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.     

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.     

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.     

Effects of residues of deltamethrin in cattle faeces on the development and survival of three species of dung-breeding insect

We report on the role of HLA-DQA1 and DQB1 alleles in determining susceptibility to insulin-dependent diabetes mellitus (IDDM) in Hong Kong Chinese and investigate whether these alleles affect the age of onset of the disease. We studied 76 unrelated Chinese patients and 250 controls. There was no apparent predisposing effect of non-aspartic acid residues at position 57 of the DQ beta chain (Asp57-) but there was an excess of homozygous genotypes containing arginine at position 52 of the DQ alpha chain (Arg52+). This excess was mainly attributable to the genotype DQA1*0301/DQA1*05011 in early-onset disease. There was a significant excess of heterodimers of DQ alpha and DQ beta carrying Arg52+ and Asp57- in both early-onset and late-onset disease, but the excess in early-onset disease was mainly attributable to a single heterodimer formed by DQA1*05011 and DQB1*0201. Of three DQA1/DQB1 genotypes containing a double dose of Arg52+ and Asp57-, only one had a strong association with both early-onset and late-onset disease. We show that early-onset IDDM and late-onset IDDM in Chinese may be separated on the basis of their associated DQA1 and DQB1 genotypes and we conclude that previously reported associations of IDDM with Arg52+ and Asp57- residues in Chinese are secondary to specific combinations of DQA1 and DQB1 alleles. We also show that DRB1 molecules play a distinct role in determining susceptibility to early-onset IDDM but the greatest effect is exerted by specific DR/DQ genotypic combinations.     

HLA-DRB1*04 and DRB1*14 alleles are associated with susceptibility to pemphigus among Japanese

It has previously been demonstrated that susceptibility to pemphigus vulgaris is associated with human leukocyte antigen (HLA)-DR4 serologic specificity among Ashkenase Jews, and with DR4 as well as DR6 (DR14) in other ethnic groups. We genotyped HLA-DRB1, DQA1, DQB1, and DPB1 alleles in 16 patients with pemphigus by polymerase chain reaction-restriction fragment length polymorphism, to find evidence of potential HLA class II allele associations with pemphigus in Japanese patients who have a relatively homogeneous ethnic background. All nine patients with pemphigus vulgaris and five of seven patients with pemphigus foliaceus carried one or two alleles of HLA-DRB1*04 (*0403, *0406) and HLA-DRB1*14 (*1401, *1405, *1406) subtypes. Sequence analysis of these DRB1*04 and DRB1*14 alleles revealed the amino acid homology of phenylalanine at position 26 and valine at position 86 with the DRB1*0402 allele that reportedly confers a strong susceptibility to pemphigus vulgaris in Ashkenazi Jews. Thus our findings, together with previous HLA studies on pemphigus vulgaris patients of different ethnic groups, suggest that HLA-DRB1*04 and DRB1*14 alleles are commonly associated with pemphigus vulgaris across racial barriers. These HLA-DRB1 alleles are likely to be also associated with pemphigus foliaceus. Further studies on more diverse ethnic populations will be helpful in determining the significance of the association between certain amino acid residues of the class II molecules and disease susceptibility to pemphigus vulgaris as well as pemphigus foliaceus.     

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.     

Prevention strategies for occupational low back pain

Ethnic comparisons are extremely important and useful for studying the HLA component involved in insulin-dependent diabetes mellitus (IDDM) predisposition. To date there have been only a few reports on the association of HLA loci and IDDM in Chinese. We report here a study on DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 in IDDM children and control adults among Han Chinese living in Taiwan. One hundred and fourteen unrelated children (62 boys) with IDDM were studied. Their ages at diagnosis were between 0.3 and 15.0 years (6.8 +/- 3.6 years). The control population consisted of 120 randomly selected normal adults. DQA1*Arg52(+/+), DQB1*nonAsp57(+/+), and DRB1*04(+/-) were associated with IDDM (RR = 11.50, 2.21, and 2.82; p = 1.11 x 10(-15), 2.84 x 10(-3), and 1.98 x 10(-4), respectively). DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 conferred risks for IDDM (RR = 12.79, 7.11, and 2.83; pc = 8.22 x 10(-4), 5.35 x 10(-3), and 5.68 x 10(-4), respectively). Combinations of DQA1*Arg52 and DRB1*04 conferred the highest risk for IDDM (RR = 19.64, pc = 5.4 x 10(-5)). DQA1*Arg52 was associated with IDDM in subjects with DQB1*nonAsp57+ (RR = 14.87, pc = 2.41 x 10(-4)) and DQB1*nonAsp57 was also associated with IDDM in subjects with DQA1*Arg52+ (RR = 8.41, pc = 1.54 x 10(-3)), suggesting that DQA1*Arg52 and DQB1*nonAsp57 are interacting. This study demonstrates that DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 confer susceptibility for IDDM to Chinese children. A combination of DQA1*Arg52 and DRB1*04 confers the highest risk and it is suggested that a susceptibility gene might be situated between DQA1*Arg52 and DRB1*04 or both are synergistic. There is an interaction between DQA1*Arg52 and DQB1*nonAsp57 and homozygosity for DQA1*Arg52/DQB1*nonAsp57, which encodes four susceptibility DQ heterodimers, confers a high risk.     

