Bam HI DR-beta and DQ-beta restriction fragment length polymorphisms (RFLPs) were found with increased frequency in white persons with seropositive rheumatoid arthritis as compared with control subjects. DR-beta 4.8-, 5.2-, and 7.0-kilobase (kb) RFLPs were observed in 86.5 percent of rheumatoid arthritis patients and in 56 percent of control subjects (p = 0.001, relative risk [RR] = 5.0). The 6.0-kb RFLP was present in 79 percent of rheumatoid arthritis patients and 32 percent of control subjects (p = 0.0002, RR = 8.0). The 4.8-, 5.2-, and 7.0-kb RFLPs correlated with DR4, -7, -9, and -w53 phenotypes and the 6.0-kb RFLP correlated only with DR4. Thus, these RFLPs do not appear to be disease-specific. A DQ-beta 3.2-kb RFLP was found in 63.5 percent of rheumatoid arthritis patients and in 38.0 percent of control subjects (p = 0.01, RR = 2.8). This fragment was frequently found in persons expressing DR1 and DQw1 phenotypes. Probes consisting of the first exon of the DR-beta-I and DR-beta-IV genes, respectively, only hybridized with the 5.2- and 6.0-kb RFLPs. These data suggest that more than one gene within the major histocompatibility complex contributes to susceptibility to seropositive rheumatoid arthritis in white persons.

Arthritis, Rheumatoid↗

PubMed1988

Restriction fragment length polymorphism analysis in ankylosing spondylitis.

We utilized the technique of restriction fragment length polymorphism (RFLP) analysis in order to examine class I major histocompatibility complex genes in 52 Alabama ankylosing spondylitis patients and 107 local control subjects. A 9.2-kilobase PvuII RFLP was identified using the class I-specific B7 cDNA probe pDP001 that was closely associated with ankylosing spondylitis, most specifically with peripheral joint (including shoulder and hip) involvement. This fragment is associated with human leukocyte antigen A3 and A9 alleles, and segregation analysis in 11 multiplex families showed the RFLP to frequently segregate independently of B27 haplotypes. Two more recent studies have not confirmed the association of the 9.2-kilobase PvuII RFLP with ankylosing spondylitis per se, believed to be due to clinical and possibly genetic differences between the patient groups studied. These data strongly suggest at least one other major histocompatibility complex class I gene to be operative in predisposition to or modification of ankylosing spondylitis.

Deoxyribonucleases, Type II Site-Specific↗

PubMed1988

Association of HLA-linked factor B with gestational diabetes mellitus in black women.

The factor B BfF allele was found significantly less frequently in nonobese black women with gestational diabetes mellitus than in the control group. The BfS allele was found more frequently, although not significantly so. These data suggest similar genetic associations among nonobese black women with gestational diabetes mellitus and those with insulin-dependent diabetes mellitus.

Alleles↗

PubMed1988

A comparison of OKT3 monoclonal antibody and corticosteroids in the treatment of acute renal allograft rejection.

The monoclonal antibody OKT3 (Ortho Pharmaceutical, Raritan, NJ) was utilized in two separate protocols for treatment of acute renal allograft rejection in patients receiving cyclosporine, azathioprine, and prednisone for maintenance immunosuppression. In Group I, 54 patients received steroids for primary treatment of acute rejection with OKT3 used for resistant rejections and second rejection episodes. In Group II, 34 patients received OKT3 as primary treatment of acute rejection while steroids were used for rescue and second rejection episodes. OKT3 successfully reversed 82% of initial acute rejection episodes in Group II as compared with a 63% reversal with steroids in Group I. Rescue treatment was required in only 15% of Group II patients compared with 33% of Group I patients. Overall patient survival was 96% and 94%, respectively, for steroid primary and OKT3 primary treatments. Allograft survival at 3 months was identical, 74% in both groups. Based on allograft survival data, OKT3 is equally effective either as primary treatment for allograft rejection, or for rescue therapy if initial corticosteroid treatment fails.

Acute Disease↗

PubMed1988

Important risk factors of allograft survival in cadaveric renal transplantation. A study of 426 patients.

