Contrasting molecular patterns of mhc class ii alleles associated with the anti-sm and anti-rnp precipitin autoantibodies in systemic lupus erythematosus

Objective. To find evidence of a potential genetic predisposition to the anti-Sm or anti-RNP precipitin autoantibody responses. Methods. HLA–DR and DQ alleles determined by restriction fragment length polymorphism and/or oligo-typing in 49 subjects with either anti-Sm alone or anti-RNP alone were compared with those in 139 race-matched normal control subjects and 59 race-matched lupus patients without anti-Sm and anti-RNP auto-antibodies. Results. Black patients with anti-Sm precipitin had increased frequencies of HLA-DR2 and the DQw6-associated DQA1*0102 (P = 0.007, odds ratio [OR] = 6.7) and DQB1*0602 (P = 0.001, OR = 9.1) chain alleles compared with normal black control subjects. Black patients with anti-RNP precipitin showed significant increases in the DQw5-associated DQA1*0101 (P = 0.03, OR = 5.5) and DQB1*0501 (P = 0.002, OR = 23.3) chain alleles compared with lupus patients without anti-Sm or RNP. White patients with anti-RNP precipitin showed an increased frequency of the DQw8-associated allele DQB1*0302 (P = 0.02, OR = 3.7) compared with normal controls, as well as an increased frequency of the DQw5-associated alleles DQA1*0101 and DQB1*0501 (P = 0.05, OR = 4.2) compared with lupus patients without anti-Sm or RNP. There were no specific HLA–DR2 or DR4 subtype associations found with either anti-Sm or RNP precipitin autoantibodies. Conclusion. There are distinct patterns of major histocompatibility complex class II allele associations with the anti-Sm versus the anti-RNP precipitin autoantibody responses, and HLA–DQ associations may be more primary than HLA–DR associations.     

DNA analysis of HLA-DR, DQ, and DP alleles in children with polyarticular juvenile rheumatoid arthritis.

HLA-DR, DQ and DP alleles were determined by restriction fragment length polymorphism analysis and oligonucleotide probe hybridization of polymerase chain reaction amplified genomic DNA in 94 Caucasian children with polyarticular juvenile rheumatoid arthritis (JRA) [13 rheumatoid factor (RF)+ and 81 RF-] and 100 healthy controls. HLA-DRw8, DQw4, DQA1*0401, DQB1*0402 were increased in frequency in those patients with RF seronegative disease, with highest frequencies seen in patients with young age at onset (< 5 years of age). These findings were similar to what we observed in children with pauciarticular JRA, especially those with young age at onset. DPB1*0301 was also found in increased frequency in the RF- group, and in particular those seronegative for antinuclear antibody. In contrast to what is observed in patients with pauciarticular JRA, the frequency of DPB1*0201 was not increased in any polyarticular JRA patient group. These data suggest that polyarticular JRA shares many genetic features with pauciarticular JRA.     

Juvenile idiopathic arthritis (JIA) is primarily associated with HLA-DR8 but not DQ4 on the DR8-DQ4 haplotype

BACKGROUND: Juvenile idiopathic arthritis (JIA) is strongly associated with the DR8-DQ4 haplotype. The genes encoding DR8 and DQ4 are in strong linkage disequilibrium (LD) and occur together on the same HLA haplotype in almost all patients and controls. Because of the strong LD it is not clear whether DR8, DQ4, or both, are primarily associated with JIA. OBJECTIVE: To unveil the primary association of JIA--that is, with DR8 or DQ4. METHODS: DRB1, DQA1, and DQB1 alleles of 585 Norwegian and 47 Polish unrelated patients with JIA (categorised as pauciarticular and rheumatoid factor negative polyarticular JIA), and of 3155 Norwegian and 158 Polish unrelated controls, were typed using a polymerase chain reaction or oligonucleotide hybridisation and sequence-specific primers method. RESULTS: Several haplotypes which encoded DR8 (that is, carried DRB1*08) and which did not encode DQ4 (that is, did not carry DQA1*0401) were found. Such haplotypes were found in three Norwegian patients and two controls (p=0.029). In the Polish population such haplotypes were found among four patients with JIA and two controls (p=0.025). No haplotypes which carried DQA1*0401 and DQB1*0402 in the absence of DRB1*08 were found, either among patients with JIA (Polish and Norwegian) or among the controls (Polish). CONCLUSION: On the DR8-DQ4 haplotype the DRB1*08 allele is primarily associated with JIA.     

