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.     

Association of human leukocyte antigen class II genes with autoantibody profiles, but not with disease susceptibility in Japanese patients with systemic sclerosis.

OBJECT: To examine the role of human leukocyte antigen (HLA) class II genes in the development of systemic sclerosis (SSc) as well as in the clinical and serologic expression of SSc in patients. METHODS: HLA-DRB1, DRB3, DRB4, DQB1, and DPB1 alleles were determined by genotyping; and serum antinuclear antibodies were identified using indirect immunofluorescence, double immunodiffusion and immunoprecipitation. PATIENTS: One hundred and five Japanese patients with SSc and 104 race-matched healthy controls. RESULTS: Frequencies of DRB1 and DQB1 alleles were not different between SSc patients and healthy controls, while DPB1*0901 was marginally increased in SSc patients. In contrast, SSc-related autoantibodies were closely associated with the clinical features. HLA class II genes were detected as follows: anti-DNA topoisomerase I antibody with diffuse cutaneous involvement, pulmonary fibrosis, and DRB1*1502-DQB1*0601-DPB1*0901; anti-U1RNP antibody with overlapping features of lupus and/or myositis and DRB1*0401/*0802-DQB1*0302; and anticentromere antibody with limited cutaneous involvement and DRB1*0101-DQB1*0501-DPB1*0402. In the analysis of the association of HLA class II and the clinical features in SSc patients significant differences were obtained only for the increased frequencies of arthritis and rheumatoid factor in patients with DRB1*0405 compared to those without. CONCLUSION: HLA class II genes strongly influence the production of SSc-related autoantibodies rather than the development of SSc. In addition, SSc is a composite disease of distinctive subsets defined by serum autoantibodies, which have specific clinical and HLA class II associations.     

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.     

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.     

Genetics of the HLA Region in the Prediction of Type 1 Diabetes

Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40–50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated “DR3”) and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; abbreviated “DR4”). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.7–20.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.12–7.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated “DR2”; OR = 0.03; 95% CI, 0.01–0.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by class I allele B*39:06 (OR =10.31; 95% CI, 4.21–25.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoantibodies directed against islet-cell antigens. Inclusion of additional moderate HLA risk haplotypes may help identify the majority of children with T1D before the onset of the disease.     

HLA-DQB1 DPB1 alleles in Japanese patients with adult-onset Still’s disease

Abstract

Objective: HLA class II alleles are major determinants of genetic predisposition to rheumatic diseases. Predisposing effects of HLA had been suggested in AOSD, however, ethnic differences may account for variations in AOSD association with HLA. We determined the contribution of HLA-DQB1, DPB1 alleles to susceptibility to Adult-onset Still’s disease (AOSD) in the Japanese population.

Methods: HLA-DQB1 and DPB1 alleles were analyzed in 87 Japanese patients with AOSD and 413 Japanese healthy subjects.

Results: We found significant association between HLA-DQB1*06:02 (Pc?=?0.010, odds ratio: 2.54) and AOSD, whereas there was no association between the DQB1*06:02 allele and disease phenotypes of AOSD. Moreover, we did not find a predisposing effect of the HLA-DPB1 allele to AOSD. Haplotype analysis showed that presence of DRB1*15:01–DQB1*06:02 was associated with Japanese patients with AOSD. However, conditional logistic regression tests were unable to demonstrate independent association between DRB1*1501 or DQB1*0602 and AOSD.

Conclusions: Our results show significant association between AOSD and the HLA DQB1*06:02 allele, and between the DRB1*1501–DQB1*06:02 haplotype and AOSD susceptibility. These findings suggest that genetic susceptibility to AOSD depends on the genotype combinations of HLA DRB1 and DQB1 alleles.     

Clinical,serologic, and immunogenetic studies in childhood-onset systemic lupus erythematosus

Objective. To determine the frequency of systemic lupus erythematosus (SLE)—associated clinical manifestations, autoantibodies, and HLA class II alleles in a large cohort of patients with childhood-onset SLE. Methods. Eighty children with SLE onset before age 18 (27 before age 11) were studied for the frequency of renal, neuropsychiatric, and hematologic complications as well as for anti—native DNA, Ro, La, Sm, and U1 RNP autoantibodies. HLA—DR, DQ, and DP alleles were determined by oligotyping. The results were compared with findings in 213 adults with SLE onset at or after age 18 years. Results. Renal involvement was more frequent in those with childhood-onset SLE, especially those with onset before age 11 (82%, compared with 53% in adults). Anti—U1 RNP was more common in American blacks with SLE onset before age 18. HLA—DRB1*0301, DQA1*0501, DQB1*0201 was more common in Caucasians and DRB1*1503, DRB5*0101, DQA1*0102, DQB1*0602 in American blacks, regardless of age at SLE onset. Anti-Sm autoantibodies were most highly associated with HLA—DQA1*0102 and DQB1*0602. Conclusion. While childhood-onset SLE shares many immunogenetic and serologic similarities to adultonset disease, important clinical differences nevertheless exist in children with this disease.     