Multiple risk factors contribute to the allograft survival of patients who have cadaveric renal transplantation. A retrospective review of 19 such factors in 426 patients identified race, DR match, B + DR match, number of transplants, and preservation time to have a significant influence. The parametric analysis confirmed the effect to be primarily in the early phase, i.e., first 6 months. All patients received cyclosporine with other methods of immunosuppression resulting in an overall 1-year graft survival rate of 66%. The overall 1-year graft survival rate in the white race was 73% and in the black race was 57% (p = 0.002). Allograft survival and DR match showed white recipients with a 1 DR match to have 75% survival at 1 year compared with 57% in the black patient (p = 0.009). If HLA B + DR match was considered, the white recipient allograft survival increased to 76%, 84%, and 88% for 1, 2, and 3 match kidneys by parametric analysis. Patients receiving first grafts had better graft survival (68%) than those undergoing retransplantation (58%) (p = 0.05). Organ preservation less than 12 hours influenced allograft survival with a 78% 1-year survival rate compared with 63% for kidneys with 12-18 hours of preservation. Despite the benefits of B + DR typing, short preservation time, and first transplants to the white recipient, the allograft survival in the black recipient remained uninfluenced by these parameters.

Adolescent↗

PubMed1987

Association of a 9.2-kilobase Pvu II class I major histocompatibility complex restriction fragment length polymorphism with ankylosing spondylitis.

We analyzed DNA restriction fragment length polymorphism (RFLP) in 53 white ankylosing spondylitis (AS) patients and 92 healthy controls, utilizing a full-length HLA-B7 complementary DNA probe. A 9.2-kilobase (kb) Pvu II fragment was found to be significantly increased in frequency in B27 positive AS patients compared with the B27 positive control group (P = 0.00085, relative risk = 7.2). The presence of both B27 and the 9.2-kb RFLP in an individual conferred a relative risk for AS of 297, compared with a relative risk of 119 in those who had B27 alone. The 9.2-kb RFLP appears to be a marker for AS which, with HLA-B27, contributes further to susceptibility to the disease. Our findings indicate that this fragment and HLA-B27 segregate independently in familial studies of AS.

Genetic Techniques↗

PubMed1987

Analyses of HLA linkage in white families with multiple cases of seropositive rheumatoid arthritis.

Families with multiple cases of seropositive rheumatoid arthritis (RA), identified through 2 probands with the disease, were analyzed for genetic linkage between an autosomal susceptibility gene for RA and the HLA loci. These analyses were carried out over a wide range of penetrances (0.1-0.4), with prevalence for the disease fixed at 0.01 or 0.04. In some models, a sporadic frequency of 20% was assumed. Close linkage to the HLA loci was ruled out for all models where the gene was autosomal dominant, except for those with low penetrance and with prevalence set at 0.04. The models in which the gene was autosomal recessive produced results similar to those in models where it was autosomal dominant when prevalence was set at 0.01, and close linkage was ruled out, except at very low penetrances. With prevalence set at 0.04, the autosomal recessive gene model produced log odds scores which were all negative (-2.6 to -0.3). Therefore, the evidence in these families does not support close linkage with HLA, even though a significant DR4 RA population association exists. The data suggest that non-major histocompatibility complex (MHC) genes may contribute to the development of RA and, therefore, disease susceptibility may involve the genetic interaction of one or more MHC genes and non-MHC genes, in addition to environmental agents.

Arthritis, Rheumatoid↗

PubMed1987

Enhanced in vitro IgM rheumatoid factor synthesis in seropositive rheumatoid arthritis families.

We studied the patterns of in vitro IgM RF production by peripheral blood mononuclear leukocytes (MNL) in first- and second-degree relatives and non-blood relatives of 14 RA patients. In all these included 25 individuals with RA (14 probands, 11 other affected members), 88 non-affected first- and second-degree relatives and 15 non-affected non-blood relatives. In vitro production of IgM RF and IgM by MNL from RA patients was similar to what we and others have previously described. Spontaneous production of IgM RF was demonstrated by MNL from some RA patients and the ratio of IgM RF to total IgM was higher for patients than controls. The non-blood relatives failed to demonstrate spontaneous in vitro IgM RF production. In contrast, MNL from approximately 16% of non-affected blood relatives spontaneously produced IgM RF. Spontaneous IgM RF production in this group did not correlate with HLA-DR3 or HLA-DR4 and was found in Caucasoids. American blacks, simplex (one affected individual), and multiplex (more than one affected individual) families. Linkage analysis using either a recessive or dominant model of inheritance failed to detect linkage among affected and non-affected family members.

Arthritis, Rheumatoid↗

PubMed1987

Association of restriction fragment-length polymorphisms with major histocompatibility complex class II phenotypes in white and black individuals.

