Familial juvenile onset psoriasis is associated with the human leukocyte antigen (HLA) class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303: a population- and family-based study

To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.     

An increased risk of Crohn's disease in individuals who inherit the HLA class II DRB3*0301 allele

The role of inflammatory T cells in Crohn's disease suggests that inherited variations in major histocompatibility complex (MHC) class II genes may be of pathogenetic importance in inflammatory bowel disease. The absence of consistent and strong associations with MHC class II genes in Caucasian patients with inflammatory bowel disease probably reflects the use of less precise typing approaches and the failure to type certain loci by any means. A PCR-sequence-specific oligonucleotide-based approach was used to type individual alleles of the HLA class II DRB1, DRB3, DRB4, and DRB5 loci in 40 patients with ulcerative colitis, 42 Crohn's disease patients, and 93 ethnically matched healthy controls. Detailed molecular typing of the above alleles has previously not been reported in patients with inflammatory bowel disease. A highly significant positive association with the HLA-DRB3*0301 allele was observed in patients with Crohn's disease (P = 0.0004) but not in patients with ulcerative colitis. The relative risk for this association was 7.04. Other less significant HLA class II associations were also noted in patients with Crohn's disease. One of these associations involved the HLA-DRB1*1302 allele, which is known to be in linkage disequilibrium with HLA-DRB3*0301. These data suggest that a single allele of an infrequently typed HLA class II locus is strongly associated with Crohn's disease and that MHC class II molecules may be important in its pathogenesis.     

DRB1*15 and DRB1*03 extended haplotype interaction in primary Sj?gren's syndrome genetic susceptibility

OBJECTIVE: Sj?gren's syndrome (SS) is a chronic autoimmune disease with a genetic component. Among the genetic factors, the role of HLA class II genes has been suggested and a positive association with DRB1*03 allele has been described. However, there is no consensus on a unique HLA locus for this disease nor on the role of the HLA gene product in the disease. The aim of this study was to analyse prospectively MHC region involvement in the genetic susceptibility to SS by studying DRB1, DQB1, DPB1, TAP1, TAP2 genes and TNF microsatellites in a population of 45 primary SS patients. METHODS: All the polymorphisms studied were analysed at the genomic level using PCR-based methodologies. RESULTS: Concerning HLA class II alleles, the highest relative risk to develop the disease was associated with the DRB1*15-DRB1*0301 heterozygous genotype (17.8% vs 3.5% in controls - pc < 0.005, OR = 5.96). Analysing other genes located on the same region allowed us to further determine the DRB1 haplotypes at risk. For instance, the DRB1*0301 haplotype involved in the genetic susceptibility to SS was more often associated with the DPB1* 0201 and TNF-a2 alleles in SS patients than in controls. Moreover, all the DRB1*15-DRB1*0301 SS patients were TAP1-0101, TAP2-0101 homozygous, allowing us to deduce the extended genotype at risk as DRB1*15, TAP1-0101, TAP2-0101/DRB1*0301, TAP1-0101, TAP2-0101 which was carried by only 3 controls out of the 130 tested (p < 0.01, OR = 6.68). CONCLUSION: This study confirmed the role of the MHC region in the susceptibility to Sj?gren's disease, and for the first time suggests a synergistic interaction between two HLA-DRB1 extended haplotypes in the genetic mechanisms controlling the disease.     

HLA-DRB1*0701 and DRB1*1401 are associated with genetic susceptibility to psoriasis vulgaris in a Taiwanese population

