Genetic factors in autoimmune thyroid disease analyzed by restriction fragment length polymorphisms of candidate genes.

Possible genetic effects on the development of autoimmune thyroid disease were studied by analysis of restriction fragment length polymorphisms (RFLPs) of candidate genes. Peripheral blood leukocyte DNA was obtained from 65 caucasian patients with Graves' disease, 63 caucasian patients with Hashimoto's thyroiditis, and 65 caucasian controls. RFLP analysis was carried out on genomic DNA, using probes for DR beta, DQ alpha, DQ beta, DP alpha, DP beta, T-cell receptor TCR alpha, and thyroid peroxidase. The methodology allowed HLA-DR and DQ typing and provided information on specific RFLP patterns related to T cell receptor (TCR)alpha, DP alpha and -beta, and -beta, and thyroid peroxidase. HLA-DR3 frequency was significantly increased in patients with Graves' disease, as reported previously by others, but neither DNA-derived subtype of DR3 was differentially increased. HLA-DQw2 was also present in increased frequency because of its linkage disequilibrium with HLA-DR3. It is uncertain whether the primary susceptibility is with DQ, DR, or another nearby locus. Susceptibility was not related in these studies to genetic loci recognized in these studies involving DQ alpha, DP, TCR, or thyroid peroxidase. A significant linkage disequilibrium between DR3 and a specific DX alpha RFLP was observed in Graves' disease, but is believed to be representative of a generalized linkage disequilibrium between DR3 and DX alpha, rather than a specific abnormality in Graves' disease. Previous studies indicating association with specific TCR RFLPs could not be reproduced. The relative risk for carriers of HLA-DR3 subtype A in this study was 7.37-fold. RFLP analysis offers the possibility of investigating linkage in a variety of candidate genes as well as established genetic relationships for potentially important subtypes. While the significant relationship with HLA-DR3/DQw2 was reconfirmed, the involvement of other genes or haplotypes could not be established.     

A DR4-associated DR-DQ haplotype is significantly associated with rheumatoid arthritis

Forty-three patients with seropositive, erosive rheumatoid arthritis (RA) and 24 members of 5 RA multicase families were studied for HLA class II gene polymorphism, using restriction fragment analysis with complementary DNA probes for DR beta and DQ beta chains. This method generates HLA-DR-DQ haplotypes that are highly correlated with HLA-DR serology. Thirty-five of the 43 RA patients (81%) were positive for one or for both of the DR4-associated DR-DQ haplotypes, 4.1 and 4.2. Among these patients, the 4.1 haplotype was found significantly more often than in DR4+ controls (P less than 0.01). The haplotype segment C3;B15;DR4 was present in all RA patients in 4 of the 5 families, and included the DR-DQ4.1 haplotype.     

Restriction fragment length polymorphism analysis of HLA-DR, DQ, DP and C4 alleles in Caucasians with systemic lupus erythematosus.

HLA-DR, DQ, DP and C4 null alleles were determined by restriction fragment length polymorphism (RFLP) analysis in 60 Caucasian patients with systemic lupus erythematosus (SLE) and 66 controls. DR3 (DRw17) and DQw2.1 were increased in frequency in the patients with SLE associated with the presence of C4A null genes. HLA-DP alleles determined by RFLP analysis of genomic DNA as well as of PCR amplified DNA were not associated with SLE or any clinical or autoantibody subset thereof. No DR, DQ, or C4 null gene association was found with renal or neuropsychiatric involvement or nDNA antibodies (or levels thereof). These data suggest that the primary predisposition to SLE lies with HLA-DR or C4 null alleles, and not with HLA-DP.     