DNA restriction fragment length polymorphism of HLA-DR2 haplotypes in normal individuals and in patients with rheumatoid arthritis.

A strong association between HLA-DR4 and rheumatoid arthritis (RA) has been found in a number of populations. In contrast, the incidence of DR2 is decreased in patients with RA, suggesting that this specificity may confer some protection against the disease. A number of subtypes of DR2 have been defined by serology, by responses in mixed lymphocyte culture reaction, and, more recently, by restriction fragment length polymorphism. These subtypes of DR2 are in linkage disequilibrium with different subspecificities of DQw1. It is thus likely that the distribution of these subtypic DR,DQ haplotypes in DR2 positive patients with RA may be important in understanding the genetic basis of susceptibility/resistance to RA. In this paper a study of the subtypes of DR2,DQw1 haplotypes in 18 patients with RA, who required sodium aurothiomalate as a disease remitting drug, and unrelated healthy individuals is reported. Three subtypes of DR2 haplotypes, DRw15 (Dw2),DQw1.2(DQw6), DRw15(Dw12),DQw1.12(DQw6), and DRw16(Dw21),DQw1, AZH (DQw5), were analysed with a cDNA probe for the DQ beta gene. The data show that DR2 positive patients with RA carried either the DRw15(Dw2),DQw6 or DRw15(Dw12),DQw6 haplotype. No patient with RA was positive for the DRw16(Dw21),DQw5 subspecificity. In contrast, six of 29 (21%) normal healthy DR2,DQw1 positive individuals carried the DRw16(Dw21),DQw5 haplotype. These data together with earlier results on the distribution of the DR4,DQw7 haplotype in patients with RA support the hypothesis that DQB1 chain polymorphism may be important in determining susceptibility to severe RA.     

DNA analysis of HLA-DR and DQ genes in American blacks with systemic lupus erythematosus

We studied DNA polymorphisms of HLA-DR and DQ alleles in 63 American black patients with systemic lupus erythematosus (SLE). We found no HLA-DR beta, DQ alpha, or DQ beta restriction fragment length polymorphism (RFLP) or RFLP-determined DR or DQ specificity associated with SLE in either the patients or in 57 control subjects. DRw52b was positively associated with renal involvement and negatively associated with anti-nuclear RNP antibodies. Antibodies to Ro (SS-A) and La (SS-B) were associated with DR3(DRw17), DQw2.3. Early-onset SLE (less than or equal to 20 years of age) was associated with DRw8, and the frequency of neuropsychiatric involvement correlated negatively with a 3.7-kb Taq I DQ alpha RFLP. This suggests a role for DR and DQ genes in the clinical and serologic expression of SLE in American blacks.     

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

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

Linkage between rheumatoid arthritis susceptibility and the presence of HLA-DR4 and DR beta allelic third hypervariable region sequences in southern Chinese persons.

OBJECTIVE. To analyze HLA-DR and DQ associations with rheumatoid arthritis (RA) in patients from southern China. METHODS. In 66 patients and 45 controls, restriction fragment length polymorphism studies were performed using DRB, DQA, and DQB probes, and DRB allele-specific typing of polymerase chain reaction-amplified DRB DNA. RESULTS. The frequency of HLA-DR4 was significantly increased among RA patients (42.4% versus 17.8%). Increased frequencies of the DQA3 allele (77.8% versus 48.9%) and the DQB1*0302 allele (71.0% versus 46.3%), which are in linkage disequilibrium with DR4, were also found. Oligonucleotide typing showed that the amino acid sequence LLEQRRAA, spanning amino acid positions 67-74 of the DR beta molecule, was found in 19 of 49 patients and 5 of 32 controls. The main DR4 allelic subtypes found in the population were DRB1*0404 and DRB1*0405, both of which carried the sequence. There was no difference in subtype distribution between patients and controls. CONCLUSION. Chinese RA patients have an increased frequency of HLA-DR4 alleles which possess the same DRB third allelic hypervariable sequence shown to be associated with susceptibility in Caucasian RA patients.     

