB1*03 status was considered. Patients with AIH showed only a weak association with DQB1*03 (P = 0.02). CONCLUSIONS: These results show that, of the polymorphisms tested within the MHC, GD is most strongly associated with DRB1*03, and associations with other immunoregulatory genes previously described in Caucasian subjects most likely reflect linkage disequilibrium. AIH differs from GD, being less influenced by the MHC region.     

Association of the HLA-DRB1 gene with susceptibility to aortoarteritis in a Chinese Han population.

Aortoarteritis is a chronic inflammatory disease mainly affecting the aorta and its major branches. Recent immunogenetic studies indicate that certain human leucocyte antigen (HLA) alleles are significantly associated with aortoarteritis in several populations. The purpose of the present study was to investigate the relationship between the HLA-DRB1 alleles and aortoarteritis in a Chinese Han population. HLA-DRB1 genotypes were identified by PCR-SSP and PCR-RFLP in 84 Chinese patients with aortoarteritis and 102 healthy Chinese controls. It was found that the HLA-DRB1*04 allele (38.1% in patients vs. 15.7% in controls, p<0.001, relative risk (RR)=2.43) and the HLA-DRB1*07 allele (47.6% vs. 10.8%, p<0.001, RR = 4.42) were significantly associated with aortoarteritis. Furthermore, there was no significant difference in the frequency of the DRB1*0405 subtype between the patient and control groups. Thus the susceptibility to aortoarteritis in this Chinese Han population was closely related with the HLA-DRB1*04 and DRB1*07 alleles. Thus individuals with the HLA-DRB1*04 and DRB1*07 alleles may be at higher risk for developing aortoarteritis.     

The prevalence of human leukocyte antigen (HLA) DR/DQ/DP alleles in Kuwaiti children with oligoarticular juvenile idiopathic arthritis

We have determined the prevalence of human leukocyte antigen (HLA)-DR, DQ and DP alleles in Kuwaiti children with oligoarticular juvenile idiopathic arthritis (OA-JIA) and healthy controls using the PCR-SSP (sequence specific primers) method. The analysis took into account the presence of antinuclear antibodies and chronic anterior uveitis. DRB1*03 (RR 2.20, P<0.001), DRB1*08 (RR 5.280, P<0.026), DQA1*0501 (RR 1.930, P<0.001), DQB1*0304 (RR 7.920, P<0.002), DQB1*0501 (RR 3.080, P<0.007) and DPB1*0101 (RR 8.8, P<0.001) were the main HLA alleles associated with OA-JIA in Kuwaiti Arabs in this study. DRB1*03 was detected in 71% of children with positive ANA, and in 50% of children with anterior uveitis. DQA1 alleles *0501, *0103 and *0105 (P<0.001; 0.029 and 0.024 respectively) were found to be associated with OA-JIA. In contrast, DQA1*0301 and DQA1*0302 alleles appear to be protective in Kuwaiti children (RR 0.153, P<0.001 and RR 0.278, P<0.016 respectively). The DQB1 alleles *0304 and *0501 were associated with OA-JIA (P<0.002 and P<0.007 respectively). In the case of DPB1, only one allele (*0101) was associated with OA-JIA (P<0.001). Most Kuwaiti Arab patients with OA-JIA who carried a DQ or DP susceptibility allele also had an accompanying DRB1*03 or *8 allele.     

Association between HLA class Ⅱ gene and susceptibility or resistance to chronic hepatitis B

AIM: To investigate the association between the polymorphism of HLA-DRB1, -DQA1 and -DQB1 alleles and viral hepatitis B. METHODS: HLA-DRB1, -DQA1 and -DQB1 alleles in 54 patients with chronic hepatitis B, 30 patients with acute hepatitis B and 106 normal control subjects were analyzed by using the polymerase chain reaction/sequence specific primer (PCR/SSP) technique. RESULTS: The allele frequency of HLA-DRB1*0301 in the chronic hepatitis B group was markedly higher than that in the normal control group (17.31% vs 5.67 %), there was a significant correlation between them (X^2= 12.3068,PC=0.0074, RR=4.15). The allele frequency of HLA-DQAI*0501 in the chronic hepatitis B group was significantly higher than that in the normal control group (25.96 % vs 13.68 %), there was a significant correlation between them (X^2=9.2002, PC=0.0157, RR=2.87). The allele frequency of HLA-DQBI*0301 in the chronic hepatitis B group was notably higher than that in the normal control group (35.58 % vs 18.87 %), there was a significant correlation between them (x^2=15.5938, PC=0.0075, RR=4.07). The allele frequency of HLA-DRB1*1101/1104 in the chronic hepatitis B group was obviously lower than that in the normal control group (0.96 % vs 13.33 %), there was a significant correlation between them (X^2=11.9206, PC=0.0145, RR=18.55). The allele frequency of HLA-DQAI*0301 in the chronic hepatitis B group was remarkably lower than that in the normal control group (14.42 % vs30 %), there was a significant correlation between them (X^2=8.7396, PC=0.0167, RR=0.35). CONCLUSION: HLA-DRBI*0301, HLA-DQAI*0501 and HLA-DQBI*0301 are closely related with susceptibility to chronic hepatitis B, and HLA-DRB1*1101/1104 and HLA-DQAI*0301 are closely related with resistance to chronic hepatitis B. These findings suggest that host HLA class Ⅱ gene is an important factor determining the outcome of HBV infection.     

