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D G Doherty

Publications and source records attributed to D G Doherty.

At least 37 records · Page 2Linked to original sources
PubMed1994

Polymorphism in the human complement C4 genes and genetic susceptibility to autoimmune hepatitis.

Susceptibility to autoimmune hepatitis is associated with the HLA-DR3 and DR4 haplotypes, but which genes are directly involved in the pathogenesis, has not been established. Low levels of complement component C4 and elevated frequencies of C4 null allotypes have been described in patients, suggesting that the C4 genes, which are closely linked with the HLA loci, may play a role. We therefore examined restriction fragment length polymorphisms in the C4 and 21-hydroxylase genes, and determined HLA-A and B phenotypes, and HLA-DR, DQ and DP genotypes in a large series of Caucasoid patients with autoimmune hepatitis and matched controls. A DNA deletion of the C4A gene and the 21-hydroxylase A pseudogene was found to be present in 50% of patients compared to 23% of controls (Pc < 0.005, relative risk = 3.3). This increase, however, appears to be due to linkage disequilibrium with HLA-DR52a which was most strongly associated with the disease. Complete C4A deficiency, determined by homozygosity for the deletion increased the risk to 18.1 (16% versus 1%, Pc < 0.005), suggesting an additional role for C4 in disease susceptibility. C4 deletions were associated with an increased mortality and tendency to relapse whilst on treatment but did not correlate with age of onset of disease. Our data suggest that MHC-encoded susceptibility to autoimmune hepatitis is polygenic, involving the HLA-DR genes plus other loci, and C4 deficiency may be a marker of disease susceptibility and/or severity.

Adolescent↗
PubMed1993

Human leukocyte antigen A1-B8-DR3-DQ2-DPB1*0401 extended haplotype in autoimmune hepatitis.

Genetic susceptibility to autoimmune hepatitis is associated with the human leukocyte antigen haplotype A1-B8-DR3 and DR4. To date, only one study in Japan has considered the human leukocyte antigen DP locus in this disease, and no studies have been reported in whites. In this study we used a series of sequence-specific oligonucleotide probes to determine human leukocyte antigen DPB1 genotypes in 101 unrelated white northern European patients and 105 racially and geographically matched controls. The aims of the study were twofold: first, to determine the degree of DPB-encoded susceptibility to autoimmune hepatitis, and, second, to establish whether susceptibility can be extended to include human leukocyte antigen DPB. None of 17 DPB1 alleles was significantly associated with the susceptibility to autoimmune hepatitis. Although one particular seven-locus haplotype A1-B8-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201-++ +DPB1*0401 was significantly associated with the disease (27% vs. 7%, relative risk = 5.14, p < 0.0005), the association with this haplotype was weaker than that for the six-locus haplotype excluding DPB (40% vs. 11%, RR = 5.52, p < 0.0005). When the patients first seen at ages younger than 16 yr (pediatric patients) were considered separately, the greatest relative risk was for the seven-locus haplotype (41% vs. 7%; relative risk = 9.60, p < 0.0005). The results of this study further confirm that major histocompatibility complex-encoded susceptibility to autoimmune hepatitis is located at or close to the human leukocyte antigen DR locus; however, the A1-B8-DR3-DQ2-DPB1*0401 extended haplotype may be important in determining the age of onset and severity of disease.

Adolescent↗
PubMed1992

Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern Chinese.

OBJECTIVE: To investigate the predisposing role of major histocompatibility complex (MHC) genes to systemic lupus erythematosus (SLE) in a Chinese population. METHODS: Polymorphism in the HLA-DRB, DQB, complement component C4, and 21-hydroxylase genes was analyzed by restriction fragment length polymorphism analysis and oligonucleotide probing of in vitro-amplified DNA from 88 Chinese patients with SLE and 69 matched control subjects. RESULTS: HLA-DRw15 and DQw1 were significantly more frequent in patients (corrected P less than 0.006, relative risk 5.2), but none of the 9 sequence variants of DQw1 were increased. The C4A gene deletion usually associated with SLE in Caucasoid and black patients was absent from all Chinese subjects, but possession of other C4 deletions and of DRw15 conferred the greatest risk (relative risk = 8.3). CONCLUSION: Different MHC haplotypes predispose to lupus in Chinese than in other ethnic groups. Our data suggest that the susceptibility lies at, or telomeric to, the DR locus, and that DRw15 and C4 deletions may act synergistically in conferring disease susceptibility.

China↗
PubMed1992

Genotype analysis for delta F508, G551D and R553X mutations in children and young adults with cystic fibrosis with and without chronic liver disease.

