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W Thomson

Publications and source records attributed to W Thomson.

At least 91 records · Page 5Linked to original sources
PubMed1994

"Homozygosity" for the HLA-DR shared epitope contributes the highest risk for rheumatoid arthritis concordance in identical twins.

OBJECTIVE: To assess the contribution of HLA-DRB1 alleles in determining rheumatoid arthritis (RA) concordance in monozygotic twins. METHODS: Ninety-one monozygotic twins pairs in which at least 1 twin was affected were typed for HLA-DRB1 using both serologic methods and polymerase chain reaction amplification with sequence-specific oligonucleotide hybridization. The role of DR4 and of the shared epitope in disease concordance was investigated. Relative risks (RR) with 95% confidence intervals were determined. RESULTS: Increased concordance for RA was observed in both DR4 positive and shared epitope positive pairs (RR 3.4 and 3.7, respectively). A 5-fold risk for RA concordance was seen in twins who were "homozygous" for the shared epitope, compared with those negative for the shared epitope. CONCLUSION: In the absence of the shared epitope, RA concordance in monozygotic twins is rare. In contrast, "homozygosity" for the shared epitope is the most important factor in determining RA concordance.

Arthritis, Rheumatoid↗
PubMed1994

Tap gene associations in UK caucasoids.

The authors determined the allele frequencies of the TAP1 and TAP2 transporter genes in a healthy UK Caucasoid population by ARMS-PCR. TAP1A was the most frequent TAP1 allele by far, being present in 76% of subjects. TAP1 alleles could not be assigned in 24% of subjects, since the combinations TAP1A/1b and TAP1C/1D cannot be separated. TAP2A was the most frequent TAP2 alleles (75% of subjects) followed by TAP2B (43%), TAP2C (11%), TAP2D (8%) and TAP2E (6%). The authors also identified an individual with a previously undescribed TAP2 allele, TAP2H (isoleucine at amino acid [aa] 379, alanine at aa 565, alanine at aa 665). It was not possible to assign unequivocally TAP2 alleles in 15 individuals (9%) as TAP2A/D and TAP2C/E cannot be distinguished from each other. To address this problem a separate study of families of rheumatoid arthritis (RA) patients selected for this ambiguity were studied. In all five informative families, TAP2A/2D was confirmed as the combination present. In the population studied no evidence was found for linkage disequilibrium between TAP1 and TAP2 or between the TAP genes and HLA-DP. There was no evidence for extensive linkage disequilibrium between the TAP genes and HLA-DQR, although TAP2B was associated with DRI (delta = 0.056, corrected P < 0.01) and TAP2D with DR4 (delta = 0.018). In the RA families studied, TAP2D was found on DRB1*0401-bearing haplotypes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Increased frequency of TAP2B in early onset pauciarticular juvenile chronic arthritis.

OBJECTIVES: To determine whether polymorphisms of the TAP genes, which lie within the major histocompatibility complex (MHC), are associated with juvenile chronic arthritis (JCA). METHODS: Eighty five JCA patients and 166 white controls were typed for the TAP gene alleles using ARMS-PCR. The same populations were analysed for DRB1 and DPB1 alleles using PCR-SSO typing. RESULTS: TAP2B was increased in early onset pauciarticular JCA (EOPA-JCA) compared with controls (62% v 44% Odds ratio (OR) 2.1, 95% CI 0.9-4.7). After allowing for the known linkage disequilibrium between TAP2B and DR1 the association of TAP2B and EOPA-JCA was maintained (OR 3.5, 95% CI 1.3-9.7). HLA-DRB1*04 and TAP2D were found to be in linkage disequilibrium in both the control (delta 0.018 p < 0.05) and JCA patient groups (delta 0.021 p < 0.05). No linkage disequilibrium was found between the TAP and DPB1 alleles. CONCLUSIONS: The association between TAP2B and EOPA-JCA is a further indication of the heterogeneity which exists in this clinically defined subgroup of patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Twin concordance rates for rheumatoid arthritis: results from a nationwide study.