HLA-DR-DQ haplotypes and genotypes in Finnish patients with rheumatoid arthritis

OBJECTIVES: To elucidate the contribution of HLA-DR-DQ haplotypes and their genotypic combinations to susceptibility to rheumatoid arthritis, and to evaluate the various models for HLA associated risk for the disease in a series of Finnish patients. METHODS: 322 Finnish patients with rheumatoid arthritis were typed for common north European HLA-DR-DQ haplotypes and compared with a series of 1244 artificial family based control haplotypes. RESULTS: The association of the so called shared epitope (SE) haplotypes (DRB1*0401, *0404, *0408, and *01) with rheumatoid arthritis was confirmed. The DRB1*0401 haplotypes carried a far stronger risk for the disease than the (DRB1*01/10)-(DQA1*01)-DQB1*0501 haplotypes. Seven protective HLA haplotypes--(DRB1*15)-(DQA1*01)-DQB1*0602; (DRB1*08)-(DQA1*04)-DQB1*04; (DRB1*11/12)-DQA1*05-DQB1*0301; (DRB1*1301)-(DQA1*01)-DQB1*0603; (DRB1*1302)-(DQA1*01)-DQB1*0604; (DRB1*07)-DQA1*0201-DQB1*0303; and (DRB1*16)- (DQA1*01)-DQB1*0502--were identified. In accordance with the reshaped shared epitope hypothesis, all the protective DRB1 alleles in these haplotypes share either isoleucine at position 67 or aspartic acid at position 70 in their third hypervariable region motif. However, differences in the disease risk of haplotypes carrying the same DR but different DQ alleles were also found: (DRB1*07)-DQA1*0201-DQB1*0303 was protective, while (DRB1*07)-DQA1*0201-DQB1*02 was neutral. The same haplotypes carried different risks for rheumatoid arthritis depending on their combination in genotypes. CONCLUSIONS: When assessing the influence of HLA genes on the susceptibility to rheumatoid arthritis, not only should the HLA-DR or -DQ alleles or haplotypes be unravelled but also the genotype. The effect of HLA class II region genes is more complicated than any of the existing hypotheses can explain.     

Human leukocyte antigen class II alleles and rubella-specific humoral and cell-mediated immunity following measles-mumps-rubella-II vaccination

We examined associations between human leukocyte antigen (HLA) class II genes and both rubella-specific immunoglobulin G antibodies and lymphoproliferative responses after measles-mumps-rubella-II (MMR-II) vaccination, in a population-based sample of 346 schoolchildren. The DPB1*0301, DPB1*0401, DPB1*1301, and DPB1*1501 alleles were significantly associated with rubella vaccine-induced antibodies. Alleles suggestive of being positively associated with rubella-specific lymphoproliferative stimulation indices were DPB1*0301, DQB1*0501, DRB1*0101, and DRB1*1104. Conversely, the DPB1*0401, DPB1*1001, DPB1*1101, DQB1*0202, and DRB1*0701 alleles were negatively associated with rubella-specific lymphoproliferation. This study of HLA class II-restricted humoral and cellular immune responses to rubella provides significant insight into mechanisms of vaccine response and new vaccine development.     

HLA class II genotypes associated with chronic hepatitis C virus infection and response to α‐interferon treatment in Poland

Abstract: Aims/Background: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II‐encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. Methods: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR‐protocol in 129 unrelated patients with chronic hepatitis C (anti‐HCV and HCV‐RNA positive) and 103 healthy unrelated racially‐matched control subjects. Fifty‐five patients were treated with α‐interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non‐responders. Results: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR‐DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501‐DQA1*01‐DQB1*0602 (24.0% vs. 12.6%; p=0.027) and DRB1*0701‐DQA1*0201‐DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to α‐interferon treatment (41.4% vs. 12.6%; p=0.00048). Conclusions: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701‐DQA1*0201‐DQB1*02 haplotype is associated with both chronic infection and response to α‐interferon. Interestingly, the same haplotype is reportedly associated with non‐response to hepatitis B vaccination.     

Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5'-flanking region of the TNFalpha gene and HLA genes

OBJECTIVE: To study polymorphisms in the 5'-flanking promoter/enhancer region of the tumor necrosis factor alpha (TNFalpha) gene and in the coding regions of HLA class I and class II genes, in order to better understand the genetic background of juvenile rheumatoid arthritis (JRA). METHODS: One hundred eleven Japanese JRA patients (50 with systemic disease, 29 with pauciarticular disease, and 32 with polyarticular disease) and 575 healthy Japanese subjects were examined for the allele frequencies of the TNFalpha, HLA-A, and HLA class II (DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1) genes, by DNA typing using the polymerase chain reaction-sequence-specific oligonucleotide probe method. RESULTS: The frequencies of the polymorphic allele at positions -1,031 (T to C substitution, termed -1,031C), -863 (C to A, termed -863A), and -857 (C to T, termed -857T) of the TNFalpha gene in patients with systemic JRA, but not in those with polyarticular or pauciarticular JRA, were significantly higher than in the healthy controls. The allele frequencies of DRB1*0405 and DQB1*0401 in systemic JRA, but not in the other JRA types, were significantly higher than in controls. Linkage analysis showed that the presence of both the TNFalpha -857T allele and DRB1*0405 yielded a significantly increased odds ratio (3.84), while the presence of only 1 of them did not yield a high odds ratio (0.87 and 1.58). CONCLUSION: The -1,031C/-863A allele and the -857T allele of the TNFalpha gene, both of which are related to high production of tumor necrosis factor alpha, are associated with systemic JRA. The -857T allele may enhance the effect of the DRB1*0405/DQB1*0401 haplotype in predisposing to development of systemic JRA.     

Interrelationship of major histocompatibility complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis

Objective. To examine interrelationships among myositis subsets, autoantibodies, and major histocompatibility complex (MHC) class II alleles across ethnic lines, and to localize genetic susceptibility (presence of HLA–DR versus DQ) to myositis within the MHC class II region. Methods. MHC class II alleles (HLA–DRB1, DQA1, and DQB1, detected by DNA oligotyping) and myositis-specific autoantibodies (MSA) were determined in 224 patients with various myositis syndromes, including 89 whites, 89 African-Americans, 25 Mexican-Americans, and 21 Japanese. Results. Anti–Jo-1 (histidyl–transfer RNA [tRNA] synthetase) and other MSAs (anti–PL-12, anti–PL-7, anti-OJ, anti-EJ, anti-KJ, anti-tRNA, and anti–signal recognition particle) were equally distributed among the races, but occurred more often in patients with polymyositis (PM) than in those with dermatomyositis (DM) or other myositis syndromes. MSA frequencies were significantly positively associated with anti–Ro (SS-A) (P = 0.002), and significantly negatively associated with anti–U1 RNP (P = 0.003). Frequencies of the HLA–DRB1*0301 (DR3), DQA1*0501, and DQB1*0201 (DQ2) alleles (and haplotype) were each increased in white patients with myositis, especially those with PM, but most strikingly in those with MSAs. However, in the other ethnic groups, except the Japanese group, only frequencies of HLA–DQA1*0501 and the structurally similar DQA1*0401 alleles were significantly increased. The presence of HLA–DQA1*0501 or *0401 was most significantly associated with anti–Jo-1, anti–PL-12, and other MSAs, compared with myositis patients without MSAs (P = 0.0008, P_corr = 0.01, odds ratio [OR] = 3.7), and with normal, ethnically matched controls (P = 3 × 10⁻⁷, P_corr = 1 × 10⁻⁶, OR = 6.5). Among MSA-positive patients who were negative for HLA–DQA1*0501 and *0401, including Japanese patients, the HLA–DQA1*0101 and *0103 alleles predominated. In addition, there appeared to be a negative association of the HLA–DR2 alleles (DRB1*1501 and *1503) with PM (P = 0.007, P_corr not significant, OR = 0.39), but not with DM or myositis overall. Conclusion. By transracial gene mapping, genetic susceptibility to anti–Jo-1 and other MSAs in patients with myositis can be localized within the MHC region to the HLA–DQA1 locus.     

Alteration of the influences of HLA classes I and II alleles on the perinatal hepatitis B virus infection after immunoprophylaxis in Korean children.