Genetic factors have been implicated in the pathogenesis of liver disease in cystic fibrosis. To investigate whether liver disease is associated with particular mutations of the defective gene in cystic fibrosis, we have determined the frequencies of three mutations--delta F508, G551D and R553X--in 111 children and young adults with cystic fibrosis by analysis of genomic DNA segments amplified by the polymerase chain reaction. Twenty-nine patients had severe liver disease with portal hypertension, 19 had clinical and/or biochemical evidence of liver disease but no associated portal hypertension and 63 had no evidence of liver disease. No significant differences in the frequencies of the delta F508, G551D or R553X mutations in the three clinical subgroups were found, and we conclude that the development of liver disease in cystic fibrosis is unlikely to be associated with a specific mutation in the gene. However, because 27% of cystic fibrosis chromosomes do not have a defined mutation, this possibility cannot be ruled out. A familial concordance for clinical liver disease of 20% in this study, compared with a reported prevalence of 4.7%, suggests that genes outside the cystic fibrosis locus and/or environmental factors are involved in the pathogenesis of liver disease in cystic fibrosis.

Adolescent↗
PubMed1992

Amino acid substitutions at position 38 of the DR beta polypeptide confer susceptibility to and protection from primary sclerosing cholangitis.

Previous studies based on serological HLA phenotyping have implicated genes in the HLA class II region in susceptibility to and protection from primary sclerosing cholangitis. In a recent report, the HLA DRw52a antigen was present in all 29 patients who had been referred for liver transplantation. In this study, HLA DRB, DQA and DQB genotypes were studied using gene amplification and sequence-specific oligonucleotide probing in 71 patients with primary sclerosing cholangitis and 68 healthy controls to determine the frequency among the patients of the DRB3*0101 allele that encodes DRw52a and whether other class II alleles are involved in susceptibility or protection. DRB3*0101 was the most strongly associated allele, being present in 55% of the patients and 22% of the controls. Survival among the DRB3*0101-positive patients was reduced compared with the DRB3*0101-negative patients. Both DRB3*0101 and DRB5*0101, a possible second DRB susceptibility allele, encode a leucine residue at position 38 of the DR beta molecule. The DRB4*0101 allele, which encodes DRw53 and may be protective, encodes an alanine residue at this position. Susceptibility to and protection from primary sclerosing cholangitis may result from amino acid substitutions at position 38 of the DR beta molecule because maximum relative risk was conferred by two leucine-38-containing DR beta molecules, whereas minimum relative risk was conferred by two alanine-38-containing molecules.

Alleles↗
PubMed1992

HLA genotyping of colorectal carcinoma in the Chinese population.

The HLA-DR genotypes of 61 primary colorectal carcinomas obtained from patients of Chinese origin were determined by using DNA-RFLP. No increase or decrease of a particular HLA genotype could be ascertained with the disease, although we detected an antigen frequency of 29.5% for the serologically ill-defined DR"X3" specificity. We identified and sequenced HLA-DRB1 and DRB3 genes from the DR"X3" haplotype. The DR"X3" DRB1 gene was found to be identical to DRB1*1201 (DR5[w12]). A unique observation is its unusual linkage with DRB3*0101 (DRw52a) or DRB3*0301 (DRw52c) instead of the usual linkage with DRB3*0201/2 (DRw52b). These associations are rare in whites and blacks.

Alleles↗
PubMed1992

HLA DQA, DQB, and DRB genotyping by oligonucleotide analysis: distribution of alleles and haplotypes in British caucasoids.

A precise method for comprehensive HLA DQA and DQB genotyping using gene amplification and hybridization with sequence-specific oligonucleotide (SSO) probes is described. Twenty-four SSO probes were used to detect all DQ allotypes defined by nucleotide sequence variation in the second exons of the DQ genes, using a standard set of conditions for all probes at each locus. Five hundred individuals were genotyped for 8 DQA1 and 16 DQB1 alleles by using this method and for 33 alleles of the DRB1, DRB3, DRB4, and DRB5 genes by using previously described SSO probes. The 4-locus DQB1-DQA1-DRB1-DRB3/4/5 haplotypes present were characterized on the basis of known linkage disequilibrium between class II alleles. Fifty-two different haplotypes that have previously been described were further characterized at the nucleotide sequence level and two novel haplotypes were identified. The distributions of these alleles and haplotypes in 177 randomly selected healthy Caucasoid controls from the United Kingdom are reported. These results identify further haplotypic diversity in the HLA class II region, even though strong linkage disequilibrium exists between the DR and DQ gene loci.

Adult↗
PubMed1991

Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors.

