Nine new dog DLA-DRB1 alleles identified by sequence-based typing.
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Alleles↗
Biomedical subjects
W Thomson
Publications and source records attributed to W Thomson.
Complement C4B null allele status confers risk for systemic lupus erythematosus in a Spanish population.
Genetic susceptibility to systemic lupus erythematosus (SLE) may vary amongst different populations. In UK patients, genes encoded in the HLA class II (DQA*0501/DRB1*0301) and class III [C4A*Q0 and tumour necrosis factor (TNF) polymorphisms] subregions appear to contribute to disease susceptibility. We have examined HLA-DRB1, C4 and TNF microsatellites in 50 Spanish SLE patients and 48 matched controls. HLA-DRB1*0301 was increased in patients but did not achieve statistical significance (41% vs. 25.5%). C4A*Q0 was not increased in patients, but C4B*Q0 allele frequency was significantly increased compared with the controls (29% vs. 6%; OR: 6.0). TNF c2 microsatellite allele frequency was also increased in SLE patients. The C4B null allele (C4B*Q0) appears to play an important role in SLE susceptibility in the Spanish population.
Alleles↗
Susceptibility to melanoma: influence of skin type and polymorphism in the melanocyte stimulating hormone receptor gene.
Allelic variation at the melanocyte stimulating hormone receptor (MC1R) gene has been linked with sun-sensitive skin types, suggesting it is a susceptibility candidate for melanoma. We determined the frequency of the val92met, asp294his, and asp84glu MC1R alleles in 190 Caucasian controls and 306 melanoma cases and studied their association with skin type and hair color. The percentage of controls with at least one val92met, asp294his, or asp84glu allele was 17.3%, 6.8%, and 3.5%, respectively. Individually, frequencies of the val92met, asp294his, or asp84glu alleles in the controls with skin types 3 and 4 were similar to those with skin types 1 and 2. Trend analysis, however, did identify an association (exact p = 0.048, two-sided test) between skin type and MC1R variants in the group comprising all controls with any one or more of these alleles. There was no association between MC1R alleles and hair color. Allele frequencies were not different in melanoma cases and controls. There were no associations between skin types and the proportion of cases with the asp294his or asp84glu alleles, though the association between skin type and the val92met allele approached significance (exact p = 0.09, two-sided test). Unexpectedly, in the group comprising all cases with one or more variant alleles, the proportion of subjects with variant alleles increased with skin types associated with tanning rather than burning, although trend analysis showed that this association did not quite reach statistical significance (exact p = 0.08, two-sided test). Asp84glu (but not val92met or asp294his) variant alleles were more common in subjects with blonde hair, although the relationship between the asp84glu allele and hair color did not achieve statistical significance (chi(2)3 = 6.16, exact p = 0.10). We interpret the data presented as indicating that polymorphism at MC1R does not appear a major determinant of skin type, at least in terms of these allelic variants. Furthermore, considered alone, these alleles are not susceptibility candidates for malignant melanoma.
Adult↗
A study of HLA-DPB1 phenotypes reveals DPB1*6301 in a rural population from Cameroon.
Several recently reported HLA-DPB1 alleles have only been identified in a single family or individuals and are of unknown distribution world-wide. Many new DPB1 alleles appear to arise as a result of gene conversion-like events, which may localize variant DPB1 alleles to the population in which they were first identified. Using two SSOP-based typing methods in parallel, we have identified HLA-DPB1*6301 in an individual from rural Cameroon which has previously only been reported in a family of Mexican-American origin. The presence of DPB1*6301 was confirmed by sequence-based typing of exon 2.
Alleles↗
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.
Aged↗
Allelic markers close to prolactin are associated with HLA-DRB1 susceptibility alleles among women with rheumatoid arthritis and systemic lupus erythematosus.
OBJECTIVE: To investigate linkage disequilibrium between HLA-DRB1 disease susceptibility alleles and microsatellite markers close to the prolactin gene, among women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and normal controls. METHODS: DNA from 89 women with RA, 76 women with SLE, and 94 controls was typed for HLA-DRB1 status and D6S422 and D6S285, 2 highly polymorphic microsatellite markers close to the prolactin gene. RA patients were stratified by DRB1*0401 status, and SLE patients were stratified by *0301 status. RESULTS: There was an excess frequency of D6S422*1 among SLE patients with DRB1*0301 (odds ratio [OR] 3.1). The frequency of this allele was also slightly in excess among RA patients with DRB1*0401 (OR 1.9). D6S285*5 was also in excess among female RA patients with DRB1*0401 (OR 3.5), and was slightly increased among female SLE patients with DRB1*0301. None of these alleles were found to be increased among *0401-positive or *0301-positive controls. CONCLUSION: These data indicate that there may be linkage disequilibrium between HLA-DRB1 alleles and microsatellite marker alleles close to the prolactin gene among women with RA and SLE. This suggests the possibility of extended haplotypes encoding for HLA-DRB1 susceptibility and high prolactin production, which contribute to susceptibility to both RA and SLE.