We report the concordance rate for RA in a nationwide study of 91 monozygotic (MZ) and 112 dizygotic (DZ) pairs. Twin pairs were recruited from both a national media campaign and a 2-month prospective inquiry of all UK rheumatologists. Disease status was established following a structured clinical and serological appraisal, together with radiological assessment where necessary. Zygosity was confirmed using DNA fingerprinting. In all, 14 (15.4%) of the MZ and four (3.6%) of the DZ pairs were disease concordant (risk ratio: 4.3 95% CI 1.5 to 12.6). There was no difference in the concordance between the media and clinical derived twins. Further the excess MZ concordance persisted after adjusting for age, age at disease onset, sex and rheumatoid factor status. Analysing the data in relation to the timing of disease onset in the first affected twin showed that subsequent disease risk in the initially unaffected co-twins of the MZ affected probands increased with increasing duration of follow-up. We conclude that the overall MZ concordance at 15% is lower than the 30% figure normally quoted from a study some 30 years ago and sets a ceiling at the potential genetic contribution to disease susceptibility.

Adult↗
PubMed1993

Multiplex ARMS-RFLP: a simple and rapid method for HLA-DR4 subtyping.

We have developed a simple and rapid non-radioactive technique for HLA-DR4 subtyping. A multiplex ARMS-RFLP (Amplification Refractory Mutation System--Restriction Fragment Length Polymorphism) system allows HLA-DR4 subtyping by analysis of the products of two multiplex ARMS reaction mixtures. For some cases, restriction enzyme digests (Hae II and/or SacII) of the products are analysed. The technique relies on the fact that an ARMS primer with a mismatch at its 3'-end with respect to the template will not be elongated under PCR conditions. Hence, by designing ARMS primers such that different HLA-DR4 alleles yield PCR products of different lengths, only two reactions, each using a mixture of different ARMS primers, are sufficient to type all of the known HLA-DR4 alleles. This system can distinguish between HLA-DR4 'homozygotes' and 'heterozygotes' since every HLA-DR4 allele can be detected. The ARMS conditions were optimized using DNA from cell lines. This technique has now been used to type a panel of rheumatoid arthritis patients and controls.

Alleles↗
PubMed1993

A shared HLA-DRB1 sequence confers RA susceptibility in Greeks.

Previous serological studies of Greek rheumatoid arthritis (RA) patients have failed to demonstrate an association with DR4. Using sequence specific oligonucleotide typing we have identified the DRB1 alleles in panels of Greek RA patients and controls. When patient and control HLA-DRB1 frequencies were compared, significantly higher frequencies of DRB1*0101 (23.3% vs. 7.0%, odds ratio [OR] 4.0, 95% confidence intervals [CI] 1.4-12.0) and DRB1*1001 (20.9% vs. 5.8%, OR 4.3, 95% CI 1.3-13.7) were found in RA patients compared with controls. No association of DRB1*04 with RA was observed (20.9% vs. 14.0% in controls) confirming earlier reports. However DRB1*04 subtyping demonstrated a small but significant increase of DRB1*0405 in patients (14.0% vs. 3.5%, OR 4.5, 95% CI 1.1-18.9). When the frequency of individuals carrying the shared RA susceptibility epitope was compared between patients and controls it was found to be significantly higher in RA patients (60.5% vs. 22.1%, OR 5.4, 95% CI 2.4-12.0). We conclude that the shared epitope is significantly associated with RA in this population, but that it is predominantly accounted for by DRB1*0101 and DRB1*1001. Previous studies of UK RA patients have demonstrated a negative association of DR2 with disease and articular erosions. HLA-DR2 variants, DRB1*1501 and *1502 are not at reduced frequency in Greek RA patients (DRB1*1501, 14.0% in patients vs. 7.0% in controls; DRB1*1502, 7.0% in patients vs. 7.0% in controls). Genes conferring RA resistance may be in linkage disequilibrium with DR2 in UK patients. This does not appear to be the case in Greek RA patients. No association was seen between RA and HLA-DPB1 type.