We analysed the allelic frequencies of class II human leucocyte antigen (HLA)-DRB1, DQA1, DQB1 and DPB1 by polymerase chain reaction/sequence-specific oligonucleotide probe hybridization typing in 76 Taiwanese psoriasis vulgaris (PSV) patients and 238 Taiwanese non-psoriatic controls. The analysis revealed the following: (i) the DRB1*0701 allele was positively associated with PSV (relative risk, RR = 6.4, corrected P-value, Pc < or = 0.001); (ii) the DRB1*1401 allele was positively associated with type I PSV (age at onset < 40 years) (RR = 3.5, Pc < or = 0.001); (iii) the DQA1*0501 allele was negatively associated with PSV (RR = 0.4, Pc < or = 0.001); (iv) there was no significant association of HLA-DP genes with PSV; and (v) there was a strong association of beta-chain phenylalanine at position 37 (Phe 37) and glutamate or glutamine at position 74 (Glu 74/Gln 74) with PSV (RR = 3.5, Pc < or = 0.001 for the association of Phe 37 with PSV: RR = 2.2, Pc < or = 0.001 for the association of Glu 74/Gln 74 with PSV). The positive association between PSV and the DRB1*0701 allele is consistent with previous reports. The negative association of the DQA1*0501 allele is reported only in Finland, whereas the positive association between PSV and the DRB1*1401 allele has never been described before. Trans-racial studies may shed further light on the association of class II HLA alleles or other closely linked genes with the development of PSV. Phe 37 (a large, non-polar amino acid) and Glu 74/Gln 74 (both negatively charged amino acids) were the polymorphic residues in pockets 9 and 4, respectively, of the beta-chain, which may have increased their affinity for the small non-polar amino acids and basic amino acids of the psoriatic antigen peptide, thereby activating the T lymphocytes. This finding may facilitate the identification of a psoriatic antigen.     

On the HLA-DQ(alpha 1*0501, beta 1*0201)-associated susceptibility in celiac disease: a possible gene dosage effect of DQB1*0201

The HLA-associated susceptibility to develop celiac disease (CD) seems mainly to be conferred by a particular HLA-DQ heterodimer encoded by the DQA1*0501 and DQB1*0201 genes either in cis or in trans position. To study the possible influence of DRB1 or other DQA1 and DQB1 alleles on the CD susceptibility conferred by these DQ genes, we performed genomic HLA typing of 94 CD patients, selected those who carried at least one copy of the DRB1*0301-DQA1*0501-DQB1*0201 haplotype (N = 89) and compared them to 47 random, healthy Norwegians matched with the patients to carry at least one copy of the above haplotype. We found an excess of DQB1*0201 homozygosity in the patients. This was due to an increased frequency of the DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*0701-DQA1*0201-DQB1*0201 haplotypes present on the other chromosome. We propose that, in individuals carrying the DQA1*0501 and DQB1*0201 alleles, the presence of a second copy of the DQB1*0201 allele increases susceptibility to CD.     

Self-reported energy intake and energy expenditure in elderly women

HLA-DRB1, -DQB1 and -DPB1 allele frequencies were investigated in a sample of the Slovak population by PCR-SSP and PCR-RFLP methods. The most frequent DRB1 alleles were DRB1*1101-5 (0.2038), DRB1*0701-2 (0.1423), and DRB1*1501-2 (0.1231). The most rare alleles found were DRB1*0901 (0.0038), and DRB1*1201 (0.015). The most common DQB1 alleles were DQB1*0301 (0.2448), DQB1*0201 (0.2098), and DQB1*0501 (0.1119), respectively. The alleles with the least occurrence rate were DQB1*0601 (0.0035) and DQB1*0401 (0.007). The most common DPB1 alleles found were DPB1*0401 (0.4329), DPB1*0402 (0.2089), and DPB1*0201 (0.1438), respectively. The least frequent alleles were DPB1*0601, *1101, and *1501 (0.0034). Allele frequencies found in our study were compared to those in Czech, Austrian, and German populations. No statistically significant differences were observed.     