Alleles↗
HLA-DQ alleles associate with cutaneous features of onchocerciasis. The Kaduna-London-Manchester Collaboration for Research on Onchocerciasis.
Onchocerciasis is associated with a spectrum of cutaneous changes, ranging from clinically normal skin to acute and chronic pathology. An important aspect of disease expression may be the level of immune response to parasite antigens, which is likely to be regulated by MHC-encoded molecules. We therefore investigated HLA class I and class II phenotypes in Nigerian residents of an area endemic for onchocerciasis. All study subjects were carefully characterized for parasite load and skin pathology. Individuals with depigmentation had increased frequencies of DQA1*0501 and DQB1*0301 compared with persons with normal skin and high microfilarial load (NSHMF) (Odds Ratios 3.6 (95% CI 1.0 to 13.2) and 3.8 (1.0 to 15.2), respectively). Conversely, individuals with depigmentation had a decreased frequency of DQA1*0101 and Cw6 compared with NSHMF (Odds Ratios 0.2 (0.1 to 0.9) and 0.1 (0.02 to 0.8), respectively). When NSHMF subjects were examined by age, a further decrease in DQA1*0501 frequency and increase in DQA1*0101 frequency were observed in older NSHMF individuals. These results strongly suggest that there is an immunogenetic basis for the spectrum of cutaneous presentations in onchocerciasis and that HLA-DQ molecules are associated with the level of immune response to parasite antigens.
Adolescent↗
Patients who develop inflammatory polyarthritis (IP) after immunization are clinically indistinguishable from other patients with IP.
Musculoskeletal symptoms may occur following various types of immunization, and it has also been suggested that, like infection, immunization may act as a trigger for rheumatoid arthritis (RA). A total of 48 of 898 (5.3%) patients with early inflammatory polyarthritis (IP) referred to the Norfolk Arthritis Register reported an immunization in the 6 weeks prior to symptom onset. There were no important clinical or demographic differences between the 48 immunized patients and 185 consecutive patients who did not report prior immunization. In addition, the frequencies of HLA-DRB1*01. *04 and the shared epitope in 33 of the immunized patients were similar to those in the 185 non-immunized patients and to those in 136 healthy controls. Further results from a case-control study suggest that the rate of immunization is higher amongst cases (5.5%) than age- and sex-matched controls (2.8%). In a small number of susceptible individuals, immunization may thus act as a trigger for RA.
Adolescent↗
Localization of eight additional genes in the human major histocompatibility complex, including the gene encoding the casein kinase II beta subunit (CSNK2B).
A wide range of autoimmune and other diseases are known to be associated with the major histocompatibility complex. Many of these diseases are linked to the genes encoding the polymorphic histocompatibility antigens in the class I and class II regions, but some appear to be more strongly associated with genes in the central 1100-kb class III region, making it important to characterize this region fully for the presence of novel genes. An approximately 220-kb segment of DNA in the class III region separating the Hsp70 (HSPA1L) and BAT1 (D6S8IE) genes, which was previously known to contain 14 genes, has been analyzed for the presence of additional genes. Genomic DNA fragments spanning the gaps between the known genes were used as probes to isolate cDNAs corresponding to five new genes within this region. Evidence from Northern blot analysis and exon trapping experiments that suggested the presence of at least two more new genes was also obtained. Partial cDNA and complete exonic genomic sequencing of one of the new genes has identified it as the casein kinase II beta subunit (CSNK2B). Two of the other novel genes lie within a region syntenic to that implicated in susceptibility to experimental allergic orchitis in the mouse, an autoimmune disease of the testis, and represent additional candidates for the Orch-1 locus associated with this disease. In addition, characterization of the 13-kb intergenic gap separating the RD (D6545) and G11 (D6S60E) genes has revealed the presence of a gene encoding a 1246-amino-acid polypeptide that shows significant sequence similarity to the yeast anti-viral Ski2p gene product.
Base Sequence↗
Mdm-2 is not induced by p53 in human keratinocytes in vivo.
Normal p53 protein protects the genome after DNA damage by delaying replication and allowing DNA repair. mdm-2 is a recently discovered protein that controls p53 activity by binding to and inactivating p53 protein. A negative feedback loop has been suggested in which p53 induces mdm-2 expression. We have shown that doses of ultraviolet B radiation that cause mild sunburn clinically, produce thymine dimers in keratinocytes detectable by immunocytochemistry. This causes an elevation of p53 protein without a concomitant p53-mediated induction of mdm-2.