Analysis of HLA alleles in Japanese patients with cirrhosis due to chronic hepatitis C

Hepatitis C virus (HCV) leads to chronic liver disease in at least 50–60% of infected people and approximately 40–50% of these patients will go on to develop cirrhosis due to chronic hepatitis C (HCV-C). The pathogenic mechanisms that result in HCV-C are unknown. Sixty Japanese patients with HCV-C were examined for HLA-A, B, C and DR alleles by serologic typing and for HLA-DQB1 alleles by DNA typing using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. As the control population, 293 healthy un-related Japanese were used. The frequencies of HLA-B61, Cw3, DR4, DQB1*0401 and DQB1*0402 were increased, while those of HLA-DR9, DQB1*0301 and DQB1*0303 were decreased in the patients. The co-ordinate increase in the frequency of HLA-DR4, DQB1*0401 or 0402 and decrease in the frequency of DR9 or DQB1*0303 were suggestive of a strong linkage disequilibrium between HLA-DR4 and DQB1*0401 or 0402 and between HLA-DR9 and DQB1*0303, respectively. From the odds ratio (OR) analysis, the combinations of HLA-Cw3+DR4-DQB1*0401 or 0402, or HLA-B61+DR4-DQB1*0401 or 0402 increased the risk for developing HCV-C when compared to each HLA allele alone. This suggested an additive effect for these classes I and II HLA allele combinations in HCV-C. In contrast, HLA-DR9-DQB1*0303 and DQB1*0301 may confer resistance to this disease. These results suggest the existence of HLA-linked susceptibility genes to HCV-C.     

Analysis by the polymerase chain reaction of histocompatibility leucocyte antigen-DR9-linked susceptibility to insulin-dependent diabetes mellitus.

DNA sequence analysis of class II HLA from Caucasian and black patients with type 1 (insulin-dependent) diabetes mellitus has suggested that aspartic acid at position 57 (Asp 57) of the DQ beta chain provides protection against insulin-dependent diabetes mellitus (IDDM). In contrast, most Japanese patients with IDDM have Asp 57-positive alleles. To determine the reason for the differences and to localize the HLA-linked diabetogenic gene in Japanese, we studied the DQA1 and DQB1 genes of Japanese patients with IDDM and control subjects by the polymerase chain reaction in combination with restriction fragment length polymorphism analysis. Associations of DQA1*0301 and DQB1*0303 with IDDM were observed. DQA1*01 was associated negatively with IDDM. The HLA-DR9 haplotype, which is associated positively with IDDM in Japanese, was associated with DQA1*0301 and DQB1*0303, indicating that the Japanese DR9 haplotype is the same as that in caucasians but different from that in blacks. Of the loci on Japanese DR9 haplotypes, the DQA1*0301 allele showed the highest association with IDDM. DQB1*0303 was also positively associated with IDDM. Since DQB1*0303 is identical to DQB1*0302 except that it contains Asp 57, the data suggests that an Asp 57-positive allele confers susceptibility to IDDM when the whole molecule of the DQ beta chain is similar to other susceptible DQ beta chains. DQA1*0301 appears to be a marker of IDDM in all these populations: Japanese, caucasian, and black.     

Specific HLA-DQB and HLA-DRB1 alleles confer susceptibility to pemphigus vulgaris