Motor organization after early middle cerebral artery stroke: a PET study

We analyzed HLA class II genes of Okinawan centenarians using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to identify primary genetic factors in the major histo-compatibility complex (MHC) region associated with human longevity. Gene frequencies of centenarians were compared with those of normal adults of the same ethnicity who were selected in the same vicinity as the centenarians. The following differences were identified in the HLA-DQB1 and DQA1 genes: the frequencies of DQB1*0503, DQA1*0101 (04) and DQA1*05 were increased in the centenarians, whereas those of DQA1*0102, DQA1*0103 and DQB1*0604 were decreased. Similarly, for the DRB1 gene, the frequencies of DRB1*0101, DRB1*1201 and DRB1*1401 were increased in the centenarians, whereas those of DRB1*0403 and DRB1*1302 were decreased. These data suggest that several alleles of the HLA-DRB1 and/or HLA-DQ genes are involved in human longevity.     

Insulin-dependent diabetes mellitus in Santiago, Chile: the role of immunogenetic and environmental factors

The role of HLA class II alleles in the genetic susceptibility to develop insulin-dependent diabetes mellitus (IDDM) was examined by means of PCR and oligospecific probes in 63 IDDM children and 74 controls subjects. In diabetic patients we found a significant increase in the alleles frequency DR3, DR4, DQB1*0302 and DQA1*0301 compared to the control group, where the most prevalent alleles were DR2, DR14 (DRB1*1402), DQA1*0101 and DQA1*0201. All the risk genotypes in the diabetic group were similar than in other caucasian groups: DR3/DR4-DQB1*0201/0302-DQA1*0301/0501 and DR4/DR4-DQB1*0302/0302-DQA1*0301/0301. The homozygote character no asp57 conferred an absolute risk (AR) of 3.87 and the marker Arg52 an AR of 5.78/100.000 bab year. The homozygosis for both markers (no Asp57 + Arg52) had an AR of 7.56/100.000 bab year. Regarding environmental factors associated with IDDM, our population under study showed a low prevalence of infectious agents (mainly mumps and rubella, specifically associated with IDDM) and a high prevalence of effective breast-feeding (over 3 months). These factors could be exercising a protector role in the development of IDDM. The factors that appear to be important in the low incidence of IDDM in Santiago de Chile are: the low prevalence of infectious agents related to IDDM, the high percentage of breast-feeding children in the population, the reduced frequency of susceptible molecules as DR3, DQB1*0201 (compared to other caucasian groups) and the presence of protective genotypes related to DR13 and DR14 observed in the non diabetic children.     

Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan

Molecular genotyping for the major histocompatibility complex (MHC) class II loci, HLA-DRB1, -DQB1 and -DQA1, in 100 patients with relapsing/remitting multiple sclerosis (MS) demonstrated an association with the HLA-DR2, DQw6-associated alleles DRB1*1501, DQB1*0602 and DQA1*0102, thereby extending this finding among MS patients in several countries to an Australian population. Analysis by the relative predispositional effect (RPE) method provided no evidence for a second susceptibility allele at either DQA1 or DQB1. However, our data and that of others suggest a negative association with DQA1*0101. Associations were found with DQB1 alleles sharing sequence homology with DQB1*0602, with DQB1 alleles encoding leucine at residue 26 (Leu 26), with DQA1 alleles encoding glutamine at residue 34 (Gln 34) and with Leu 26 plus Gln 34 alleles, but each was shown by two-loci linkage analysis to be secondary to the DRB1*1501, DQB1*0602, DQA1*0102 association. The recently reported negative association with DQA1 alleles encoding phenylalanine at amino acid 25, leucine at amino acid 69 and arginine at amino acid 52 was not found in this study, although there was a trend towards reduced phenylalanine at amino acid 25. The determination at a molecular level of an explanation for the world-wide association with these alleles remains elusive despite major advances in MHC typing.     