Association to HLA-DRB1*08, HLA-DPB1*0301 and homozygosity for an HLA-linked proteasome gene in juvenile ankylosing spondylitis

To assess the role of HLA genes other than those encoding B27 in predisposing to JAS and AAS, we analyzed the distribution of B*4001, as well as the DRB1, DPB1, and LMP2 alleles, using PCR-based techniques in 63 JAS and 44 AAS patients (all B27 positive). The NBMDR (N = 4724) provided a source of controls matched with the patients for B27 (or other markers when necessary). We found an increase of the B*4001, DRB1*08, and DPB1*0301 alleles, as well as the LMP2 b/b genotype (the latter was most pronounced among patients with acute iridocyclitis), in JAS compared to B27-positive controls. The increase of DRB1*08 and DPB1*0301 was due to an increase of DRB1*08 and DPB1*0301 in combination, whereas the association with B*4001 could be due to linkage disequilibrium with LMP2b. None of these associations were detected in AAS. We conclude that in JAS, in addition to the association to B27, there are also weaker but distinct associations to the DRB1*08, DPB1*0301 alleles and homozygosity for LMP2b.     

Urokinase-type plasminogen activator and plasminogen activator inhibitors (PAI-1 and PAI-2) in extracts of invasive cervical carcinoma and precursor lesions

BACKGROUND: HFE mutations are associated with hereditary haemochromatosis. However, a simple method capable of demonstrating the cis/trans arrangement of alleles is lacking, and linkage disequilibrium between HFE alleles and classic HLA loci is unknown. These are important issues as the pathogenic role of the mutations is not known. AIMS: To develop a simple method of genotyping HFE mutations suitable for clinical use in addition to large disease studies. PATIENTS: A total of 330 Caucasoid cadaveric organ donor controls were examined. Ten individuals previously HLA-H genotyped by polymerase chain reaction using restriction fragment length polymorphism (PCR-RFLP) were also examined to validate the method. METHODS: A simple polymerase chain reaction using sequence specific primers (PCR-SSP) capable of haplotyping the mutations was developed. HFE allele and haplotype frequencies and linkage disequilibrium with eight HLA class I and II loci were examined in the control population. RESULTS: 27% and 19.7% of patients were positive for the 63D and 282Y alleles, respectively. No chromosome carried both 63D and 282Y. Linkage disequilibrium between 282Y and HLA-A*03 was confirmed, but was not straightforward: some A*03-associated alleles (DRB1*15, DQB1*06), but not all (B*07, Cw*0702), were associated with 282Y. CONCLUSIONS: Linkage disequilibrium data suggest that an HLA-B*07 containing haplotype contains an element affording protection from haemochromatosis and may suggest the timing of the founder 282Y mutation.     

Nutritional and metabolic support strategies

We report here the identification of four novel DRB alleles using a reverse hybridization (CANTYPE) assay. Molecular cloning and sequencing confirmed the initial unusual hybridization patterns. All four new alleles were detected during routine HLA typing for the Canadian Unrelated Bone Marrow Donor Registry. DRB1*0703 is identical to DRB1*0701 except for a single nucleotide substitution (AGA-->AGT), changing codon 29 from Arg to Ser, a so far undetected DRB polymorphism. DRB1*0817 differs from DRB1*0801 by a single nucleotide substitution (TAC-->TTC), changing codon 47 from Tyr to Phe. This polymorphism has not, until now, been identified in DRB1*08 alleles. Compared with DRB3*0301, DRB3*0302 contains a single nucleotide substitution (TAC-->CAC) at codon 30, changing the encoded Tyr to His. This polymorphism is typical for DRB3*02 alleles. DRB3*01014 is identical to DRB3*0101 except for a single silent nucleotide substitution (GGG-->GGA) at codon 84. This polymorphism has previously only been described for the DRB1*15012 allele. DRB1*0817, DRB3*0302 and DRB3*01014 may have arisen from gene conversion, but DRB1*0703 most likely was generated by a point mutation event. The DRB3*0302 allele was detected in two unrelated subjects, while the other three have each only been detected once.     

Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves' disease: replication using a population case control and family-based study

Early case control studies found association of the DRB1 allele, DR3, with Graves' disease (GD). Recent reports, claim the DQA1 allele, DQA1*0501, to be the primary susceptibility determinant within the human leukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB1*0304 (47% vs. 24%; pc < 1.4 x 10(-5)), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10(-3)) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10(-6)). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10(-5); odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (chi2 = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; chi2 = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.     