The autoimmune dermatologic disease pemphigus vulgaris (PV) is associated with the serotypes HLA-DR4 and HLA-DRw6. Based on nucleotide sequence and oligonucleotide probe analysis of enzymatically amplified DNA encoding HLA-DR beta chain (HLA-DRB) and HLA-DQ beta chain (HLA-DQB; henceforth HLA is omitted from designations), we showed previously that the DR4 susceptibility was associated with the Dw10 DRB1 allele [encoding the mixed lymphocyte culture (MLC)-defined Dw10 specificity]. The DRw6 susceptibility similarly was shown to be associated with a rare DQB allele (DQB1.3), which differed from another nonsusceptible allele by only a valine-to-aspartic acid substitution at position 57. Given the linkage disequilibrium that characterizes HLA haplotypes, it is difficult to assign disease susceptibility to a specific locus rather than to a closely linked gene(s) on the same haplotype. To address this problem, we have analyzed all of the polymorphic loci of the class II HLA region (DRB1, DRB3, DQA, DQB, and DPB) on the DRw6 haplotypes in patients and controls. In 22 PV patients, 4 different DRw6 haplotypes were found that encode the same DQ beta chain (DQB1.3) but contained silent nucleotide differences at the DQB locus as well as coding sequence differences in the DQA and DRB loci. These results, obtained by using a method for allele-specific polymerase chain reaction amplification, strongly support the hypothesis that the allele DQB1.3 confers susceptibility. This DQB allele is correlated with the MLC-defined Dw9 specificity and is associated with two different DRB1 alleles (the common "6A" associated with DRw13 and the rare "6B" associated with DRw14). Since 86% (19 of 22) of DRw6+ patients contain the DQB1.3 allele (vs. 3% of controls), whereas 64% (14 of 22) contain the DRB1 allele 6B (vs. 6% of the controls), we conclude that most of the DRw6 susceptibility to PV can be accounted for by the DQ beta chain.     

Identification of a polymorphic variant associated with HLA-DQw3 and characterized by specific restriction sites within the DQ beta-chain gene.

Restriction endonuclease digestion of genomic DNA from 24 lymphoblastoid cell lines homozygous for the HLA class II specificity DQw3, followed by hybridization with a DQ beta-chain cDNA probe, identified a genomic polymorphism with variable BamHI and HindIII recognition sites. This restriction fragment pattern was found for several haplotypes associated with the DQw3 specificity, including some haplotypes positive for the HLA-DR specificities DR4, DR5, DRw8, and DRw12. The variant fragment pattern corresponds precisely with the reactivity of a monoclonal antibody, A-10-83, previously shown to define a serologic split of DQw3. Serologic detection of the specific DQw3.1 genomic polymorphism indicated that the corresponding DQ beta-chain variants are expressed. This polymorphic restriction fragment pattern, then, represents a selective marker for DQ beta-chain genes that appear to define a DQ beta-chain-associated specificity, here called DQw3.1.     

Hla antigens in juvenile Arthritis

Using DNA techniques, we investigated the role of HLA—DR, DQ, and DP alleles in susceptibility to juvenile arthritis (JA). We studied 2 groups of patients with JA having a different disease prognosis and course. The pauciarticular form is usually benign, while the polyarticular disease frequently leads to joint destruction and disability. Persistent pauciarticular disease developed preferentially in patients having HLA—DRw13-Dw18 and DQw6-Dw18, but these antigens did not confer susceptibility in patients whose disease converted to the polyarticular form. HLA—DPw2.1 was an additional susceptibility factor for patients with JA of pauciarticular onset. In the polyarticular form of JA, HLA—DPw3 was the major factor for susceptibility, giving a relative risk of 10.3 (P < 0.0001). In addition, we found that DRw8.1 and DQw4 were increased, and HLA—DR4 was markedly decreased, in patients with pauciarticular and polyarticular disease. These results indicate that in addition to some shared factors, distinct HLA class II alleles are important in pauciarticular or polyarticular JA. We conclude that typing with oligonucleotide probes may be useful in predicting the outcome in some children with arthritis.     