汉族类风湿关节炎患者HLA—DR和—DQ基因分型研究

为探讨ＨＬＡ－ＤＲ和－ＤＱ等位基因与我国汉族类风湿关节炎（ＲＡ）的相关性，采用聚合酶链反应－限制性内切酶片段长度多态性分析（ＰＣＲ－ＲＦＬＰ）方法对汉族人群中３５例ＲＡ患者和１００名健康人的ＤＲ和ＤＱ位点进行ＤＮＡ定型分析。结果发现，ＤＲ４频率在正常人为２４．０％，在ＲＡ患者为５１．４％（Ｐ＜０．０１，ＲＲ＝３．３０）；ＤＲ４亚型位点分析发现２组均以ＤＲＢ１＊０４０５占多数，但ＤＲＢ１＊０４０５频率在ＲＡ组为３１．４％，高于正常人的１０．０％（Ｐ＜０．０１）。ＤＱ４频率在全部ＲＡ患者为３７．１％，在ＤＲ＋４ＲＡ患者为７２．２％，均高于全部正常人的１０．０％（Ｐ＜０．０１）和ＤＲ＋４正常人的４１．６％（Ｐ＝０．０３７６）；ＤＲ＋４－ＤＱ＋４ＲＡ患者的病情重于ＤＲ－４患者。结果提示，ＤＲ４、主要是ＤＲＢ１＊０４０５与ＲＡ相关，ＤＱ４可增加ＤＲ４对ＲＡ的易感性，ＤＲ＋４－ＤＱ＋４单倍型是ＲＡ病情严重程度的标志。     

Molecular analysis of HLA-DR beta and DQ beta polymorphism in Chinese with rheumatoid arthritis.

OBJECTIVES--Several studies have suggested that genetic predisposition to rheumatoid arthritis may be related to the presence of specific polymorphic HLA sequences that are often associated with HLA-DR4 haplotypes. This study was performed to determine if an association exists between Chinese with rheumatoid arthritis and a particular HLA-DR beta or DQ beta subtype. METHODS--This study used the polymerase chain reaction to amplify HLA-DR beta and DQ beta genes, and oligonucleotide probe hybridisation to examine the association of certain polymorphic sequences with rheumatoid arthritis in 23 Chinese patients from Shanghai. RESULTS--An HLA-DR4 associated sequence was significantly increased in the Chinese patients (43%) compared with healthy controls (14%) from the same location (relative risk = 4.6, 95% confidence limits 1.1 to 19.3). Analysis of the third hyperpolymorphic region of DR4 positive samples was performed to detect polymorphic sequences associated with Dw4, Dw10, Dw13, Dw14, Dw15, and KT2 cellular specificities. Examination of this region showed that 91% of patients had sequences encoding amino acids QRRAA (associated with Dw14 and Dw15) or QKRAA (associated with Dw4) compared with 64% of the DR4 positive controls. CONCLUSIONS--Rheumatoid arthritis in the Chinese is associated with HLA-DR4. There is a possible relationship between sequences within the third hyperpolymorphic region of the DRB allele and rheumatoid arthritis in the Chinese.     

DNA analysis of HLA-DR, DQ and DP genes in pauciarticular juvenile rheumatoid arthritis.

HLA-DR, DQ, and DP alleles were determined by restriction fragment length polymorphism (RFLP) and oligonucleotide hybridization analysis in 50 Caucasian children with pauciarticular juvenile rheumatoid arthritis (PaJRA) and 82 controls. There was an increased frequency of DR5, DRw8, and DQw4, as well as individual DQ alpha and beta chains, DQA*0401 and DQB1*0402, respectively, in this group of patients. There was an absolute association between DRw8, DQw4, DQA1*0401, and DQB1*0402 in the patient population. HLA-DPw2.1 was also increased in frequency. There was little evidence of linkage disequilibrium found between DPw2.1 and DR5, DRw8, or DQw4. These MHC Class II associations were more characteristic of those patients with young age of onset (less than 5 years), rather than those with onset greater than or equal to 5 years of age. Our data confirmed the previous associations of HLA-DR5, DRw8, and DPw2.1 with PaJRA and suggested a new association for DQ alpha and beta genes in the clinical expression of this disease.     