Alleles↗
PubMed1993

Absence of an association between HLA-DRB1*04 and rheumatoid arthritis in newly diagnosed cases from the community.

OBJECTIVES: To determine HLA-DR4 and DR1 allele frequencies in a series of patients with newly diagnosed early inflammatory arthritis. METHODS: HLA-DR1 and DR4 frequencies were determined by oligonucleotide typing of 208 patients classified as having either rheumatoid arthritis (RA) or undifferentiated inflammatory polyarthritis. RESULTS: The frequency of occurrence of DR4 in these patients with RA did not differ significantly from that in controls in the United Kingdom (42 v 37%). HLA-DR1 was increased in the group with inflammatory polyarthritis (25 v 18%). CONCLUSIONS: The frequency of DR4 is not increased in newly diagnosed community based patients with RA. This supports the hypothesis that DR4 is less important as a marker for susceptibility to RA than it is for disease persistence or severity.

Arthritis, Rheumatoid↗
PubMed1993

HLA allele detection using molecular techniques.

There are now many molecular biological techniques available to define HLA class I and class II alleles. Some of these are also applicable to other human polymorphic genes, in particular to those non-HLA genes encoded within the Mhc. The range of techniques available allows laboratories to choose those most suited to their purpose. The routine laboratory supporting solid organ transplants will need to type large numbers of potential recipients over a period of time, probably using PCR-SSOP while donors will be typed singly and rapidly using PCR-SSP with HLA allele compatibility determined by heteroduplex analysis. Laboratories supporting bone marrow transplantation, where time is less pressing, can choose from the whole range of techniques to determine accurately donor recipient Mhc compatibility. For disease studies, techniques defining precise HLA allele sequence polymorphisms are needed and high sample numbers have to be accommodated. When an association is established allele sequencing has to be used. In the near future, the precise role of HLA alleles in transplantation and disease susceptibility is likely to be established unambiguously.

Alleles↗
PubMed1993

Absence of rheumatoid arthritis in a rural Nigerian population.

A 2-stage population screening survey of 2,000 inhabitants of 2 rural townships in southern Nigeria was undertaken. No case of rheumatoid arthritis (RA) was discovered in those responding, although 3 cases of inflammatory polyarthritis were found. One of these individuals satisfied the modification of the American College of Rheumatology classification tree criteria that allows for missing radiographic data. Simultaneous monitoring, during a 4-month period, of the local health clinic serving the townships also failed to reveal a case of RA. Three (5.5%) of 55 individuals tested were positive for rheumatoid factor, a rate lower than in previous surveys of rural West African populations. Further immunogenetic investigation of that subsample from this population, using HLA oligonucleotide typing, suggested that HLA-DR4 was rare (1/55). Further, although HLA-DR1 was present in 7 (13%), 6 had the DRB1*0102 variant seen in black populations and not thought to be associated with RA. Our study confirmed the findings of others that rural African groups have extremely low rates of RA. In addition HLA genes containing the RA associated "shared epitope" are also relatively infrequent and might explain this reduction in RA prevalence.

Adolescent↗
PubMed1992

Population genetics of rheumatoid arthritis.

A major component of genetic susceptibility to rheumatoid arthritis (RA) appears to be explained by inheritance of HLA-DRB1 alleles, which have a conserved sequence of amino acids in the third hyper-variable region of the molecule. This "shared epitope" is found on various DR4, DR1, and DR6 variants, as well as on DR10. The evidence for this "shared epitope" in RA is examined at the population level, including how it fits in with the available epidemiologic data and RA disease severity.

Alleles↗
PubMed1991

Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis.