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.     

The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat-shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.     

MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India

Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA-DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P < 0.0001), DQA1*0101 (P = 0.001), and DQB1*0503 (P < 0.0001). These associations were due to the increased frequencies of the haplotype HLA-DRB1*1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p < 0.0001). Also, patients from Ahmedabad had a significant increase in HLA-DQB1*0302 (p = 0.03). An identical amino acid sequence (Leu-Leu-Glu-Arg-Arg-Arg-Ala-Glu), in positions 67-74 of the beta domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA-DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB1*0503 and the association with HLA-DR14 alleles would be the result of linkage disequilibrium. Third, the HLA-DRB1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared by several HLA-DR14 alleles.     

Analysis of a genetic factor of metal allergy--polymorphism of HLA-DR, -DQ gene

To reveal immunogenetic factors involved in the pathogenesis of metal allergy, 30 unrelated Japanese patients with histories of metal allergy were typed for HLA. They were confirmed by an unequivocal positive patch-test reaction to mercury, nickel or palladium. The HLA-DR and -DQ DNA were typed by using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSO) method. The frequency of each allele in the patient groups was compared to that in normal Japanese subjects. In mercury sensitive patients, there was no significant HLA association. In nickel sensitive patients, there was a significant increase of DRB4 (p < 0.05) but no significant association of DRB1 nor DQ locus, although there was an increase of DRB1*0405 (R.R = 2.36). In palladium sensitive patients, there were significant increases of DRB4 (R.R. = 15.48, p < 0.05), DR4(R.R. = 13.27, p < 0.005), DRB1*0405(R.R. = 4.43, p < 0.05), and DQB1*0401 (R.R. = 4.59, p < 0.05), and significant decreases of DRB5 (R.R. = 0.09, p < 0.05), and DQA1*0103 (R.R. = 0, p < 0.05).     

Giant cell arteritis and polymyalgia rheumatica can be differentiated by distinct patterns of HLA class II association

OBJECTIVE: To determine whether patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) exhibit identical HLA class II associations. METHODS: A case-control association study was performed on a population sample from Lugo, in Northwestern Spain. DNA samples were available for 128 patients and 145 ethnically matched controls. Within the patient group 26 exhibited both PMR and GCA, 75 PMR alone, and 27 GCA alone. HLA-DRB1, DQA1, and DQB1 phenotypes were defined by molecular based techniques. RESULTS: HLA-DRB 1*0401 was associated with GCA regardless of PMR status, although this only reached statistical significance in the total GCA group. This was also seen for DRB 1*0101, *0102, although the association was less strong. Patients with PMR without GCA were not associated with DRB1*0401 or *0101, *0102, but exhibited a significant association with DRB1*13, *14. Nonsignificant increases in DQA1 and DQB1 phenotype frequencies appeared to reflect known patterns of linkage disequilibrium with the HLA-DRB1 alleles associated with GCA and PMR groups. An association was observed between the presence of the RA DRB1 shared epitope (SE) and GCA but not with PMR in the absence of GCA. This association was primarily accounted for by the presence of a single copy of the SE, and homozygosity for the SE did not confer additional risk. A high frequency of SE-bearing DRB1 alleles was observed in patients with GCA with jaw claudication or visual manifestations, although the sample size of these subgroups was small. CONCLUSION: PMR and GCA in a Northwestern Spanish population have distinct HLA class II associations. HLA is unlikely to account for the observed high level of overlap in these patients, and other etiological factors may be involved.     

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.     