HLA class II DRB1, DQA1 and DQB1 polymorphisms in the Polish population from Wielkopolska

HLA DRB1, DQA1 and DQB1 alleles were determined by DNA PCR-SSO typing in a sample of 99 individuals originating from Wielkopolska (midwestern Poland). A high number of alleles (38 DRB1, 8 DQA1 and 14 DQB1) was detected at each locus, many of them presenting notable frequencies in this population. The three HLA loci are thus characterized by very high heterozygosity levels (93% for DRB1, 85% for DQA1, and 88% for DQB1), which confirms the results found for other European populations. A total of 6 DRB1-DQA1-DQB1 haplotypes are detected with an estimated frequency higher than 5%, namely, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*0701-DQA1*0201-DQB1*0201, DRB1*0101-DQA1*0101-DQB1*0501, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*03011-DQA1*0501-DQB1*0201, and DRB1*1301-DQA1*0103-DQB1*0603. A genetic distance analysis between the Polish and other world populations tested for HLA class II indicates that the Wielkopolska community is close to geographically close, rather than linguistically related populations from Europe. More generally, a good agreement between genetics and geography is found for DRB1 and DQB1 polymorphisms in Europe, suggesting that these two loci are highly informative for assessing historical relationships among humans.     

Primary Sj?gren's syndrome: role of the HLA-DRB1*0301-*1501 heterozygotes

OBJECTIVE: To examine the respective role of the DRB1*, DQB1*, and DPB1* HLA alleles in primary Sj?gren's syndrome (SS) and in the clinical and autoantibody profile of primary SS. METHODS: HLA-DRB1*, DQB1*, and DPB1* alleles were analyzed in 42 patients with primary SS and 200 controls by reverse dot blot hybridization for DRB1* and DPB1* and by polymerase chain reaction-restriction fragment length polymorphism for DQB1*. RESULTS: We found a significant increase of the HLA-DRB1*15-*03 heterozygote genotype frequency (19% primary SS vs 3.5% controls; p<0.0006, OR=6.49) and especially for the HLA-DRBI*1501-*0301 genotype (16.7% primary SS vs 3% controls; p<0.002, OR=6.47). The DQB1*0201-*0602 genotype was also significantly increased in primary SS (17.1% primary SS vs 4% controls; p<0.006, OR=4.86). However, the higher risk to primary SS development was associated with the DRB1*1501-*0301 genotype (OR=6.47 vs 4.86). There were no differences between patients and controls in DPB1* allele frequencies. The HLA-DRB1*15-*03 heterozygote genotype was also associated with systemic features such as hematologic manifestations and Raynaud's phenomenon (RP) and with autoantibody production such as antinuclear, anti-Ro(SSA) or La(SSB) autoantibodies and rheumatoid factor. CONCLUSION: Our data suggest a role of the HLA-DRB1*1501-*0301 heterozygote genotype in susceptibility to primary SS. Moreover, the HLA-DRB1*1501-*0301 genotype was also found to be associated with a particular form of the disease characterized by RP, hematologic manifestations, and autoantibody production.     