HLA class II gene frequencies in Crohn's disease: a population based analysis in Germany.

BACKGROUND--Ulcerative colitis is the only known inflammatory bowel disease associated with particular HLA alleles. Whereas the association with the HLA-DRB1*15 allele has been described in several independent studies for ulcerative colitis, no contribution of HLA alleles to susceptibility in Crohn''s disease has yet been shown. AIM--This study was designed to study the strength of association of HLA class II alleles as risk markers for Crohn''s disease in a homogenous population in Germany. PATIENTS--A total of 4251 randomly selected control subjects, and 162 unrelated subjects with Crohn''s disease were studied. Subjects were studied for their HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles. METHOD--HLA DNA typing was performed after locus specific amplification with the polymerase chain reaction and reverse dot blot hybridisation. RESULTS--The HLA-DRB1*07 was the only HLA class II allele found to be significantly associated with Crohn''s disease (relative risk (RR) = 1.9, 95% CI: 1.66 to 2.14; p = 0.0001). This association remained significant after correction for the number of DRB1 alleles compared. In patients with disease onset before 35 years the RR for the disease in HLA-DRB1*07 positive subjects was found to be higher (RR = 3.1, 95% CI: 2.44 to 3.76). The HLA-DRB1*03 was significantly decreased in frequency in Crohn''s disease (RR = 0.5, 95% CI: 0.39 to 0.61; p = 0.0028). CONCLUSION--The HLA-DRB1*07 allele provides risk for the disease especially in patients with younger ages of onset. These data also provide indirect evidence for an immunogenetically based heterogeneity 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.     

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-DQ等位基因与哮喘相关性研究

目的探讨在中国汉族哮喘家系中,HLA-DQ基因与哮喘的相关性。方法对98例哮喘家系成员,用PCR-序列特异性引物(PCR-SSP)技术对HLA-DQA1和B1进行基因分型,并与正常对照进行比较。结果发现DQA1*0101和DQA1*0601等位基因频率在哮喘患者组(40.0%,45.0%)较正常对照组(16.4%,13.4%)显著升高(χ2=6.1860,P<0.05,RR=3.39;χ2=11.6090,P<0.01,RR=5.27);DQB1*0303和DQB1*0601等位基因频率在哮喘患者组(55.0%,47.5%)较正常对照组(13.7%,13.7%)显著升高(χ2=15.7400,P<0.01,RR=7.68;χ2=10.9300,P<0.01,RR=5.69)。同时发现HLA-DQB1*0201等位基因频率在对屋尘螨抗原特异性IgE反应哮喘家系成员(39.4%)较家系中非特应症者（12.0％）显著高频表达(t=2.3825,P<0.05)。结论HLA-DQA1*0101,*0601和DQB1*0303,*0601是哮喘遗传易感等位基因;HLA-DQB1*0201限定对屋尘螨抗原特异性IgE反应。     

Relationship of human leukocyte antigen class Ⅱ genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients

AIM: To study the relationship of human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles with the genetic susceptibility to HBV infection and the response to interferon (IFN) in HBV-infected patients.METHODS: Low-resolution DNA typing kit was used to determine HLA-DR-1 and -DQB1 genes in 72 patients with chronic hepatitis B (CHB) and HLA-DRB1 in 200 healthy people ready to donate their bone marrow in Shanghai.Among CHB patients, 35 were treated with IFNα-1b for 24 wk.RESULTS: The frequencies of HLA-DRB1*06, DRB1*08and DRB1*16 alleles in 72 patients were higher than in 200 healthy people (2.08% vs0%, OR = 3.837, P= 0.018;11.11% vs5.50%, OR = 2.148, P= 0.034; and 6.94% vs 3.00%, OR = 0.625, P = 0.049, respectively); whereas that of DRB1*07 allele was lower (2.78% vs 7.75%,OR = 0.340, P = 0.046). The frequency of HLA-DRB1* 14allele was higher in 11 responders to IFN compared with 24 non-responders (18.18% vs2.08%, OR = 10.444,P = 0.031), whereas that of DQB1*07 allele was inverse (9.09% vs 37.50%, OR = 0.167, P= 0.021).CONCLUSION: The polymorphism of HLA class Ⅱ may influence the susceptibility to HBV infection and the response to IFN in studied CHB patients. Compared with other HLA-DRB1 alleles, HLA-DRB1*06, DRB1*08, and DRB1*16 may be associated with chronicity of HBV infection, HLA-DRB1*07 with protection against HBV infection, and HLA-DRB1*14 allele may be associated with a high rate of the response of CHB patients to IFN treatment.Compared with other HLA-DQB1 alleles, HLA-DQB1*07 may be associated with low response rate to IFN.     

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.     

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.     