DNA Damage↗
Localisation of eight additional genes in the human major histocompatibility complex, including the gene encoding the casein kinase II beta subunit, and DNA sequence analysis of the class III region.
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Blotting, Northern↗
Mannose-binding protein gene polymorphism in systemic lupus erythematosus.
OBJECTIVE: To determine whether an allelic form of mannose-binding protein (MBP) incapable of activating complement is associated with susceptibility to systemic lupus erythematosus (SLE). METHODS: MBP allele frequencies were determined by amplification refractory mutation system-polymerase chain reaction in 102 white SLE patients and 136 controls. RESULTS: The MBP allele that is unable to activate complement was present in 42 SLE patients (41%) and in 41 controls (30%) (P = 0.08, odds ratio [OR] = 1.6, 95% confidence interval [95% CI] 1.0-2.8). The gene frequency of this allele was 0.25 in SLE patients and 0.19 in controls (P = 0.08, OR = 1.5, 95% CI 1.0-2.3). CONCLUSION: Our results suggest that this allele of the MBP gene represents a minor risk factor for SLE.
Adolescent↗
Antinuclear antibodies in early onset pauciarticular juvenile chronic arthritis (JCA) are associated with HLA-DQB1*0603: a possible JCA-associated human leucocyte antigen haplotype.
A panel of 43 early onset pauciarticular (EOPA) juvenile chronic arthritis (JCA) patients have been typed for human leucocyte antigens (HLA) DRB1, DPB1, DQA1 alleles, and DQB1*0603 status using molecular-based methods. Increased frequencies of DRB1*08 [odds ratio (OR) 7.7, 95% confidence interval (CI) 2.6-22.3], DRB1*11 (OR 3.1, 95% CI 1.2-8.1), DRB1*1301 (OR 7.7, 95% CI 2.6-22.3), DPB1*0201 (OR 3.5, 95% CI 1.6-8.0), DQA1*0103 (OR 4.4, 95% CI 1.5-13.3), DQA1*0501 (OR 2.9, 95% CI 1.3-6.6), DQA1*0601 (OR 30, 95% CI 3.6-241) and DQB1*0603 (OR 7.3, 95% CI 3.0-17.6) were found in the EOPA-JCA group compared with Caucasoid controls. Stratification of the EOPA-JCA group into antinuclear antibody (ANA) positive (n = 18) and ANA negative (n = 25) individuals revealed that ANA positivity was only associated with DRB1*1301 (OR 4.2, 95% CI 1.0-17.3), DPB1*0201 (OR 4.0, 95% CI 1.0-15.7) and DQB1*0603 (OR 11.5, 95% CI 2.5-53.4). Further analysis of the relative contributions of HLA antigens to ANA status revealed that DQB1*0603 determined the primary HLA effect. No apparent interaction between DQB1*0603 and DRB1*1301 or between DQB1*0603 and DPB1*0201 was found to contribute to the association with ANA. We suggest that those ANA positive individuals with a restricted HLA background, (DQB1*0603 positive), defines a group of EOPA-JCA patients which will be especially valuable in the characterization of the ANA associated with EOPA-JCA.
Age of Onset↗
Definition of HLA-C alleles using sequence-specific oligonucleotide probes (PCR-SSOP).
Many new HLA-C locus alleles have recently been identified by DNA sequencing, and a molecular based method for their detection using PCR with sequence specific primers has been reported. However, other methods may be more appropriate for the identification of C locus alleles in larger studies. Here we describe one such system, based on PCR sequence specific oligonucleotide probes, (SSOP) for C locus typing. Advantages of SSOP typing compared to SSP are that it is easier to detect new alleles, more cost effective and less time consuming. We have developed a DNA typing method to identify the broad C locus antigens (including those not yet defined serologically) using a minimum of probes with one amplification. We use a C locus specific sense primer in exon 2 and a consensus antisense primer in exon 3, in a two-step PCR, giving a product of 710 bp. Probes were designed with similar melting temperatures (54-56 degrees C) that would identify as many alleles as possible. The method was established using DNA from B lymphoid cell lines of known C locus type, mostly 10th workshop homozygous cell lines, plus as many other sequenced cell lines as possible. The system was able to correctly identify their C locus types using only 26 probes. DNA was tested from a panel of serologically typed individuals which included many different heterozygous combinations. We found a high concordance of results, with all discrepancies being additional antigens identified by molecular typing, filling in serological blanks. We can identify all common heterozygote combinations using this method.