In hereditary hemochromatosis (HH), increased intestinal iron absorption leads to the development of iron overload. To examine the abnormal regulation of iron absorption in this disorder, we analyzed mucosal iron kinetics in six patients with HH and in five normal subjects by using a compartmental model of intestinal iron absorption and systemic ferrokinetics. Subjects were given simultaneous oral and intravenous tracer doses of iron 59-labeled citrate and iron 55-labeled transferrin, respectively. Plasma and whole-body radioactive iron levels were then monitored serially during the next 2 weeks, and mucosal iron transport rate constants were estimated by non-linear least-squares fit of the model to these data. Iron absorption was inversely related to serum ferritin concentration in both normal subjects and patients with HH but was higher in relation to serum ferritin level among the latter (p less than 0.0002). Analysis of mucosal iron kinetics demonstrated a similar inverse relationship between the rate constant for mucosal iron uptake and serum ferritin among all subjects combined, but the mean uptake rate constant in patients with HH did not differ from that of normal subjects (p = 0.71). The mean rate constant for incorporation of iron into the mucosal storage pool in patients with HH also was comparable to that of normal subjects (p = 0.94). In contrast, the rate constant for transfer of mucosal iron to the plasma was higher in patients with HH than in normal subjects for any given serum ferritin level (p less than 0.0001), and the transfer rate constant accounted for 87% of the variability in iron absorption among all subjects. We conclude that the increased iron absorption in HH is mediated primarily by an increase in the rate constant for transfer of mucosal iron to the plasma.

Ferritins↗
PubMed1990

DNA polymorphism of the C2 and factor B gene.

C2 and factor B are encoded by very closely linked loci in the class III region of the human major histocompatibility complex on chromosome 6. The factor B gene is divided into 18 exons, and is 6 kb in length whereas the C2 gene is much larger being 18 kb in length. Sequence and Southern blot analysis has defined 5 DNA polymorphisms in the DNA encompassing the C2 and factor B loci. The most interesting of these are the SstI multi-allelic polymorphism at the 5' end and the TaqI polymorphism at the 3' end of the C2 gene. Together these allow the subdivision of haplotypes carrying the C2C and factor B F alleles. A novel combination of SstI and TaqI RFLPs is reported here.

Alleles↗
PubMed1989

Long-term follow-up of patients with echocardiographically detected mitral anular calcium and comparison with age- and sex-matched control subjects.

One hundred seven patients with echocardiographically documented mitral anular calcium (MAC) and 107 age- and sex-matched control subjects without MAC were studied and followed for a mean of 4.4 +/- 2.4 (standard deviation) years. Fourteen (7%) patients were lost to follow-up. Compared with the control group, patients with MAC had higher frequency of precordial murmurs (p less than 0.0001), cardiomegaly (p less than 0.0001), left atrial enlargement (p less than 0.0001), and rhythm and conduction disturbances (p less than 0.0001). During the follow-up, patients with MAC had higher incidence of valve replacement (p less than 0.0025), permanent pacemaker implantation (p less than 0.0025), congestive heart failure (p less than 0.0001), thromboembolic cerebrovascular event (p less than 0.01), sudden death (p less than 0.001) and total cardiac death (p less than 0.0001). However, the frequencies of myocardial infarction, coronary artery bypass surgery and angioplasty, endocarditis or noncardiac death were not significantly different between patients with MAC and the control subjects. Thus, patients with MAC have higher frequencies of precordial murmurs, cardiomegaly, left atrial and ventricular enlargement, rhythm and conduction disturbances. They more frequently undergo valve replacement and permanent pacemaker implantation, develop congestive heart failure and die of cardiac causes than age- and sex-matched control subjects.

Adult↗
PubMed1989

Comparison of five antimelanoma antibodies for identification of melanocytic cells on tissue sections in routine dermatopathology.

Five antimelanoma antibodies used on routinely processed tissue sections have been compared for their value in identifying both benign and malignant melanocytic lesions. Antibodies to S-100 protein, NKIC3, HMB45, HMB50, and FKH1 were used. S-100 protein was polyclonal, but the others were monoclonal. The tissue was fixed in neutral buffered formalin and included sections from 15 primary melanomas, 5 secondary melanomas, 10 dysplastic nevi, and 10 compound nevi. Antibodies HMB45 and NKIC3 showed the greatest degree of sensitivity.

Antibodies, Monoclonal↗