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Black People↗

PubMed1987

Analysis of restriction fragment length polymorphisms in rheumatic diseases.

Considerable evidence indicates that genes residing within the major histocompatibility complex (MHC) influence susceptibility to certain rheumatic diseases, such as ankylosing spondylitis (AS) and rheumatoid arthritis (RA). However, it has not yet been possible to precisely identify the gene(s) responsible for conferring enhanced susceptibility to these diseases. The availability of recombinant DNA technology should accelerate progress in obtaining this goal. A particularly promising method in this regard is restriction fragment length polymorphism (RFLP) analysis using appropriate class I and class II MHC gene probes. In preliminary studies, RFLPs have been identified for AS and RA which associate with susceptibility to the disease. Further studies using this approach should permit localization and precise identification of the disease susceptibility gene(s) for these diseases.

Arthritis, Rheumatoid↗

PubMed1987

DR beta Taq I restriction fragment length polymorphism (RFLP) associated with insulin dependent diabetes mellitus (IDDM).

DNA from insulin-dependent diabetes mellitus patients (IDDM) and healthy control individuals was evaluated using Southern blotting to determine if a disease-associated restriction fragment length polymorphism could be found. Using a DR beta-cDNA probe hybridized to Taq I digested genomic DNA, a 3.7 kb fragment was found in all IDDM patients examined (n = 33). Although a high percentage (47 per cent) of the control population also carried the fragment, nearly one-third of those persons were serotyped as DR2. The possible role of gene regulation in the development of IDDM is discussed.

Blotting, Southern↗

PubMed1987

Influence of race on renal allograft survival in the pre- and postcyclosporine era.

In conclusion we find that white cadaveric recipients of renal allografts have clearly benefited from the use of CsA. Matching for the major histocompatibility antigens, especially HLA-B + DR, is also associated with improved allograft survival in whites. For black cadaveric recipients there was no significant improvement in allograft survival with the use of CsA nor with matching for HLA. In contrast, for recipients of LRD kidneys both races appear to benefit from the use of CsA over conventional therapy. Consequently, it is clear that with the excellent allograft survival in LRD black recipients that matching can have a significant beneficial effect. However, the differences in survival between the races of cadaveric recipients suggest that for blacks the use of CsA cannot overcome the inherent genetic or physiologic differences that may exist. These results suggest that blacks should be targeted for concentrated study, the benefits of which would be to increase our understanding of potential factors influencing allograft survival in a group that comprises an increasingly larger proportion of candidates on waiting lists throughout the United States. 1. Overall renal allograft survival in CsA-treated black recipients is significantly lower than in comparable white recipients. The major period of allograft loss is in the first 6 months after which the rates of allograft loss for blacks and whites are similar. 2. There was a 12% increase in allograft survival in CsA-treated cadaveric recipients compared to pre-CsA-treated recipients. Allograft survival in white recipients has increased 15% whereas for black recipients there was only a 5% improvement over the azathioprine-prednisone treatment group. 3. Overall, there was a significantly improved graft survival for primary transplants compared to retransplants. Renal allograft survival in black CsA-treated recipients of primary transplants was significantly lower than in comparable whites, whereas there was no significant difference in graft survival between black and white recipients of retransplants. 4. Allograft survival rates in black and white recipients of kidneys from living-related donors were not significantly different from each other in either the non-CsA or the CsA immunotherapy group. 5. Overall there was improved allograft survival with increased matching for HLA-DR or B + DR compared to a zero match in CsA-treated recipients. Significantly, the effect of matching for HLA-DR or B + DR was seen only in white recipients.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1987

Toxicity due to remission inducing drugs in RA.

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Arthritis, Rheumatoid↗

PubMed1987

Toxicity of methotrexate in rheumatoid arthritis.

Seventy-two patients with rheumatoid arthritis had been treated with pulse weekly oral methotrexate with a mean followup of one year. Minor side effects (oral ulcers, transient elevation of liver enzymes, nausea, vomiting) were present in 46 patients (63.8%), whereas major side effects (severe infection, cytopenia, respiratory failure, seizures, gastrointestinal bleeding) were present in 7 (9.7%), 2 of whom died. Patients with major side effects had shorter disease duration and increased frequency of extraarticular manifestations as compared to those with no side effects. No association between a particular clinical or genetic variable and occurrence of side effects to methotrexate was found.

Administration, Oral↗