Both DQA1 and DQB1 genes are implicated in HLA-associated protection from type 1 (insulin-dependent) diabetes mellitus in a British Caucasian population

Summary Inherited susceptibility to Type 1 (insulin-dependent) diabetes mellitus is partly determined by HLA genes. It has been suggested that protection from disease may be conferred by HLA-DQB1 genes which encode molecules with aspartate at position 57. We investigated the contributions of HLA-DRB1, DQA1 and DQB1 genes to protection from disease. Restriction fragment length polymorphism and sequence specific oligonucleotide analysis in 156 British Caucasian Type 1 diabetic and 116 control subjects showed protection from disease was associated with DR2, DRw6 and DR7 haplotypes. The most protective DQA1 allele was DQA1*0102 which occurred on both DR2 and DRw6 haplotypes. The DQB1 alleles DQB1*0303, DQB1*0602 and DQB1*0603 were associated with protection, as was DQB1*0604, which encodes an Asp-57 negative DQmolecule. Heterozygosity for both protective and predisposing HLA markers was reduced in diabetic compared with control subjects. We conclude that both DQA1 and DQB1 genes are implicated in HLA-associated protection from Type 1 diabetes in this British Caucasian population. The overall structure of the DQ heterodimer is critical and DQ-Asp 57 is of secondary importance in determining protection from disease. The effect of protective HLA types may predominate over that of predisposing markers.     

HLA-D region genes associated with autoantibody responses to histidyl-transfer RNA synthetase (Jo-1) and other translation-related factors in myositis

Myositis has been associated with HLA-B8 and DR3, especially in white patients with polymyositis and serum anti-Jo-1 antibodies. Twenty-eight patients with myositis and serum translation-related autoantibodies anti-Jo-1, anti-PL-7, anti-PL-12, anti-KJ, and anti-SRP were studied for HLA class II specificities by Southern blotting with HLA-DR beta, DQ beta, and DQ alpha probes. The association of HLA-DR3 (DRw17) with anti-Jo-1 antibodies in white myositis patients was confirmed (P = 0.003, relative risk 8.9). However, HLA-DRw52 haplotypes, regardless of subtype, were present in all of the white and black patients with serum anti-Jo-1 and other translation-related autoantibodies. Moreover, one anti-Jo-1 positive patient had HLA-DRw8, an HLA-DRw52 haplotype on which the DR beta 3 gene has been partially deleted. No HLA-DQ specificity or allele was common to all patients. The HLA-DR3, DR5, DRw6, and DRw8 haplotypes, which bear the HLA-DRw52 specificity, share the most homology in the DR beta 1 first hypervariable region at amino acid positions 9-13. Thus, this DR beta 1 region appears to be the most likely candidate "epitope" for translation-related autoimmune responses in inflammatory myositis.     

Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities

HLA class II gene polymorphism was investigated in 100 patients with clinically definite multiple sclerosis (MS) by restriction fragment length polymorphism analysis of Taq I-digested DNA using DRB, DQA, and DQB cDNA probes. Twenty-six patients had primarily chronic progressive MS and 74 had relapsing/remitting MS. The latter group included patients with a secondary progressive evolution of symptoms. Both clinical forms of MS were found to be associated with the DRw15,DQw6 haplotype. In addition, primarily chronic progressive MS was positively associated with the DQB1 restriction fragment pattern seen in DR4,DQw8, DR7,DQw9, and DRw8, DQw4 haplotypes, as well as negatively associated with the Taq I DQB1 allelic pattern corresponding to the serological specificity DQw7. Relapsing/remitting MS was positively associated with the DQB1 allelic pattern observed in the DRw17,DQw2 haplotype. These three DQB1 alleles are in strong negative linkage disequilibria with DRw15. The two susceptibility markers of each clinical form of MS act additively in determining the genetic susceptibility, as the relative risks for individuals carrying both markers roughly equal the sum of respective risks. Different alleles of the DQB1 locus defined by restriction fragment length polymorphisms contribute to susceptibility and resistance to primarily chronic progressive MS as well as to susceptibility to relapsing/remitting MS. The observed immunogenetic heterogeneity between the different clinical forms of MS favors the hypothesis that primarily chronic progressive MS and relapsing/remitting MS are two distinct disease entities.     