Some HLA alleles are known to be associated with hepatitis B virus (HBV) persistence. In order to find out the relationship between HLA and perinatal HBV infection after prophylaxis, we typed HLA classes I and II in 38 HBeAg-positive mothers, their children (19 succeeded and 19 failed in prophylaxis) and 198 HBsAg-negative healthy controls. HLA-B35 (RR=2.8, p<0.03), Cw*07 (RR=2.7, p<0.02), DRB1*07 (RR=3.6, p<0.006), DQA1*02 (RR=3.6, p<0.02) and DQB1*02 (RR=2.4, p<0.05) alleles were higher and DRB1*13 (RR=0.3, p<0.03) and DPB1*0401 (RR=0.1, p<0.01) alleles were lower frequencies in HBeAg-positive mothers than in the control. In failed children to the perinatal HBV prophylaxis, HLA-Cw*0303 allele was significantly higher (p<0.05) and DPB1*0202 allele was lower (p<0.03) than in succeeded children. These results suggest the influences of certain HLA alleles on naturally acquired chronic HBV infection may be changed by perinatal HBV prophylaxis.     

Multicenter cooperative study of HLA class II alleles in Japanese patients with systemic lupus erythematosus

The relation between HLA class II alleles and clinical findings were examined in Japanese patients with systemic lupus erythematosus (SLE). In 284 patients with multicenter SLE, HLA class II alleles were examined using the DNA typing method, and the results were compared with the clinical findings. The frequency of DRB1^*0101 and DQB1^*0501 significantly increased in male patients, and that of DRB1^*0803 significantly increased in patients over 50 years of age. In relation to cutaneous manifestations, there were positive photosensitivity associations with DQA1^*0101 and/or DQA1^*0301, malar rash with DQA1^*0101 and/or DRB1^*0901, alopecia with DQA1^*0101, skin ulcers with DRB1^*0401, and oral ulcers with DQA1^*0301. In addition, there were also positive associations of myalgia with DRB1^*1406 and negative associations of aseptic bone necrosis with DQA1^*0601, and hepatomegaly with DRB1^*0405 and/or DQA1^*0401. In relation to laboratory findings, there were positive associations of hemolytic anemia with DRB1^*1402 and negative associations of leukopenia with DQA1^*0601, lymphopenia with DQA1^*0301, and proteinuria with DRB1^*0901. Interestingly, DQA1^*0101 and/or DQB1^*0501 were significantly associated with WHO classification type II rather than type IV. In patients with SLE, some HLA types related to clinical or laboratory findings. Received: March 4, 2000 / Accepted: August 15, 2000     

HLA DPB1*0201 gene confers disease susceptibility in japanese with childhood onset type I diabetes, independent of HLA-DR and DQ genotypes

HLA is an important etiologic genetic factor in Type I diabetes and specific HLA-class II genes are closely related to the onset of the disease. Many differences in the patterns of susceptible and resistant DRB1, DQA1, and DQB1 genes have been observed among various ethnic groups. We have previously shown that DRB1*0405, DRB1*0901 and DQA1*0301-DQB1*0302 were the major susceptible alleles or haplotype to Type I diabetes while DR-DQ haplotype studies suggested the important role of DR and DQ alleles in susceptibility and resistance in Japanese patients. Based on the analysis of 90 Japanese patients with childhood onset Type I diabetes and 136 unrelated healthy Japanese controls by polymerase chain reaction-restriction fragment polymorphism method (PCR-RFLP), we report here the association of Type I diabetes with DPB1*0201 (relative risk = 2.29; Pc = 0.027) in this population. Comparison of linkage disequilibrium patterns between patients and controls showed that the significantly high prevalence of DPB1*0201 among patients cannot be attributed simply to linkage disequilibrium with susceptible DRB1 alleles and DQA1-DQB1 haplotypes. Our results suggest that in addition to alleles at the DRB1, DQA1, DQB1 loci, polymorphism at DPB1 locus also influences the risk of Type I diabetes.     

Association of hla–dr4-dw15 (drb1*0405) and dr10 with rheumatoid arthritis in a spanish population

Objective. To analyze the associations of HLA class II antigens with rheumatoid arthritis (RA) in a Spanish population. Methods. We used DNA oligotyping to determine DR types, DQA1 and DQB1 alleles, and DR4 variants in 70 unrelated seropositive RA patients and 189 healthy controls living in Spain. Results. A significantly higher frequency of DR4 was seen in RA patients compared with controls (relative risk [RR] = 2.40). The DR10 specificity correlated most strongly with disease susceptibility (RR = 3.84). A significant decrease in the frequency of DR7 was observed in the RA patients (RR = 0.48). DR4-Dw15 (DRB1*0405) was found to be the unique DR4 allele associated with RA (RR = 4.27, P < 0.05), whereas Dw4 (DRB1*0401) and Dw14 (DRB1*0404/0408) showed no association, and both D10 (DRB1*0402) and Dw13 (DRB1*0403/0407) were negative risk factors for the disease. Approximately one-third of the cases of RA could not be explained by the “shared epitope” hypothesis. Investigation of the DQ alleles associated with DR4 showed that the haplotype Dw15-DQ8 (DRB1*0405-DQB1*0302) was a susceptibility factor for RA (RR = 6.36, P < 0.05). Conclusion. Our results suggest that HLA class II alleles involved in RA susceptibility can vary among different Caucasian populations.     