Use of pooled DNA samples to detect linkage disequilibrium of polymorphic restriction fragments and human disease: studies of the HLA class II loci.

A rapid method has been developed and used to search for restriction fragment length polymorphisms (RFLPs) that are in linkage disequilibrium with disease-associated loci. By using genomic blot-hybridization analysis with DQ beta-chain and DR beta-chain cDNA probes, we examined DNA polymorphisms within the HLA class II loci associated with susceptibility to insulin-dependent mellitus (IDDM). To facilitate the search for informative RFLPs, we compared pooled DNA samples from IDDM patients with pooled DNA samples from randomly selected control individuals, instead of using the conventional approach of examining DNA samples from individuals in two groups. (The conditions under which this approach is useful are treated theoretically in the Appendix.) Several specific polymorphic restriction fragments associated with IDDM were revealed by using this economical and rapid approach. The restriction enzymes and probes identified as informative in this screening were then used to analyze HLA-DR-typed IDDM families, homozygous typing cells, and unrelated individuals to determine the association of the specific restriction fragments with HLA-DR serological type and the frequency in control and IDDM populations. Some individual polymorphic fragments for which the IDDM population was enriched correlated strongly with HLA-DR3, whereas others correlated strongly with HLA-DR4. Some fragments (e.g., a 10-kilobase Taq I fragment detected with the DR beta probe) that were more prevalent in the IDDM population subdivided the serologically defined HLA-DR type and may be informative markers for IDDM susceptibility.     

Novel genetic markers of rheumatoid arthritis in Chilean patients, by DR serotyping and restriction fragment length polymorphism analysis.

OBJECTIVE. The analysis of genetic markers of rheumatoid arthritis (RA) in a population in which the DR4 serotype is not strongly associated with the disease. METHODS. Chilean RA patients (56 seropositive and 22 seronegative) and 141 controls were studied by serotyping. Southern blot analysis of Bam HI restriction fragment length polymorphism (RFLP) was done in genomic DNA from 46 patients with seropositive RA, 17 patients with seronegative RA, and 45 controls, using a complementary DNA probe specific for DRB1 genes. RESULTS. The prevalence of the HLA-DR9 haplotype was strikingly higher in seropositive RA patients (21%) than in controls (3%) (Pcorr less than 0.0008, by Fisher's exact test; relative risk [RR] = 9.34). The prevalence of DR4 and DR1 haplotypes, although slightly increased, did not achieve a significant preponderance. The simultaneous presence of two Bam HI fragments (3.6 kb and 4.5 kb) was found with higher prevalence in seropositive patients (83%; RR = 9; Pcorr less than 0.00002) than in controls (36%), and seemed higher in seronegative RA patients as well (71%; RR = 4). Furthermore, its prevalence remained increased in comparisons of DR4 positive controls (36%) with DR4 positive seropositive patients (100%; RR = 67; Pcorr less than 0.0002) and DR4 positive seronegative patients (100%; RR = 36; Pcorr less than 0.006), even after excluding the DR9 positive individuals. A tendency toward higher association with DR1 seropositive RA patients (67%; RR = 12), a group with no DR4 or DR9 positive individuals, than in DR1 positive controls (14%), was also observed. CONCLUSION. The HLA-DR9 haplotype was definitively consolidated as a very strong genetic marker exclusively for seropositive RA in Chilean patients, as suggested by our previous observations. RFLP analysis showed that the simultaneous presence of 3.6-kb and 4.5-kb Bam HI fragments constituted a better RA marker than did any of the heretofore studied haplotypes. These fragments together would be linked to RA independently of the DR1, DR4, and DR9 haplotypes. The overall evidence indicates that Chilean seropositive RA patients display a genetic background that is different from that underlying RA susceptibility in other populations and suggests the existence of common, as well as distinct, genetic elements predisposing to seronegative and seropositive 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 and disease manifestations in rheumatoid arthritis--a Canadian experience