Anxiety responses of parents during and after the hospitalization of their 5- to 11-year-old children

Pemphigus vulgaris (PV) is an autoimmune disease of the skin and mucous membranes characterized by an autoantibody response against an epidermal cadherin. We performed high resolution HLA class II typing in 19 patients with PV from Rawalpindi, Pakistan and 19 non-Jewish European PV patients from Boston by sequence-specific oligonucleotide probe hybridization. The results were compared with two separate ethnically matched control populations. WE found that PV patients from Pakistan had significantly increased frequencies of DRB1*1404 (p = 0.01), DQA1*0101 (p = 0.02), and DQB1*0503 (p = 0.01). Among the patients of non-Jewish European ancestry, DRB1*1401 (p < 10(-6)), DQA1*0101 (p < 10(-5)) and DQB1*0503 (p < 10(-6)), were increased in PV patients. Formal linkage analysis between the major histocompatibility complex and the PV antibody was performed in 67 relatives of the 19 Pakistani patients. The results showed strong evidence for linkage of HLA-DRB1*1404, DQA1*0101, DQB1*0503, with the presence of PV antibody in relatives' families with a significant logarithm of the odds score of 6.06. Based on the three dimensional structure of class II molecules, we propose that HLA-DQA1*0101 and DQB1*0503, encode a negatively charged P9 peptide binding pocket of the DQ molecule and are significantly associated with susceptibility to PV in non-Jewish populations.     

Sleep ontogenesis revisited: a longitudinal 24-hour home polygraphic study on 15 normal infants during the first two years of life

In order to investigate the genetic basis of susceptibility to Henoch-Schoenlein purpura (HS), blood samples of 152 patients, 105 of whom had renal disease, were collected in a two-step study. The evaluation of DRB, DQB and DQA polymorphism was done by analysis of the restriction polymorphisms produced by TaqI enzyme. DRB1*07 was less frequent in patients than in the control group (gene frequency 0.09 and 0.18, respectively; P = 0.0023), whereas 64% of the patients were positive for DRB1*01 and/or DRB1*11 compared with 48% of the control group (P = 0.0069). Polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) typing of DRB1*01- and DRB1*11-positive individuals did not show any deviation of frequencies of DRB1*01 subtypes between patients and controls, whereas among DRB1*11 subtypes DRB1*1104 was significantly increased in the patients (Pc = 0.033). The comparison between patients with renal disease and those without renal disease showed no significant differences in the frequency of the single DRB, DQB and DQA alleles. The study of restriction polymorphisms in the switch region of the constant genes alpha 1, alpha 2 and mu of the heavy chains of immunoglobulins, using the enzyme Sacl and a specific probe, did not show any difference between 44 patients and 54 controls. This study demonstrates that susceptibility to HS also has a genetic origin: on one hand, the presence of DRB1*01 or DRB1*11 makes disease onset easier; on the other hand, DRB1*07 could induce some resistance to the disease. It is suggested that, as well as for other diseases caused by an impaired immune response, single amino acids in a key position in the HLA-DRB molecule make it more or less easy to recognize some antigenic peptide, towards which an immune response leading to disease is triggered.     

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.     

Evidence of a strong, positive association between atopy and the HLA class II alleles DR4 and DR7

BACKGROUND: Atopy, with or without associated asthma, provides a useful model for evaluating the genetic factors that control human immune responsiveness. HLA class II gene products are involved in the control of immune responses. OBJECTIVES: We investigated whether susceptibility or resistance to the disease was associated with HLA class II genes. METHODS: Blood samples were obtained from two groups of unrelated European-born white adults: 56 atopic patients (52 of them with asthma) and 39 healthy controls with no personal or familial history of asthma or atopy. Genomic DNA was extracted from peripheral blood lymphocytes. The exons of DQA1, DQB1, DRB and DPB1 genes were selectively amplified by the polymerase chain reaction (PCR) method. Genotyping was carried out by digestion of the amplified DNA products with allele-specific endonucleases (PCR-RFLP), which can recognize allelic variations in the polymorphic exon. RESULTS: We found no significant differences in the frequency of DPB1 alleles between patients and controls. HLA class II DR4 and DR7 alleles were present in 39.2% of the patients and in 2.5% of the healthy subjects (Pc*2 < or = 3.9 10(-3)). Conversely, DQA1*0103 and DQB1*0502 alleles were more frequent in the control subjects. These results confirm a previous study of an extended pedigree, which showed that DR4 and DR7 alleles were absent in all healthy members of the family and were frequently observed in atopic and/or in asthmatic subjects. CONCLUSION: We observed that HLA-DR 4 and DR7 alleles are significantly implicated in their susceptibility to the disease and suggest that this susceptibility is more related to atopy than to specific responses to allergens. According to previous studies, we could also submit that in atopic patients with asthma, DR4 alleles at the least, could be more closely associated with atopy than with asthma per se. Conversely, we suggest that some allelic DQA1 and DQB1 sequences might confer protection against the disease.