Relationship of human leukocyte antigen class Ⅱ genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients

AIM: To study the relationship of human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles with the genetic susceptibility to HBV infection and the response to interferon (IFN) in HBV-infected patients. METHODS: Low-resolution DNA typing kit was used to determine HLA-DR-1 and -DQB1 genes in 72 patients with chronic hepatitis B (CHB) and HLA-DRB1 in 200 healthy people ready to donate their bone marrow in Shanghai. Among CHB patients, 35 were treated with IFNa-lb for 24 wk. RESULTS: The frequencies of HLA-DRB1~*06, DRB1~*08 and DRB1~*16 alleles in 72 patients were higher than in 200 healthy people (2.08% vs0%, OR=3.837, P=0.018; 11.11% vs 5.50%, OR=2.148, P=0.034; and 6.94% vs 3.00%, OR=0.625, P=0.049, respectively); whereas that of DRB1~*07 allele was lower (2.78% vs 7.75%, OR=0.340, P=0.046). The frequency of HLA-DRB1~*14 allele was higher in 11 responders to IFN compared with 24 non-responders (18.18% vs 2.08%, OR=10.444, P=0.031), whereas that of DQB1*07 allele was inverse (9.09% vs 37.50%, OR=0.167, P=0.021). CONCLUSION: The polymorphism of HLA class II may influence the susceptibility to HBV infection and the response to IFN in studied CHB patients. Compared with other HLA-DRB1 alleles, HLA-DRB1~*06, DRB1~*08, and DRB1~*16 may be associated with chronicity of HBV infection, HLA-DRB1~*07 with protection against HBV infection, and HLA-DRB1~*14 allele may be associated with a high rate of the response of CHB patients to IFN treatment. Compared with other HLA-DQB1 alleles, HLA-DQB1~*07 may be associated with low response rate to IFN.     

Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences

OBJECTIVE: To examine the entire HLA region for loci (other than the DRB1 locus) associated with rheumatoid arthritis (RA) susceptibility, by typing HLA-DRB1 alleles and multiple single-nucleotide polymorphisms (SNPs) in the Japanese population. METHODS: The HLA-DRB1 alleles and 88 SNPs distributed over the HLA gene complex were genotyped, for 828 patients with RA and 1,032 control subjects. The data were evaluated for linkage disequilibrium, and case-control associations were analyzed in 2 ways, in the presence or absence of the disease-susceptibility DRB1 allele, to detect loci independent of the DRB1 allele. RESULTS: HLA-DRB1 alleles *0405, *0401, *0901, *0101, *1401, *1602, *0403, and *1405 were significantly associated with RA in the Japanese population. The smallest P value (P = 1.4 x 10(-27)) was observed in association with an intronic SNP of the NOTCH4 gene, which was due to strong linkage disequilibrium with the HLA-DRB1 allele. A strong association that was independent of HLA-DRB1 shared epitope alleles was observed in 2 SNPs: one in the intron of the MICA gene, the other in the intron of the HLA-DQB2 gene. Their association with RA, independent of HLA-DRB1 shared epitope alleles, was suggestive (P = 0.0024 [corrected P (P(corr)) = 0.068, and P = 0.00037 [P(corr) = 0.012], respectively). CONCLUSION: These findings suggest that 1 or more other loci besides the HLA-DRB1 or other DRB1 (non-shared epitope, non-*0901) alleles are involved in RA susceptibility/protection.     

抗甲状腺药物致白细胞减少易感性与HLA-DRB1基因多态性及ANCA的关联性

目的 研究安徽地区汉族Graves病患者使用抗甲状腺药物(ATD)致白细胞减少的易感性与HLA-DRB1基因多态性及抗中性粒细胞胞浆抗体(ANCA)的相关性.方法 采用聚合酶链反应-序列特异性引物方法(PCR-SSP)检测76例ATD致白细胞减少的Graves病患者、98例ATD治疗后白细胞正常患者和230名健康对照者的等位基因HLA-DRB1* 08032、DRBI* 1501、DRB1*0901的频率.采用间接免疫荧光法(IIF)检测白细胞减少组和白细胞正常组Graves病患者的血清ANCA阳性率.结果 (1)与健康对照组及细胞正常组比较,白细胞减少组患者等位基因DRB1 * 08032、DRB1*1501频率明显增加(OR分别为3.06,1.77,4.03和2.28,均P＜0.05),DRB1* 0901频率明显减低(OR为0.33和0.43,P＜0.05).(2)与甲巯咪唑治疗后白细胞正常组患者比较,甲巯咪唑致白细胞减少组患者血清ANCA阳性率明显增加(x2 =4.878,P＜0.05).(3)与未携带等位基因DRB1*08032和DRB1*1501的患者比较,携带者血清中ANCA阳性率明显增加(x2为5.682,5.429,4.009和4.549,均P＜0.05).结论 等位基因HLA-DRB1*08032、HLA-DRB1*1501可能是安徽地区汉族人ATD致白细胞减少的易感基因;HLA-DRB1*0901可能是其保护基因或抗性基因.免疫反应可能参与了ATD致白细胞减少的发生.免疫反应的发生可能存在遗传易感性.