Rheumatoid arthritis in southern Spain: toward elucidation of a unifying role of the HLA class II region in disease predisposition

OBJECTIVE: To evaluate the contributions of HLA-DQ and -DR polymorphisms to susceptibility to rheumatoid arthritis (RA) in a population in southern Spain, and to compare the value of the shared epitope (SE) and RA protection (RAP) models in accounting for the HLA class II region's contribution to RA predisposition. METHODS: One hundred sixty RA patients and 153 healthy controls were typed for HLA-DRB1 and -DQB1 using high-resolution DNA techniques. Distributions of predisposing DRB1 alleles in patients and control subjects according to the SE model were compared with distributions of predisposing DQ and protective DERAA-positive DRBI alleles according to the RAP model. RESULTS: DQ3 (DQBI*03 and *04 combined with DQA1*03) and DQ5 (DQB1*0501/DQA1*0101) alleles predisposed individuals to RA independently of SE-positive DRB1 alleles. DQ3/3-homozygous individuals had the strongest risk of developing RA. DQ3 molecules predisposed to RA more than did DQ5 molecules. The weaker predisposition mediated by DQ5 included the DRB1*1001-carrying haplotype; no DRB1*1001-homozygous patients were observed. DRBI*0401 played a unique role in the contribution of DQ3-DR4 haplotypes to RA, in spite of its low frequency in southern Spain. CONCLUSION: The low prevalences of RA and of mild disease observed in Spain, and in southern Europe in general, can be explained in great part by the low frequency of DQ3-DR4 haplotypes, especially those carrying DRB1*0401. However, the overall distribution of HLA-DQ and -DR alleles in RA patients compared with control subjects is similar to that in other European and North American populations. A model involving both DQ and DR can best account for the contribution of HLA to RA.     

Transfusion-Associated Graft-versus-Host Disease in an Immunocompetent Patient following Cardiac Surgery

Objectives: We determined which of the 22 blood components obtained from unrelated donors and transfused to an apparently immunocompetent patient following open heart surgery caused transfusion-associated graftversus-host disease (TA-GVHD). Methods: Serologic and molecular methods were used to type the donors, the patient's family members, and the patient's postmortem tissues for HLA and a genetic marker on chromosome 17. Results: Two donors were homozygous for the HLA class I antigens A1 B8, for which the patient was heterozygous. Both donors were heterozygous, not homozygous as expected, for the class II alleles. One of them had the same class II alleles as the patient (DRB1*0301, DRB3*0101/DRB1*0404, DRB4*0103). The patient's tissues were chimeric for restriction fragments at 17 p 13 of this donor. Conclusion: One-way HLA match leading to TA-GVHD can be caused by donor blood that is homozygous for class I and heterozygous for class II alleles. Two blood components given to our patient had such one-way HLA match. Class II alleles of the lymphocytes in one component were identical with those of the recipient and caused TA-GVHD. Class II alleles of the lymphocytes in the other component differed from those of the recipient and were eliminated either by the immune system of the patient or the lymphocytes that caused the TA-GVHD (graft versus graft).     

HLA and T cell receptor β-chain DNA polymorphisms identify a distinct subset of patients with pauciarticular-onset juvenile rheumatoid arthritis

Objective. To evaluate and extend upon a reported association of a T cell receptor (TCR) V _β coding region polymorphism with pauciarticular-onset juvenile rheumatoid arthritis (JRA). Methods. TCR V _β6.1 genotypes and haplotypes in JRA and control groups were determined by DNA amplification. Results. Haplotypes of the V _β6.1 gene which encode a nonfunctional form of V _β6.1 were significantly associated with pauciarticular JRA in patients possessing the HLA–DQA1*0101 allele (P = 0.0073). Conclusion. A TCR V _β gene segment in the vicinity of V _β6.1, possibly V _β6.1, is apparently involved in the pathogenesis of pauciarticular-onset JRA in DQA1*0101-positive individuals.     

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.