Response to hepatitis B vaccine: multiple HLA genes are involved

The mechanism underlying the impaired immune response to hepatitis B vaccines in up to 10% of healthy subjects is not known. An increased incidence of poor responsiveness in subjects with HLA-DR3+ or -DR7+ haplotypes has been documented, suggesting that HLA-DR-linked genes may regulate the human response to hepatitis B surface antigen. However, not all HLA-DR3+ and/or -DR7+ individuals are poor responders, and subjects with identical HLA-DR haplotypes sometimes display totally divergent antibody responses to vaccination. HLA class II DNA typing was performed in well and poorly responding hepatitis B vaccine recipients and we analyzed the role of the single HLA-DR, -DP, and -DQ molecules and of their associated (interaction) haplotypes in the response to hepatitis B vaccination. Statistical analysis revealed that HLA-DRB1*010*, -DR5, -DPB1*040*, -DQB1*0301, and -DQB1*0501 were more abundant in good responders, whereas HLA-DRB1*07, -DPB1*1101, and -DQB1*020* were associated with poor response, with DQB1*020* showing the strongest association with poor responsiveness. We further investigated whether there were interactions between the HLA factors contributing to poor responsiveness. We show here that HLA-DPB1*02 was negatively associated with responsiveness when it occurred in association with haplotype DRB1*0701/DRB4*0101-DQB1*020*, and DRB4*0101 was negatively associated with responsiveness when it occurred in association with haplotype DRB1*0301/DRB3*0101-DQB1*020*. Our results indicate that the immune response to hepatitis B vaccine is largely determined by HLA-DR, -DP, and -DQ genes and that interaction between HLA molecules that are not in linkage disequilibrium contributes to poor responsiveness.     

Use of statistical programs for nonparametric tests of small samples often leads to incorrect P values: examples fromAnimal Behaviour

To determine if serum antibody response to the 60-kDa chlamydial heat-shock protein (Chsp60) was associated with scarring trachoma, responses to Chlamydia trachomatis and to Chsp60 from 148 Gambian subjects with trachomatous scarring and from 148 controls without clinical evidence of disease from trachoma-endemic communities were characterized. Chsp60 response was found in 32% of cases and 16% of controls (P < .001). Although C. trachomatis titer was also higher in cases than controls, the prevalence of Chsp60 response between the 2 groups remained significantly different after stratifying for C. trachomatis titer (weighted odds ratio [OR] = 2.1, P = .02). Chsp60 response and C. trachomatis serovar A titer of > or =128 were independently associated with scarring trachoma. The presence of HLA class II allele DRB1*0701 was positively correlated with Chsp60 response (OR = 2.6, P = .02), and DQB1*0301 and DQB1*0501 were negatively associated (OR = 0.42, P < .001; OR = 0.55, P = .46, respectively).     

Characteristics of the innervation of the head and neck

The association of HLA-DRB1 and DQB1 genes with IDDM in Koreans was assessed using 115 IDDM patients and 140 nondiabetic controls. DQB1*0201 is the only DQB1 allele positively associated with IDDM while DQB*0602, *0601 and *0301 are negatively associated. Three DRB1 alleles (DRB1*0301, DRB1*0407 and DRB1*0901) are positively associated while four DR allele groups (DRB1*15, DRB1*12, DRB1*10 and DRB1*14) are negatively associated. However, Haplotype analyses indicated that DQB1*0302, DRB1*0405 and DRB1*0401 may confer susceptibility because the DRB1*0405-DQB*0302 and DRB1*0401-DQB1*0302 haplotypes are positively associated with the disease. The lack of association in Koreans with the DQB1*0302 allele, which appears predisposing in studies of non-Orientals, is due to its strong linkage disequilibrium (LD) with the protective DRB1*0403 and *0406 alleles, while the lack of association with DRB1*0405 is because of its strong LD with the protective DQB1*0401 allele. Nine DR/DQ genotypes confer significantly increased risk to IDDM. Seven of the nine genotypes (DR3/4s, DR1/4s, DR4s/13, DR4s/8, DR4s/7, DR9/13 and DR3/9) were also found to be at high risk to IDDM in other populations, while the two others (DR1/9 and DR9/9) are only found in Koreans. Surprisingly, DR4/4 homozygotes are not associated with high risk to IDDM in Koreans. This observation can be explained by the high frequency of protective DR4 subtypes and the protective DQ alleles (0301 and 0401) associated with the susceptible DR4 alleles. Our analyses indicate that the counterbalancing act between susceptible DRB1 and protective DQB1, and vice versa, that has already been observed in Chinese and Japanese, is the major factor responsible for the low incidence of diabetes in Koreans.     