After nearly 18 years of research, the association between human leukocyte antigens A1-B8-DR3 and autoimmune chronic active hepatitis still provokes debate. The principal reasons for this are disease heterogeneity and racial variation in the distribution of human leukocyte antigens between populations. The aim of the present study was to reexamine the relationship between these antigens and autoimmune chronic active hepatitis in a well-characterized series of patients. Ninety-six outpatients with autoimmune chronic active hepatitis and an additional 14 referred for liver transplantation with end-stage autoimmune chronic active hepatitis were studied. Human leukocyte antigen frequencies were compared with those of 100 racially and geographically matched controls. The A1-B8-DR3 haplotype was present in 38% of patients compared with 11% of controls (chi 2 = 20.6, p less than 0.0005). When all the DR3-positive patients were eliminated, there was a striking secondary association with DR4; 35 (80%) of 44 remaining patients were DR4 positive compared with 31 (39%) of 79 DR3-negative controls (Fisher's exact probability test p = 0.000031, pc = 0.0013). In addition patients with A1-B8-DR3 are seen at a significantly younger age than those without (39.75 yr vs. 48.21 yr, p less than 0.025), relapse more frequently (52% of patients with A1-B8-DR3 relapsed on one or more occasions compared with 34% of patients without this haplotype) and are more frequently referred for liver transplantation. These data indicate for the first time that two genes within the major histocompatibility complex closely linked to the DR3 and DR4 genes independently confer susceptibility to autoimmune chronic active hepatitis.

Adolescent↗
PubMed1990

HLA phenotypes and gene polymorphisms in juvenile liver disease associated with alpha 1-antitrypsin deficiency.

Chronic liver disease affects up to 20% of children with alpha 1-antitrypsin deficiency owing to the PiZZ genotype. Previous observations of a familial occurrence and abnormal immune responses to liver antigens in these patients suggests that immunoregulatory genes may be involved in the pathogenesis of liver damage. We have identified HLA phenotypes and class II (HLA-DR) gene polymorphisms in 140 white PiZZ subjects, of whom 92 (83 index patients) had liver disease, and 206 first-degree relatives. DR3* was present in 35 of 75 (46.7%) unrelated patients with liver disease compared with 5 of 28 (17.8%) patients without (p less than 0.01) and 23 of 100 controls (p less than 0.001). DR4 was increased in patients without liver disease; it was present in 17 of 28 (60.7%) compared with 29 of 75 (38.7%) patients with liver disease (p less than 0.05) and 36 of 100 controls (p less than 0.025). Using Southern blot analysis with HLA-DRB and DQB DNA probes, we identified two polymorphisms of DR3, only one (Dw25) of which is raised in PiZZ individuals with liver disease (9 of 55: 16.4%) compared with 1 of 23 (4.4%) without and 2 of 52 (3.9%) controls (p less than 0.05). Analysis of the segregation of HLA haplotypes in 77 families revealed no concordance for liver disease with HLA in those with affected sibships, indicating that, although DR3-Dw25 is associated with liver disease in alpha 1-antitrypsin deficiency, other factors must play a pathogenic role.

Adolescent↗
PubMed1984

Butylated hydroxyanisole and lung tumor development in A/J mice.

A diet containing 0.75% butylated hydroxyanisole (BHA) did not enhance the development of lung tumors in A/J mice if fed for 8 weeks after administration of urethan, benzo[a]pyrene (B[a]P), or dimethylnitrosamine (DMN). Prefeeding animals with BHA partially protected animals against the tumorigenic effect of urethan and B[a]P. Partial protection was also seen in animals given B[a]P and then exposed to BHA in the diet. The two isomers of BHA (3-tert.-butyl-4-hydroxyanisole and 2-tert.-butyl-4-hydroxyanisole) were synthesized and injected ip. They failed to enhance lung tumor development. It is concluded that BHA is not a promoting agent as is butylated hydroxytoluene (BHT) for lung tumors in mice. One possible explanation is that BHA in the diet does not produce the extensive cell proliferation seen in the lungs of mice fed BHT.

Animals↗
PubMed1977

Interferon induction by radioprotective mercaptoalkylamines and derived thiophosphates.

Radioprotective thiols (five mercaptoalkylamines and four derived thiophosphates) induced interferon and resistance to virus infection. Interferon production occurred in human and mouse nonlymphoid cell cultures. One of the thiols, S,2-aminoethylisothiourea, given intraperitoneally, protected mice against two unrelated viruses--Semliki forest virus and Herpesvirus hominis type 1. Two structurally different radioprotective thiols--the disulfide cystamine and L-cysteine--were unable to induce the firus resistance state or interferon.

Animals↗