Forty-eight Canadian patients with rheumatoid arthritis (RA) were tissue typed for class 1 (HLA-A, B, and C) and class 2 (HLA-DR and DQ) antigens in an attempt to identify HLA associations and to relate them to disease manifestations and drug toxicity. HLA-DR4 was found with a significantly higher frequency among patients with RA than in the control population. DR4 correlated with presence of rheumatoid nodules and pulmonary manifestations, and was more frequent among patients who had vasculitis. All 4 patients who died were DR4 positive. DR2 and DR7 were less frequent in our patients. There was no association between the presence of DR3 or DR4 and drug toxicity.     

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.     

HLA class II sequence polymorphisms and susceptibility to rheumatoid arthritis in Greeks. The HLA-DR beta shared-epitope hypothesis accounts for the disease in only a minority of Greek patients.

OBJECTIVE. In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA-DR beta found notably in the HLA-DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen. METHODS. We characterized HLA-DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization. RESULTS. DNA analysis in the RA patients showed that although individual HLA-DR allelic associations were weak, a relatively conserved HLA-DR beta motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA-DR beta 1 of 43.5% of the RA patients versus 15.5% of the controls (uncorrected P = 0.00004). CONCLUSION. Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA-DR beta motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.     

Does the locus on chromosome 11 implicated in susceptibility to HLA-DR4 dependent type I diabetes mellitus also affect susceptibility to rheumatoid arthritis?

There is a polygenic component to rheumatoid arthritis (RA) in addition to the known association with HLA-DR4. It has previously been shown in another autoimmune disease (type I diabetes mellitus) that a gene on chromosome 11p can act with HLA-DR4 to enhance susceptibility (relative risk 5-6). It is therefore possible that this locus may also affect the development of RA. Genotype frequencies at this locus, defined by a dimorphic Fok 1 restriction site, were compared in 139 healthy controls and 213 patients with classical/definite RA. In contrast with diabetes there was no increase in genotypes lacking the Fok 1 site, either in the rheumatoid group overall (125/211 compared with 86/139 controls) or in the DR4 positive rheumatoid group (76/140 compared with controls). These results indicate that the interaction between DR4 and a locus on chromosome 11p is not common to all DR4 associated autoimmune diseases.     

Susceptibility to relapsing polychondritis is associated with hla–-dr4

Objective. To determine the frequency of HLA class II antigens in Caucasian central European patients with relapsing polychondritis (RP). Methods. HLA class I, DR, and DQ specificities were identified in 41 patients with RP, and the frequencies were compared with those in 204 healthy, unrelated control subjects. HLA typing was performed using the standard complement-dependent microcytotoxicity assay. HLA–DR genotyping of 12 DR4-positive RP patients and 57 controls was performed by allele-specific oligonucleotide probing after amplification of genomic DNA by polymerase chain reaction. Results. A significant increase in DR4 antigen frequency was found in the patients (56.1%) as compared with that in healthy controls (25.5%) (P_corr < 0.001). Genotyping of DR4-positive patients and controls revealed no predominance of any DR4 subtype. Conclusion. There are important clinical similarities and overlaps between RP and rheumatoid arthritis (RA). In RA, the association with DR4 has been well established. Our findings show that although there is a DR4 association with RP, the situation is sufficiently distinct from that of RA to imply considerable differences in pathogenesis of the two conditions.     

HLA-DQ-RELATED RESTRICTION FRAGMENT LENGTH POLYMORPHISMS IN RHEUMATOID ARTHRITIS: EVIDENCE FOR A LINK WITH DISEASE EXPRESSION

Eighty-three patients with rheumatoid arthritis (RA) were investigatedfor HLA-DQ and DR locus restriction fragment length polymorphisms(RFLP). Of the 83 patients, 61 (73%) possessed the DR4 alleleand within this group we have investigated the relative frequenciesof two DQ beta gene variants of DQw3, DQw7 and DQw8, one ofwhich we had previously found to be raised in Felty's syndrome.This analysis revealed a significantly higher frequency of DQw7containing haplotypes in DR4 positive rheumatoid patients (64%)than in DR-matched healthy controls (42%). Furthermore, thedistribution of DQw7 was biased towards those patients withgreater disability indicated by the HAQ score, more systemicdisease and higher titres of rheumatoid factor, suggesting thatDQw7 may contribute to disease expression. KEY WORDS: HLA system, Disease association, Rheumatoid factor     

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.     