Glomerular filtration rate and kidney size after six years disease duration in non-insulin-dependent diabetic subjects

To evaluate the association of TNFB NcoI polymorphism with SLE in the Korean population, we investigated the frequencies of the TNFB and HLADRB1 alleles in 281 controls and 97 SLE patients, including 56 patients with nephritis and 41 patients without nephritis. The frequency of the TNFB*2 homozygote in SLE was significantly increased over controls (43.3% vs 28.5%, RR = 1.9,p < 0.01). In SLE with nephritis, the TNFB*2 homozygote was more significantly increased (57.1% vs 28.5%, RR = 3.4,p < 0.0001), whereas there was no significant difference between SLE without nephritis and controls. The study of HLA-DRB 1 alleles revealed the increased frequencies of DRB1*02 and *03 (30.9% vs 18.2%, RR = 2.0,p < 0.01; 8.2% vs 2.1%, RR = 4.1,p < 0.05). There was no significantly different distribution of HLA-DRB1 alleles between SLE patients with nephritis and without nephritis. We found positive LD between TNFB*1 and HLA-DR1B1*13, and between TNFB*2 and the particular DRB1 allele: *15, *04, and *07 in controls and/or in SLE patients. After stratification for each HLADRB1 allele, SLE with nephritis showed a higher frequency of TNFB*2 homozygote compared with the corresponding controls in DRB1*15, *08, and *09 positives. Our results suggest that the TNFB*2 homozygote may be a strong susceptibility gene of SLE with nephritis in the Korean population.     

Absence of strong HLA-DR/DQ-DP linkage disequilibrium in the British and French Canadian Caucasoid populations

HLA-DR/DQ-DP linkage disequilibrium was investigated in healthy, unrelated British (n = 150) and French Canadian (n = 67) Caucasoid subjects. HLA-DR and DQ typing was performed by Taq I DNA-RFLP analysis, while DPB1 typing was performed by PCR-SSOP. chi 2 and Fisher's exact tests were performed for all 2-locus biallelic comparisons and coefficients of linkage disequilibrium determined. In the British population, only one example of linkage disequilibrium, significant at P = 0.05 (after correction for the number of comparisons made) was seen (DPB1*0101-DRB1*0301[17(1)]). Additional associations, significant at P = 0.05 before correction for the number of comparisons were also seen, including DPB1*0401-DRB1*15, DPB1*1101-DRB1*0701(7(1)), DPB1*1701-DRB1*0701/ 2(7(2)), DPB1*0101-DQA1*0501, DPB1*0401-DQA1*0102, DPB1*0501-DQA1*0102, DPB1*0101-DQB1*0201, DPB1*0401-DQB1*0602/0603 and DPB1*1101-DQB1*0201. With one exception (DPB1*1101-DQB1*0201), none of these associations was seen in the French Canadian group. These results indicate that although more frequent than thought hitherto, HLA class II linkage disequilibrium involving DPB1 alleles is generally weak, and can differ even between different caucasoid populations. This may have implications for HLA and disease studies.     

Taking the pith out of reality: a reflexive methodology for psychiatric nursing research

HLA-DQ genes are the main inherited factors predisposing to IDDM. This gene region harbors long terminal repeat (DQ LTR) elements of the human endogenous retrovirus HER V-K, which we analyzed for a possible association with disease. We first investigated whether LTR segregate with DQ alleles in families. Members (n = 110) of 29 families with at least one diabetic child, unrelated patients with IDDM (n = 159), and healthy controls (n = 173) were analyzed. Genomic DNA was amplified for DQ LTR3 by a nested primer approach as well as for DQA1 and DQB1 second exons, to assign DQA1 and DQB1 alleles. DQ LTR segregated in 24 families along with DQ alleles. Of the 29 families, 20 index patients were positive for DQ LTR. The DQ LTR was in all patients on the haplotype carrying the DQA1 *0301 and DQB1 *0302 alleles. A majority of patients had DQ LTR (62%) compared with controls (38%) (p < 1.3 x 10(-5)), even after matching for the high-risk alleles DQA1 *0501, DQB1 *0201-DQA1 *0301, and DQB1 *0302 (79% of patients and 48% of controls; p < 0.02). Subtyping for DRB1 *04 alleles in all DQB1 *0302+ individuals showed 56% DRB1 *0401, DQB1 *0302 [LTR' patients vs. 29% controls with the same haplotype (p < 0.002)]. In conclusion, these data demonstrate the segregation of DQ LTR with DQA1, DQB1 alleles on HLA haplotypes. Furthermore their presence on DRB1 *0401-, DQA1 *0301-, and DQB1 *0302-positive haplotypes suggest that they contribute to DQ-related susceptibility for IDDM.     