Alleles↗
Absence of TAP 2D in Yoruba Nigerians.
We have characterized TAP allele frequencies in a panel of 71 Yoruba Nigerians using ARMS-PCR. With the exception that TAP 2D was absent in Nigerians, TAP 2 allele frequencies in this population were found to be similar to those in a UK white population. HLA-DR4 also was found to be at a low frequency in Yoruba Nigerians (1.4%). This may reflect the absence of TAP 2D in Nigerians as DR4 and TAP 2D are in linkage disequilibrium in UK Caucasoids. The most frequent TAP 1 allele in Yoruba Nigerians was TAP 1A (49%). However, this value will be an underestimate as TAP1 alleles could not be unequivocally assigned in 41% of subjects using the ARMS-PCR methodology.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Lack of influence of non-inherited maternal HLA-DR alleles on susceptibility to rheumatoid arthritis.
OBJECTIVE: To reproduce findings from previous reports that non-inherited maternal HLA class II antigens might contribute to rheumatoid arthritis (RA) susceptibility in the offspring. METHODS: Families were recruited from the Arthritis and Rheumatism Council's National Repository of RA families and HLA-DRB1 alleles were examined in these individuals and their first degree relatives using DNA typing methods. RESULTS: There was no evidence of an increase in either non-inherited maternal HLA-DR4 or the HLA-DRB1 shared epitope as a whole compared with the frequency expected using the non-inherited paternal antigens as controls. CONCLUSIONS: The numbers of probands who were shared epitope negative were small, but we are unable to confirm in these families the findings that non-inherited maternal HLA contributes an additional susceptibility factor to rheumatoid arthritis.
Alleles↗
HLA-DRB1*0401/0404 genotype and rheumatoid arthritis: increased association in men, young age at onset, and disease severity.
OBJECTIVE: To confirm the reported strong association between the HLA-DRB1*0401/0404 genotype and susceptibility to rheumatoid arthritis (RA), and to investigate the influence of sex, age at disease onset, and variables of disease severity on the strength of this association. METHODS: A case control design was adopted comparing the frequency of specific HLA-DRB1 genotypes between 201 Caucasian patients with RA and 139 controls. HLA typing was performed using a polymerase chain reaction based oligonucleotide approach with HLA-DR4 subtyping using an amplification refractory mutation system RFLP technique. RESULTS: The risk of RA in those carrying a single shared epitope (SE) allele was 4 times, and in those carrying 2 SE alleles, 8 times that in the SE negative individuals. This increase was highest in individuals carrying 2 different SE alleles, with the risk in *0401/*0404 cases being 26 times higher. This genotype was associated with a 90-fold increased risk in men and this was more than doubled when age at disease onset was below 30. In all patients with RA, this genotype was associated with a substantially increased risk of being rheumatoid factor positive and having subcutaneous nodules and/or radiological erosion. CONCLUSION: Possession of the HLA-DRB1*0401/*0404 genotype carries a substantially high risk for RA development specifically in its more severe forms. The risks are particularly increased in young men.
Adolescent↗
HLA-DPB1*0201 is associated with particular clinical features of rheumatoid arthritis.
AIMS: to determine the effect of HLA-DPB1 status on rheumatoid arthritis (RA) susceptibility and disease expression. METHODS: HLA-DPB1 alleles were identified in 158 RA patients and 106 controls using PCR-sequence specific oligonucleotide probing. HLA-DPB1 allele frequencies were compared between patient and control groups and the strength of associations assessed using odds ratios and with 95% confidence intervals (CI). Associations observed in the total RA group were confirmed using a relative predispositional effect (RPE) analysis. RESULTS: an association between DPB1*0201 and RA was observed (OR 1.8, 95% CI 1.0-3.4). By contrast, negative associations were found with DPB1*0301 (OR 0.5, 95% CI 0.3-1.0) and DPB1*1101 (OR 0.06, 95% CI 0.001-0.5). These associations were confirmed using RPE analysis. On further analysis the increase in DPB1*0201 and decrease in DPB1*0301 frequencies in RA was found to be independent of DR4 status. The association of DPB1*0201 with RA appears to be most pronounced in male patients (OR 3.3, 95% CI 1.3-8.3), seronegative patients (OR 2.6, 95% CI 0.9-7.3) those with non-erosive disease (OR 2.6, 95% CI 0.9-7.3) or in patients with high titre antinuclear antibodies (OR 2.4, 95% CI 0.8-7.1). CONCLUSIONS: HLA-DPB1 alleles may be associated with the pattern of disease expression in certain RA patients and in some cases confer protection against disease.
Adult↗