An extended HLA-D region haplotype associated with celiac disease

Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. We previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II beta-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. We now report the isolation of this beta-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP beta chain. This celiac disease-associated HLA-DP beta-chain gene was flanked by HLA-DP alpha-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DP alpha-chain genes of celiac disease patients also were studied by RFLP analysis; 84% of HLA-DR3, -DQw2 patients had a 16-kb Xba I fragment that was present in only 36% of HLA-DR3, -DQw2 controls. Moreover, 79% of these patients had both alpha- and beta-chain polymorphisms in contrast to 27% of controls. Thus, celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP alpha- and beta-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion.     

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.     

HLA-DR and DQ matching by DNA restriction fragment length polymorphism methods and the outcome of mixed lymphocyte reaction tests in unrelated bone marrow donor searches. The IMUST Study.

The use of DNA restriction fragment length polymorphism (DNA-RFLP) typing for HLA-DR and DQ genes was assessed in 96 patients who were HLA-A,B and DR matched by serology with one or more potential unrelated marrow donors (UD). Two hundred recipient-donor pairs from 10 transplant centres in the UK were studied. DNA-RFLP revealed serological errors in HLA-DR typing and identified additional recipient-donor mismatches. Of the 200 allegedly serologically matched pairs, 55 (28%) were mismatched for HLA-DR and/or DQ by DNA-RFLP typing. Of the 200 pairs, 68 (34%) mixed lymphocyte reactions (MLR) were negative and 132 (66%) positive. There was a significant correlation between DNA-RFLP defined mismatch and MLR positivity. However quantitative studies revealed no trend towards increasing MLR relative response index (RRI) with cumulative RFLP defined mismatch (i.e. for DR plus DQ compared with DR or DQ alone). RFLP matching for HLA-DR and DQ failed to predict a negative MLR. The RRI in the graft-versus-host direction was greater in RFLP matched pairs who carried HLA-DR4 than in matched pairs lacking DR4, suggesting that failure of RFLP to characterize DR4 subtypes was one reason why routine prediction of a negative MLR was not possible. Despite these limitations we have shown that DNA-RFLP is a reliable method for HLA-DR, DQ typing in routine UD searches in diverse clinical centres. By reducing the number of UD tested in MLR, RFLP typing can substantially reduce the work involved in donor selection.     

Association of rheumatoid arthritis with a dominant DR1/Dw4/Dw14 sequence motif, but not with T cell receptor beta chain gene alleles or haplotypes.

HLA-DR, HLA-DQ, and T cell receptor beta (TCR beta) chain gene polymorphisms were investigated in 43 patients with rheumatoid arthritis (RA), in 10 patients with Felty's syndrome (FS), and in 5 RA multicase families. RA was found to be strongly associated with a DRB1 gene sequence motif present in DR1, DR4-Dw4, and DR4-Dw14 alleles. Ninety-three percent of RA patients were positive for at least 1 of these alleles, providing strong support for the "shared epitope hypothesis." The frequency distribution of this sequence motif suggests a dominant mode of inheritance. All 10 FS patients were DR4-Dw4 positive. Different DR-DQ associations among DR4 positive RA and FS patients indicate heterogeneity in the genetic susceptibility to these 2 disease entities. Furthermore, analyses of TCR V beta 8, V beta 11, and C beta gene polymorphisms did not support the notion of an influence of TCR beta germline allotypes on RA susceptibility.