Kindling induced mossy fiber sprouting has no functional significance in developing seizure discharges in rats]

The influence of host immunogenetics on the outcome of vertically transmitted HIV infection in children was examined in a multicenter cross sectional study of long term survivors and rapid progressors. Sequence-based typing was performed for the DRB1, DQB1 and HLA-A loci. 36.7% of 30 children surviving more than 8 years had one or more of the HLA-DR13 alleles, versus none of 14 rapidly progressing children who died within 2 years of age, p = 0.009, Haldane RR = 17.1. The alleles variably associated with this beneficial response to HIV were: DRB1*1301, DRB1*1302, DRB1*1303 and DRB1*1310, suggesting that the DR13 effect acted as a dominant trait. An additional 6 children were typed only by the SSOP method resulting in 44.4% of 36 long term surviving children with a DR13 allele and none of 14 rapid progressors, p = 0.002, Haldane RR = 23.3. No single DQB1 allele accounted for the HLA-DR13 allele association. In contrast, the presence of HLA A*2301 was associated with rapid progression to AIDS, 4% of long term survivors vs. 57.1% of 7 rapid progressors, p = 0.0006, RR = 0.031. Although the sample size is small, the marked differences in allele frequency along with differences between the peptide binding pockets of the HLA-A9 group of alleles including HLA A*2301 and the remainder of the HLA-A alleles suggest a structural basis for the dominant disadvantageous immune response to HIV conferred by A*2301.     

Contribution of DRB1*04 variants to predisposition to or protection from insulin dependent diabetes mellitus is independent of dq

Certain DQ alpha/beta dimeric molecules have been shown to play a major role in determining susceptibility or resistance to IDDM. Whether or not predisposition associated with DR4 haplotypes is exclusively due to linkage to DQB1*0302 and DQA1*0301 alleles is still a controversial issue. A modifying effect of certain DRB1*04 subtypes on the susceptibility encoded by DQ alleles is possible, since not all DRB1*04-DQB1*0302 haplotypes are associated with the disease. The distribution of DRB1*04 subtypes was analysed in 240 DR4-positive Caucasian IDDM patients and 110 DR4-positive healthy controls using allele-specific hybridization after genomic amplification. Although an important contribution to IDDM predisposition was encoded by the DQB1*0302 allele which was found in the majority of patients (94.2% vs 64.7% in controls, Odd's ratio OR = 8.8, P < 0.0001), differences between DRB1*04 variants persisted after the effect of the DQB1 locus was removed by matching patients and controls for DQB1*0302. Thus, the DRB1*0402 allele conferred a strong IDDM-predisposing effect (OR = 3.1, P < 0.02) which was highly significant in the absence of DR3 on the second haplotype (OR = 5.6, P < 0.0001) but was not visible among DR3/4 heterozygote individuals. Conversely, the DRB1*0404 allele conferred a strong protective effect (OR = 0.26, P < 0.0001) which was dominant even in the presence of the associated high risk DR3 haplotype (OR = 0.21, P < 0.03). These data indicate that DQ molecules are not the sole contributors to the DR4-associated IDDM predisposition, and that peculiar DR4 subtypes play a significant role in susceptibility to or protection from the disease. DRB1*0402 differs from DRB1*0404 by only two acidic residues at positions 70 and 71 within the peptide binding groove, instead of amide and basic amino acids. This might induce changes of peptide binding specificity that correlate with the genetic linkage of IDDM predisposition.