中国人群1型糖尿病HLA-DQ基因多态性的Meta分析

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

Sequence and evolution of HLA-DR7- and -DRw53-associated beta-chain genes.

cDNA clones representing products of the DR7 and DRw53 beta-chain genes were isolated from the human B-lymphoblastoid cell line MANN (DR7,DRw53,DQw2, DPw2). The DRw53 beta sequence was identical to a DRw53 beta sequence derived from cells with a DR4 haplotype. In contrast, the DR7 beta sequence was as unrelated to DR4 beta sequence as it was to other DR beta-related genes, except at the 3'-untranslated region. These results suggest that the DR7 and DR4 haplotypes may have been derived relatively recently from a common ancestral haplotype and that the DR4 and DR7 beta-chain genes have undergone more rapid diversification in their beta 1 domains, most probably as a result of natural selection, than have the DRw53 beta-chain genes. Short tracts of sequence within the DR7 and DRw53 beta 1 domains were shared with other DR beta sequences, indicating that exchanges of genetic information between beta 1 domains of DR beta-related genes have played a part in their evolution. Serological analysis of mouse L-cell transfectants expressing surface HLA-DR7 molecules, confirmed by antibody binding and allelic sequence comparisons, identified amino acid residues that may be critical to the binding of a monomorphic DR- and DP-specific monoclonal antibody.     

Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris.

Previous studies demonstrated that HLA-DR4 was markedly increased among Ashkenazi Jewish patients with pemphigus vulgaris (PV), almost entirely as the common Jewish extended haplotype [HLA-B38, SC21, DR4, DQw8] or as the haplotype HLA-B35, SC31, DR4, DQw8, and that HLA-DR4, DQw8 was distributed among patients in a manner consistent with dominant expression of a class II (D-region or D-region-linked) susceptibility gene. In the present study of major histocompatibility complex (MHC) haplotypes in 25 non-Jewish PV patients, DR4, DQw8 was found in 12 of the patients and DRw6, DQw5 was found in 15. Only 3 patients had neither. Only 1 of the DR4, DQw8 haplotypes was [HLA-B38, SC21, DR4, DQw8] and 2 were HLA-B35, SC31, DR4, DQw8; most were the presumed fragments (SC31, DR4, DQw8) or (SC21, DR4, DQw8) or DR4, DQw8 with some other complotype. Of the patients with DRw6, DQw5, all were DRw14, DQw5, and 6 had a rare Caucasian haplotype, HLA-Bw55, SB45, DRw14, DQw5. Four of 6 of these were found in patients of Italian extraction, as was the 1 normal example. The non-Jewish patients were of more Southern European extraction than our controls. This suggests that there are two major MHC susceptibility alleles in American patients with PV. The more ancient apparently arose on a haplotype in the Jews, HLA-B38(35), SC21(SC31), DR4, DQw8, and spread to other populations largely as D-region segments. The other arose in or near Italy on the haplotype HLA-Bw55, SB45, DRw14, DQw5 and has also partially fragmented so that many patients carry only DRw14, DQw5. The available data do not permit the specific localization of either the DR4, DQw8- or the DRw14, DQw5-linked susceptibility genes.     

HLA antigens in Italian type 1 diabetic patients: role of DR3/DR4 antigens and breast feeding in the onset of the disease

HLA-A, B, C, DR and DQ typing was performed in 381 Italian insulin-dependent diabetic patients and in 905 normal Italian subjects. The diabetic patients had significantly higher frequencies of HLA-Cw7, B8, B18, DR3, DR4, DQw2 and DQw3 and significantly lower frequencies of HLA-B17, Bw51, DR2, DR7 and DRw11. The frequency of heterozygosity for HLA-DR3/DR4 was significantly higher in patients who developed the disease in the first 2 years of life and DR3+/DR4-, DQw2 and DQw3 alleles were higher in those aged less than 14 years at onset. The HLA-DR4 allele was associated with onset of diabetes in autumn and HLA-B18 with onset in Autumn-winter. Diabetic children who were breast fed had a later onset of insulin-dependent diabetes mellitus than those who were bottle fed but these differences were independent of HLA typing (11.18±0.72 years vs 9.23±0.42 years; mean±SEM). We conclude that: (1) in general, HLA distribution in Italian insulin-dependent diabetic patients reflects previous data reported in other European and North American populations; (2) HLA-DR3 and DR4 are strongly associated with insulin-dependent diabetes in Italy as well, and these alleles seem to predispose to an earlier onset of the disease; and (3) breast feeding may delay the onset of the disease.     

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.